Science.gov

Sample records for human retrovirology htlv

  1. Conference highlights of the 15th international conference on human retrovirology: HTLV and related retroviruses, 4-8 june 2011, Leuven, Gembloux, Belgium

    PubMed Central

    2011-01-01

    The June 2011 15th International Conference on Human Retrovirology: HTLV and Related Viruses marks approximately 30 years since the discovery of HTLV-1. As anticipated, a large number of abstracts were submitted and presented by scientists, new and old to the field of retrovirology, from all five continents. The aim of this review is to distribute the scientific highlights of the presentations as analysed and represented by experts in specific fields of epidemiology, clinical research, immunology, animal models, molecular and cellular biology, and virology. PMID:22035054

  2. Conference highlights of the 16th International Conference on Human Retrovirology: HTLV and related retroviruses, 26-30 June 2013, Montreal, Canada.

    PubMed

    Barbeau, Benoit; Hiscott, John; Bazarbachi, Ali; Carvalho, Edgar; Jones, Kathryn; Martin, Fabiola; Matsuoka, Masao; Murphy, Edward L; Ratner, Lee; Switzer, William M; Watanabe, Toshiki

    2014-02-24

    The 16th International Conference on Human Retrovirology: HTLV and Related Retroviruses was held in Montreal, Québec from June 26th to June 30th, 2013 and was therefore hosted by a Canadian city for the first time. The major topic of the meeting was human T-lymphotropic viruses (HTLVs) and was covered through distinct oral and poster presentation sessions: clinical research, animal models, immunology, molecular and cellular biology, human endogenous and emerging exogenous retroviruses and virology. In this review, highlights of the meeting are provided by different experts for each of these research areas.

  3. Conference Highlights of the 16th International Conference on Human Retrovirology: HTLV and Related Retroviruses, 26–30 June 2013, Montreal, Canada

    PubMed Central

    2014-01-01

    The 16th International Conference on Human Retrovirology: HTLV and Related Retroviruses was held in Montreal, Québec from June 26th to June 30th, 2013 and was therefore hosted by a Canadian city for the first time. The major topic of the meeting was human T-lymphotropic viruses (HTLVs) and was covered through distinct oral and poster presentation sessions: clinical research, animal models, immunology, molecular and cellular biology, human endogenous and emerging exogenous retroviruses and virology. In this review, highlights of the meeting are provided by different experts for each of these research areas. PMID:24558960

  4. International Retrovirology Association brings together scientists and clinicians to bridge discoveries about human T-lymphotropic viruses from the laboratory to clinical trials.

    PubMed

    Murphy, Edward; Jacobson, Steven; Franchini, Genoveffa; Taylor, Graham P; Hanchard, Barrie; Morgan, Owen; Lairmore, Michael

    2005-03-29

    Human T-lymphotropic virus type 1 (HTLV-1) and HTLV-2 were among the first human retroviruses discovered in the early 1980's. The International Retrovirology Association is an organized effort that fostered the efforts of scientists and clinicians to form interdisciplinary groups to study this group of retroviruses and their related diseases. The Association promotes excellent science, patient education, and fosters the training of young scientists to promote "bench-to-bedside" research. The International Conference on Human Retrovirology: HTLV and Related Viruses sponsored by the Association supports clinicians and researchers in the exchange of research findings and stimulation of new research directions. This years conference will be held from June 22 to 25, in Montego Bay, Jamaica http://www.htlvconference.org.jm/. Since its inception in 1988, these conferences have provided a highly interactive forum for the global community of HTLV scientists. This is of particular importance as HTLV research enters its third decade and a new generation of scientists takes over this important work. Many of the scientists attending the meeting will be from developing countries where HTLV is endemic, consistent with the history of international collaborations that have characterized HTLV research. The International Conference on Human Retrovirology provides a unique opportunity for researchers of all disciplines interested in HTLV infections to meet their peers and to address the questions facing clinicians and scientists who study retroviruses, like HTLV.

  5. Human histocultures (tissue explants) in retrovirology

    PubMed Central

    Arakelyan, Anush; Fitzgerald, Wendy; Grivel, Jean-Charles; Vanpouille, Christophe; Margolis, Leonid

    2014-01-01

    Summary Viral pathogenesis is studied predominantly in cultures of primary isolated cells or cell lines. Many retroviruses efficiently replicate only in activated cells. Therefore, in order to become efficient viral producers cells should be artificially activated, a procedure which significantly changes cell physiology. However, for many viral diseases, like HIV-1 and other retroviruses’ diseases, critical pathogenic events occur in tissues and cell isolation from their native microenvironment prevents single cell cultures from faithfully reflecting important aspects of cell-cell and cell-pathogen interactions that occur in the context of complex tissue cytoarchitecture. Tissue explants (histocultures) that retain tissue cytoarchitecture and many aspects of cell-cell interactions more faithfully represent in vivo tissue features. Human histocultures constitute an adequate model for studying viral pathogenesis under controlled laboratory conditions. Protocols for various human histocultures as applied to study retroviral pathogenesis, in particular of HIV-1, have been refined by our laboratory and are described in the present publication. Human histocultures of human tonsils and lymph nodes, as well as of recto-sigmoid and cervico-vaginal tissues can be used to study viral transmission, pathogenesis and as a pre-clinical platform for antivirals evaluation. PMID:24158827

  6. Infection with human retroviruses other than HIV-1: HIV-2, HTLV-1, HTLV-2, HTLV-3 and HTLV-4.

    PubMed

    Nicolás, David; Ambrosioni, Juan; Paredes, Roger; Marcos, M Ángeles; Manzardo, Christian; Moreno, Asunción; Miró, José M

    2015-08-01

    HIV-1 is the most prevalent retrovirus, with over 30 million people infected worldwide. Nevertheless, infection caused by other human retroviruses like HIV-2, HTLV-1, HTLV-2, HTLV-3 and HTLV-4 is gaining importance. Initially confined to specific geographical areas, HIV-2, HTLV-1 and HTLV-2 are becoming a major concern in non-endemic countries due to international migration flows. Clinical manifestations of retroviruses range from asymptomatic carriers to life-threatening conditions, such as AIDS in HIV-2 infection or adult T-cell lymphoma/leukemia or tropical spastic paraparesis in HTLV-1 infection. HIV-2 is naturally resistant to some antiretrovirals frequently used to treat HIV-1 infection, but it does have effective antiretroviral therapy options. Unfortunately, HTLV still has limited therapeutic options. In this article, we will review the epidemiological, clinical, diagnostic, pathogenic and therapeutic aspects of infections caused by these human retroviruses.

  7. The discovery of HTLV-1, the first pathogenic human retrovirus.

    PubMed

    Coffin, John M

    2015-12-22

    After the discovery of retroviral reverse transcriptase in 1970, there was a flurry of activity, sparked by the "War on Cancer," to identify human cancer retroviruses. After many false claims resulting from various artifacts, most scientists abandoned the search, but the Gallo laboratory carried on, developing both specific assays and new cell culture methods that enabled them to report, in the accompanying 1980 PNAS paper, identification and partial characterization of human T-cell leukemia virus (HTLV; now known as HTLV-1) produced by a T-cell line from a lymphoma patient. Follow-up studies, including collaboration with the group that first identified a cluster of adult T-cell leukemia (ATL) cases in Japan, provided conclusive evidence that HTLV was the cause of this disease. HTLV-1 is now known to infect at least 4-10 million people worldwide, about 5% of whom will develop ATL. Despite intensive research, knowledge of the viral etiology has not led to improvement in treatment or outcome of ATL. However, the technology for discovery of HTLV and acknowledgment of the existence of pathogenic human retroviruses laid the technical and intellectual foundation for the discovery of the cause of AIDS soon afterward. Without this advance, our ability to diagnose and treat HIV infection most likely would have been long delayed.

  8. The discovery of HTLV-1, the first pathogenic human retrovirus

    PubMed Central

    Coffin, John M.

    2015-01-01

    After the discovery of retroviral reverse transcriptase in 1970, there was a flurry of activity, sparked by the “War on Cancer,” to identify human cancer retroviruses. After many false claims resulting from various artifacts, most scientists abandoned the search, but the Gallo laboratory carried on, developing both specific assays and new cell culture methods that enabled them to report, in the accompanying 1980 PNAS paper, identification and partial characterization of human T-cell leukemia virus (HTLV; now known as HTLV-1) produced by a T-cell line from a lymphoma patient. Follow-up studies, including collaboration with the group that first identified a cluster of adult T-cell leukemia (ATL) cases in Japan, provided conclusive evidence that HTLV was the cause of this disease. HTLV-1 is now known to infect at least 4–10 million people worldwide, about 5% of whom will develop ATL. Despite intensive research, knowledge of the viral etiology has not led to improvement in treatment or outcome of ATL. However, the technology for discovery of HTLV and acknowledgment of the existence of pathogenic human retroviruses laid the technical and intellectual foundation for the discovery of the cause of AIDS soon afterward. Without this advance, our ability to diagnose and treat HIV infection most likely would have been long delayed. PMID:26696625

  9. African Origin of Human T-Lymphotropic Virus Type 2 (HTLV-2) Supported by a Potential New HTLV-2d Subtype in Congolese Bambuti Efe Pygmies

    PubMed Central

    Vandamme, Anne-Mieke; Salemi, Marco; Van Brussel, Marianne; Liu, Hsin-Fu; Van Laethem, Kristel; Van Ranst, Marc; Michels, Ludovic; Desmyter, Jan; Goubau, Patrick

    1998-01-01

    We identified a potential new subtype within human T-cell lymphotropic virus type 2 (HTLV-2), HTLV-2d, present in members of an isolated Efe Bambuti Pygmy tribe. Two of 23 Efe Pygmies were HTLV-2 seropositive, with HTLV-2 Western blot and enzyme-linked immunosorbent assay reactivities. From one of them the entire genome of the HTLV-2 strain Efe2 could be amplified and sequenced. In all gene regions analyzed, this strain was the most divergent HTLV-2 strain, differing by 2.4% (tax/rex) to 10.7% (long terminal repeat) from both subtypes HTLV-2a and HTLV-2b, yet major functional elements are conserved. The similarity between the HTLV-2 Efe2 Gag and Env proteins and the corresponding HTLV-2a and -2b proteins is consistent with the observed serological reactivity. In the proximal pX region, one of the two alternative splice acceptor sites is abolished in HTLV-2 Efe2. Another interesting feature of this potential new subtype is that it has a Tax protein of 344 amino acids (aa), which is intermediate in length between the HTLV-2a Tax protein (331 aa) and the HTLV-2b and -2c Tax proteins (356 aa) and similar to the simian T-cell lymphotropic virus type 2 (STLV-2) PP1664 Tax protein. Together these two findings suggest a different phenotype for the HTLV-2 Efe2 strain. Phylogenetic analyses confirmed that the Pygmy Efe2 strain potentially belonged to a new and quite divergent subtype, HTLV-2d. When the STLV-2 bonobo viruses PP1664 and PanP were used as an outgroup, it was clear that the Pygmy HTLV-2 Efe2 strain had the longest independent evolution and that HTLV-2 evolution is consistent with an African origin. PMID:9557723

  10. Investigating human T cell lymphotropic retrovirus (HTLV) Tax function with molecular and immunophenotypic techniques.

    PubMed

    Forlani, Greta; Accolla, Roberto S; Tosi, Giovanna

    2014-01-01

    Human T cell Lymphotropic Viruses 1 and 2 (HTLV-1 and HTLV-2) are the first described human retroviruses. HTLV-1 is the causative agent of an aggressive malignancy of CD4+ T lymphocytes named adult T-cell leukemia/lymphoma (ATLL) and of a chronic neurological disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 shares many similarities with HTLV-1, but displays lower or absent association to diseases. Among the proteins encoded by HTLVs, the viral transactivator Tax exerts an essential role in viral transcription as well as in cell transformation. Different experimental methods to study Tax activity on HTLV-LTR promoter and Tax subcellular distribution are described. Emphasis is given to the functional and physical interaction between Tax-1/Tax-2 and cellular cofactors which may have an impact on the infectivity process of the HTLVs and on the capacity of cell transformation.

  11. ORIGIN AND PREVALENCE OF HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 (HTLV-1) AND TYPE 2 (HTLV-2) AMONG INDIGENOUS POPULATIONS IN THE AMERICAS

    PubMed Central

    Paiva, Arthur; Casseb, Jorge

    2015-01-01

    Human T-lymphotropic virus type 1 (HTLV-1) is found in indigenous peoples of the Pacific Islands and the Americas, whereas type 2 (HTLV-2) is widely distributed among the indigenous peoples of the Americas, where it appears to be more prevalent than HTLV-1, and in some tribes of Central Africa. HTLV-2 is considered ancestral in the Americas and is transmitted to the general population and injection drug users from the indigenous population. In the Americas, HTLV-1 has more than one origin, being brought by immigrants in the Paleolithic period through the Bering Strait, through slave trade during the colonial period, and through Japanese immigration from the early 20th century, whereas HTLV-2 was only brought by immigrants through the Bering Strait. The endemicity of HTLV-2 among the indigenous people of Brazil makes the Brazilian Amazon the largest endemic area in the world for its occurrence. A review of HTLV-1 in all Brazilian tribes supports the African origin of HTLV-1 in Brazil. The risk of hyperendemicity in these epidemiologically closed populations and transmission to other populations reinforces the importance of public health interventions for HTLV control, including the recognition of the infection among reportable diseases and events. PMID:25651320

  12. XBP-1, a novel human T-lymphotropic virus type 1 (HTLV-1) tax binding protein, activates HTLV-1 basal and tax-activated transcription.

    PubMed

    Ku, Sebastian C Y; Lee, Jialing; Lau, Joanne; Gurumurthy, Meera; Ng, Raymond; Lwa, Siew Hui; Lee, Joseph; Klase, Zachary; Kashanchi, Fatah; Chao, Sheng-Hao

    2008-05-01

    X-box binding protein 1 (XBP-1), a basic leucine zipper transcription factor, plays a key role in the cellular unfolded protein response (UPR). There are two XBP-1 isoforms in cells, spliced XBP-1S and unspliced XBP-1U. XBP-1U has been shown to bind to the 21-bp Tax-responsive element of the human T-lymphotropic virus type 1 (HTLV-1) long terminal repeat (LTR) in vitro and transactivate HTLV-1 transcription. Here we identify XBP-1S as a transcription activator of HTLV-1. Compared to XBP-1U, XBP-1S demonstrates stronger activating effects on both basal and Tax-activated HTLV-1 transcription in cells. Our results show that both XBP-1S and XBP-1U interact with Tax and bind to the HTLV-1 LTR in vivo. In addition, elevated mRNA levels of the gene for XBP-1 and several UPR genes were detected in the HTLV-1-infected C10/MJ and MT2 T-cell lines, suggesting that HTLV-1 infection may trigger the UPR in host cells. We also identify Tax as a positive regulator of the expression of the gene for XBP-1. Activation of the UPR by tunicamycin showed no effect on the HTLV-1 LTR, suggesting that HTLV-1 transcription is specifically regulated by XBP-1. Collectively, our study demonstrates a novel host-virus interaction between a cellular factor XBP-1 and transcriptional regulation of HTLV-1. PMID:18287238

  13. Origin and prevalence of human T-lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) among indigenous populations in the Americas.

    PubMed

    Paiva, Arthur; Casseb, Jorge

    2015-01-01

    Human T-lymphotropic virus type 1 (HTLV-1) is found in indigenous peoples of the Pacific Islands and the Americas, whereas type 2 (HTLV-2) is widely distributed among the indigenous peoples of the Americas, where it appears to be more prevalent than HTLV-1, and in some tribes of Central Africa. HTLV-2 is considered ancestral in the Americas and is transmitted to the general population and injection drug users from the indigenous population. In the Americas, HTLV-1 has more than one origin, being brought by immigrants in the Paleolithic period through the Bering Strait, through slave trade during the colonial period, and through Japanese immigration from the early 20th century, whereas HTLV-2 was only brought by immigrants through the Bering Strait. The endemicity of HTLV-2 among the indigenous people of Brazil makes the Brazilian Amazon the largest endemic area in the world for its occurrence. A review of HTLV-1 in all Brazilian tribes supports the African origin of HTLV-1 in Brazil. The risk of hyperendemicity in these epidemiologically closed populations and transmission to other populations reinforces the importance of public health interventions for HTLV control, including the recognition of the infection among reportable diseases and events. PMID:25651320

  14. Genome-wide Determinants of Proviral Targeting, Clonal Abundance and Expression in Natural HTLV-1 Infection

    PubMed Central

    Melamed, Anat; Laydon, Daniel J.; Gillet, Nicolas A.; Tanaka, Yuetsu; Taylor, Graham P.; Bangham, Charles R. M.

    2013-01-01

    The regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression of the provirus, which in turn determines the abundance and pathogenic potential of infected T cell clones in vivo. We recently developed a high-throughput method for the genome-wide amplification, identification and quantification of proviral integration sites. Here, we used this protocol to test two hypotheses. First, that binding sites for transcription factors and chromatin remodelling factors in the genome flanking the proviral integration site of HTLV-1 are associated with integration targeting, spontaneous proviral expression, and in vivo clonal abundance. Second, that the transcriptional orientation of the HTLV-1 provirus relative to that of the nearest host gene determines spontaneous proviral expression and in vivo clonal abundance. Integration targeting was strongly associated with the presence of a binding site for specific host transcription factors, especially STAT1 and p53. The presence of the chromatin remodelling factors BRG1 and INI1 and certain host transcription factors either upstream or downstream of the provirus was associated respectively with silencing or spontaneous expression of the provirus. Cells expressing HTLV-1 Tax protein were significantly more frequent in clones of low abundance in vivo. We conclude that transcriptional interference and chromatin remodelling are critical determinants of proviral latency in natural HTLV-1 infection. PMID:23555266

  15. Complete nucleotide sequence of an Amerindian human T-cell lymphotropic virus type II (HTLV-II) isolate: identification of a variant HTLV-II subtype b from a Guaymi Indian.

    PubMed Central

    Pardi, D; Switzer, W M; Hadlock, K G; Kaplan, J E; Lal, R B; Folks, T M

    1993-01-01

    The complete nucleotide sequence of a human T-cell lymphotropic virus type II (HTLV-II) isolate from a Panamanian Guaymi Indian was determined and analyzed. When this new viral isolate (HTLV-IIG12) was compared with prototypic HTLV-IIMoT, the overall nucleotide sequence similarity was 95.4%, while the predicted amino acid sequence similarity was 97.5%. Although the overall percentage of nucleotide and amino acid identity with prototypic HTLV-IIMoT (subtype a) was high, HTLV-IIG12 displayed several distinctive features that defined it as an HTLV-II subtype b. However, there were several characteristics unique to this isolate, which included a cluster of nucleotide substitutions in the pre-gag region and changes in restriction enzyme sites within the pre-gag region and the gag, pol, env, and pX genes. In addition, two nucleotide changes in the C terminus of the Tax protein coding sequence inserted an Arg residue for a stop codon and appeared to result in a larger tax gene product in HTLV-IIG12. Although the HTLV-IIG12 isolate appears to be a variant of the prototypic HTLV-IIb, this information represents the first complete nucleotide sequence of any HTLV-II subtype b. These data will allow further studies on the evolutionary relationships between the HTLV-II subtypes and between HTLV-I and HTLV-II. PMID:8331724

  16. Crystal structures of inhibitor complexes of human T-cell leukemia virus (HTLV-1) protease

    SciTech Connect

    Satoh, Tadashi; Li, Mi; Nguyen, Jeffrey-Tri; Kiso, Yoshiaki; Gustchina, Alla; Wlodawer, Alexander

    2010-09-28

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report a high-resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate-resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed study of structure-activity relationships was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease.

  17. Crystal Structures of Inhibitir Complexes of Human T-Cell Leukemia Virus (HTLV-1) Protease

    SciTech Connect

    Satoh, Tadashi; Li, Mi; Nguyen, Jeffrey-Tri; Kiso, Yoshiaki; Gustchina, Alla; Wlodawer, Alexander

    2010-09-17

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report a high-resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate-resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed study of structure-activity relationships was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease.

  18. The retrovirus HTLV-1 inserts an ectopic CTCF-binding site into the human genome

    PubMed Central

    Satou, Yorifumi; Miyazato, Paola; Ishihara, Ko; Yaguchi, Hiroko; Melamed, Anat; Miura, Michi; Fukuda, Asami; Nosaka, Kisato; Watanabe, Takehisa; Rowan, Aileen G.; Nakao, Mitsuyoshi

    2016-01-01

    Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes malignant and inflammatory diseases in ∼10% of infected people. A typical host has between 104 and 105 clones of HTLV-1–infected T lymphocytes, each clone distinguished by the genomic integration site of the single-copy HTLV-1 provirus. The HTLV-1 bZIP (HBZ) factor gene is constitutively expressed from the minus strand of the provirus, whereas plus-strand expression, required for viral propagation to uninfected cells, is suppressed or intermittent in vivo, allowing escape from host immune surveillance. It remains unknown what regulates this pattern of proviral transcription and latency. Here, we show that CTCF, a key regulator of chromatin structure and function, binds to the provirus at a sharp border in epigenetic modifications in the pX region of the HTLV-1 provirus in T cells naturally infected with HTLV-1. CTCF is a zinc-finger protein that binds to an insulator region in genomic DNA and plays a fundamental role in controlling higher order chromatin structure and gene expression in vertebrate cells. We show that CTCF bound to HTLV-1 acts as an enhancer blocker, regulates HTLV-1 mRNA splicing, and forms long-distance interactions with flanking host chromatin. CTCF-binding sites (CTCF-BSs) have been propagated throughout the genome by transposons in certain primate lineages, but CTCF binding has not previously been described in present-day exogenous retroviruses. The presence of an ectopic CTCF-BS introduced by the retrovirus in tens of thousands of genomic locations has the potential to cause widespread abnormalities in host cell chromatin structure and gene expression. PMID:26929370

  19. HUMAN T-LYMPHOTROPIC VIRUS 1 (HTLV-1) AND HUMAN T-LYMPHOTROPIC VIRUS 2 (HTLV-2): GEOGRAPHICAL RESEARCH TRENDS AND COLLABORATION NETWORKS (1989-2012)

    PubMed Central

    GONZÁLEZ-ALCAIDE, Gregorio; RAMOS, José Manuel; HUAMANÍ, Charles; de MENDOZA, Carmen; SORIANO, Vicent

    2016-01-01

    Publications are often used as a measure of research work success. Human T-lymphotropic virus (HTLV) type 1 and 2 are human retroviruses, which were discovered in the early 1980s, and it is estimated that 15-20 million people are infected worldwide. This article describes a bibliometric review and a coauthorship network analysis of literature on HTLV indexed in PubMed in a 24-year period. A total of 7,564 documents were retrieved, showing a decrease in the number of documents from 1996 to 2007. HTLV manuscripts were published in 1,074 journals. Japan and USA were the countries with the highest contribution in this field (61%) followed by France (8%). Production ranking changed when the number of publications was normalized by population (Dominican Republic and Japan), by gross domestic product (Guinea-Bissau and Gambia), and by gross national income per capita (Brazil and Japan). The present study has shed light on some of the defining features of scientific collaboration performed by HTLV research community, such as the existence of core researchers responsible for articulating the development of research in the area, facilitating wider collaborative relationships and the integration of new authors in the research groups. PMID:26910450

  20. HUMAN T-LYMPHOTROPIC VIRUS 1 (HTLV-1) AND HUMAN T-LYMPHOTROPIC VIRUS 2 (HTLV-2): GEOGRAPHICAL RESEARCH TRENDS AND COLLABORATION NETWORKS (1989-2012).

    PubMed

    González-Alcaide, Gregorio; Ramos, José Manuel; Huamaní, Charles; Mendoza, Carmen de; Soriano, Vicent

    2016-01-01

    Publications are often used as a measure of research work success. Human T-lymphotropic virus (HTLV) type 1 and 2 are human retroviruses, which were discovered in the early 1980s, and it is estimated that 15-20 million people are infected worldwide. This article describes a bibliometric review and a coauthorship network analysis of literature on HTLV indexed in PubMed in a 24-year period. A total of 7,564 documents were retrieved, showing a decrease in the number of documents from 1996 to 2007. HTLV manuscripts were published in 1,074 journals. Japan and USA were the countries with the highest contribution in this field (61%) followed by France (8%). Production ranking changed when the number of publications was normalized by population (Dominican Republic and Japan), by gross domestic product (Guinea-Bissau and Gambia), and by gross national income per capita (Brazil and Japan). The present study has shed light on some of the defining features of scientific collaboration performed by HTLV research community, such as the existence of core researchers responsible for articulating the development of research in the area, facilitating wider collaborative relationships and the integration of new authors in the research groups. PMID:26910450

  1. Hospital admissions for human T-cell lymphotropic virus type-1 (HTLV-1) associated diseases in Dominica.

    PubMed

    Adedayo, O; Grell, G; Bellot, P

    2003-06-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that is endemic in certain regions of the world, and may account for significant morbidity and mortality among hospitalised patients. Sixty six HTLV-1 seropositive patients admitted to hospital with HTLV-1 associated diseases from 1995-99 were studied. HTLV-1 screening was done with ELISA and confirmed on western blot testing. There were 32 females (48.5%) and 34 males (51.5%). The mean age was 56 years and the age range was 9-89 years. The main associated diseases were tropical spastic paraparesis or HTLV-1 associated myelopathy in 18.2% of cases, acute form of adult T-cell leukaemia/lymphoma 7.6%, lymphomas 15.2%, and ectoparasites/endoparasites in 40.9%. HTLV-1 is associated with diseases in Dominica and association with severe forms of strongyloidiasis and scabies is particularly noted.

  2. Comparative study of human and rabbit cell infection with cell-free HTLV-I.

    PubMed

    Yamade, I; Isono, T; Ishiguro, T; Yoshida, Y

    1993-01-01

    Infection of human and rabbit cells with cell-free HTLV-I was studied by PCR analysis. Both human and rabbit PBL were infected similarly by cell-free virus of both human and rabbit cell origin. Cells were infected with the cell-free virus without prior treatment and regardless of the concentration of the culture supernatant containing the virus. Human and rabbit cell lines were also infected similarly by the cell-free virus, the proviral DNA persisting for more than two months. The culture supernatants of HTLV-I-producing cells could thus be a potential cause of laboratory infections. PMID:8423456

  3. From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis

    PubMed Central

    Pérès, Eléonore; Bagdassarian, Eugénie; This, Sébastien; Villaudy, Julien; Rigal, Dominique; Gazzolo, Louis; Duc Dodon, Madeleine

    2015-01-01

    The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1), is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in the generation of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed. PMID:26690200

  4. Leukotrienes Are Upregulated and Associated with Human T-Lymphotropic Virus Type 1 (HTLV-1)-Associated Neuroinflammatory Disease

    PubMed Central

    Trindade, Bruno Caetano; Sorgi, Carlos Artério; Nicolete, Larissa Deadame de Figueiredo; Malta, Tathiane Maistro; Pinto, Mariana Tomazini; Takayanagui, Osvaldo Massaiti; Covas, Dimas Tadeu; Filho, Olindo Assis Martins; Kashima, Simone; Faccioli, Lúcia Helena

    2012-01-01

    Leukotrienes (LTs) are lipid mediators involved in several inflammatory disorders. We investigated the LT pathway in human T-lymphotropic virus type 1 (HTLV-1) infection by evaluating LT levels in HTLV-1-infected patients classified according to the clinical status as asymptomatic carriers (HACs) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients. Bioactive LTB4 and CysLTs were both increased in the plasma and in the supernatant of peripheral blood mononuclear cell cultures of HTLV-1-infected when compared to non-infected. Interestingly, CysLT concentrations were increased in HAM/TSP patients. Also, the concentration of plasma LTB4 and LTC4 positively correlated with the HTLV-1 proviral load in HTLV-1-infected individuals. The gene expression levels of LT receptors were differentially modulated in CD4+ and CD8+ T cells of HTLV-1-infected patients. Analysis of the overall plasma signature of immune mediators demonstrated that LT and chemokine amounts were elevated during HTLV-1 infection. Importantly, in addition to CysLTs, IP-10 was also identified as a biomarker for HAM/TSP activity. These data suggest that LTs are likely to be associated with HTLV-1 infection and HAM/TSP development, suggesting their putative use for clinical monitoring. PMID:23284797

  5. Programmed death-1 (PD-1)/PD-1 ligand pathway-mediated immune responses against human T-lymphotropic virus type 1 (HTLV-1) in HTLV-1-associated myelopathy/tropical spastic paraparesis and carriers with autoimmune disorders.

    PubMed

    Kozako, Tomohiro; Yoshimitsu, Makoto; Akimoto, Masaki; White, Yohann; Matsushita, Kakushi; Soeda, Shinji; Shimeno, Hiroshi; Kubota, Ryuji; Izumo, Shuji; Arima, Naomichi

    2011-11-01

    Human T-lymphotropic virus-1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia-lymphoma in individuals with dysfunctional immune responses. In this study, to characterize the HTLV-1-specific cytotoxic T lymphocyte (CTL) populations in asymptomatic HTLV-1 carriers (ACs), HAM/TSP patients, and carriers with autoimmune disorders (CAIDs), we examined the role of programmed death-1 and its ligand (PD-1/PD-L1) in HTLV-1-specific CTL functions using an HTLV-1 Tax/HLA-A*0201 tetramer and an HTLV-1 Tax/HLA-A*2402 tetramer. Interestingly, the percentage of HTLV-1 Tax301-309/HLA-A*2402 tetramer(+)CD8(+) cells expressing PD-1 in ACs was significantly higher than the percentage of HTLV-1 Tax11-19/HLA-A*0201 tetramer(+)CD8(+) cells expressing PD-1. PD-1 expression was significantly downregulated on HTLV-1-specific CTLs in HAM/TSP compared with ACs. PD-L1 expression was observed in a small proportion of unstimulated lymphocytes from ACs and was greater in ACs than in HAM/TSP and CAIDs after short-term culture. Furthermore, CTL degranulation was impaired in HAM/TSP, whereas anti-PD-L1 blockade significantly increased CTL function in ACs. Downregulation of PD-1 on HTLV-1-specific CTLs and loss of PD-L1 expression in HAM/TSP and CAIDs, along with impaired function of HTLV-1-specific CTLs in HAM/TSP, may underlie the apparently dysfunctional immune response against HTLV-1. PMID:21851845

  6. Isolation and molecular characterization of a human T-cell lymphotropic virus type II (HTLV-II), subtype B, from a healthy Pygmy living in a remote area of Cameroon: an ancient origin for HTLV-II in Africa.

    PubMed

    Gessain, A; Mauclère, P; Froment, A; Biglione, M; Le Hesran, J Y; Tekaia, F; Millan, J; de Thé, G

    1995-04-25

    We report characterization of a human T-cell lymphotropic virus type II (HTLV-II) isolated from an interleukin 2-dependent CD8 T-cell line derived from peripheral blood mononuclear cells of a healthy, HTLV-II-seropositive female Bakola Pygmy, aged 59, living in a remote equatorial forest area in south Cameroon. This HTLLV-II isolate, designated PYGCAM-1, reacted in an indirect immunofluorescence assay with HTLV-II and HTLV-I polyclonal antibodies and with an HTLV-I/II gp46 monoclonal antibody but not with HTLV-I gag p19 or p24 monoclonal antibodies. The cell line produced HTLV-I/II p24 core antigen and retroviral particles. The entire env gene (1462 bp) and most of the long terminal repeat (715 bp) of the PYGCAM-1 provirus were amplified by the polymerase chain reaction using HTLV-II-specific primers. Comparison with the long terminal repeat and envelope sequences of prototype HTLV-II strains indicated that PYGCAM-1 belongs to the subtype B group, as it has only 0.5-2% nucleotide divergence from HTLV-II B strains. The finding of antibodies to HTLV-II in sera taken from the father of the woman in 1984 and from three unrelated members of the same population strongly suggests that PYGCAM-1 is a genuine HTLV-II that has been present in this isolated population for a long time. The low genetic divergence of this African isolate from American isolates raises questions about the genetic variability over time and the origin and dissemination of HTLV-II, hitherto considered to be predominantly a New World virus.

  7. High prevalence of human T-lymphotropic virus type 1 (HTLV-1) in immigrant male-to-female transsexual sex workers with HIV-1 infection.

    PubMed

    Zehender, Gianguglielmo; Colasante, Chiara; De Maddalena, Chiara; Bernini, Flavia; Savasi, Valeria; Persico, Tiziana; Merli, Stefania; Ridolfo, Annalisa; Santambrogio, Sara; Moroni, Mauro; Galli, Massimo

    2004-10-01

    Human T-lymphotropic virus type 1 and 2 (HTLV-1 and HTLV-2) infections in Europe are limited to intravenous drug users and migrants coming from areas in which they are endemic. A survey was undertaken of HTLV-1 and HTLV-2 infections in 393 recent immigrants: 167 HIV-1 positive subjects (including 52 male-to-female transsexual sex workers) and 226 pregnant HIV-1 negative women. The prevalence of HTLV-1 was 3.6% in the HIV-1 positive group and 0.9% in the HIV-1 negative group. The highest HTLV-1 prevalence in both groups was found in persons from Latin America, particularly those born in Peru (up to 26% in the HIV-1 positive group). All of the HIV-1/HTLV-1 co-infected individuals were male-to-female transsexual sex workers in whom the overall prevalence of HTLV-1 infection was 11.5%. HTLV-2 was only found in the HIV-1 positive group (prevalence 1.2%); all of the infected subjects were transsexual sex workers from Brazil (overall prevalence 6.4%). Phylogenetic analysis showed that all of the HTLV-1 isolates were of the cosmopolitan type, clustering with other strains circulating in the patients' birthplaces; the HTLV-2 isolates were of subtype 2a, and clustered significantly with other Brazilian strains. These results suggest the independent origin of each infection in the patient's birthplace. The data raise concerns about the further spread of HTLV infections mainly through the sexual route.

  8. Human T-cell leukemia virus type 1 (HTLV-1) Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB.

    PubMed

    Motai, Yosuke; Takahashi, Masahiko; Takachi, Takayuki; Higuchi, Masaya; Hara, Toshifumi; Mizuguchi, Mariko; Aoyagi, Yutaka; Terai, Shuji; Tanaka, Yuetsu; Fujii, Masahiro

    2016-02-01

    Human T-cell leukemia virus type 1 (HTLV-1) is a causative retrovirus of adult T-cell leukemia and HTLV-1-associated myelopathy. Unlike HTLV-1, the same group of retrovirus HTLV-2 has not been found to be associated with these diseases. HTLV-1 and HTLV-2 encode transforming proteins Tax1 and Tax2, and a few distinct activities of Tax1 from those of Tax2 have been proposed to contribute to the HTLV-1-specific pathogenesis of disease. One significant difference of Tax1 from Tax2 is the activation of transcription factor NF-κB2/p100/p52. We found that Tax1 but not Tax2 induces the expression of OX40 ligand (OX40L) in a human T-cell line. To induce the OX40L expression, Tax1 but not Tax2 was observed to interact with NF-κB2/p100/p52 and RelB and the distinct interaction activity was mediated by the Tax1 amino acid region of 225-232. In addition, Tax1 but not Tax2 or Tax1/225-232 interacted with p65, p50, and c-Rel; however, the interactions were much less than those noted with NF-κB2/p100/p52 and RelB. OX40L is a T-cell costimulatory molecule of the tumor necrosis factor family, and its signal plays a critical role in establishing adaptive immunity by inducing the polarized differentiation of T-cells to cells such as T helper type 2 and T follicular helper cells. Therefore, the present findings suggest that Tax1 might alter the immune response to HTLV-1 and/or differentiation of HTLV-1-infected T-cells via OX40L induction, thereby acting as a factor mediating the distinct phenotypes and pathogenesis of HTLV-1 from that of HTLV-2. PMID:26739459

  9. Heat Shock Enhances the Expression of the Human T Cell Leukemia Virus Type-I (HTLV-I) Trans-Activator (Tax) Antigen in Human HTLV-I Infected Primary and Cultured T Cells

    PubMed Central

    Kunihiro, Marie; Fujii, Hideki; Miyagi, Takuya; Takahashi, Yoshiaki; Tanaka, Reiko; Fukushima, Takuya; Ansari, Aftab A.; Tanaka, Yuetsu

    2016-01-01

    The environmental factors that lead to the reactivation of human T cell leukemia virus type-1 (HTLV-I) in latently infected T cells in vivo remain unknown. It has been previously shown that heat shock (HS) is a potent inducer of HTLV-I viral protein expression in long-term cultured cell lines. However, the precise HTLV-I protein(s) and mechanisms by which HS induces its effect remain ill-defined. We initiated these studies by first monitoring the levels of the trans-activator (Tax) protein induced by exposure of the HTLV-I infected cell line to HS. HS treatment at 43 °C for 30 min for 24 h led to marked increases in the level of Tax antigen expression in all HTLV-I-infected T cell lines tested including a number of HTLV-I-naturally infected T cell lines. HS also increased the expression of functional HTLV-I envelope gp46 antigen, as shown by increased syncytium formation activity. Interestingly, the enhancing effect of HS was partially inhibited by the addition of the heat shock protein 70 (HSP70)-inhibitor pifithlin-μ (PFT). In contrast, the HSP 70-inducer zerumbone (ZER) enhanced Tax expression in the absence of HS. These data suggest that HSP 70 is at least partially involved in HS-mediated stimulation of Tax expression. As expected, HS resulted in enhanced expression of the Tax-inducible host antigens, such as CD83 and OX40. Finally, we confirmed that HS enhanced the levels of Tax and gp46 antigen expression in primary human CD4+ T cells isolated from HTLV-I-infected humanized NOD/SCID/γc null (NOG) mice and HTLV-I carriers. In summary, the data presented herein indicate that HS is one of the environmental factors involved in the reactivation of HTLV-I in vivo via enhanced Tax expression, which may favor HTLV-I expansion in vivo. PMID:27409630

  10. Heat Shock Enhances the Expression of the Human T Cell Leukemia Virus Type-I (HTLV-I) Trans-Activator (Tax) Antigen in Human HTLV-I Infected Primary and Cultured T Cells.

    PubMed

    Kunihiro, Marie; Fujii, Hideki; Miyagi, Takuya; Takahashi, Yoshiaki; Tanaka, Reiko; Fukushima, Takuya; Ansari, Aftab A; Tanaka, Yuetsu

    2016-07-11

    The environmental factors that lead to the reactivation of human T cell leukemia virus type-1 (HTLV-I) in latently infected T cells in vivo remain unknown. It has been previously shown that heat shock (HS) is a potent inducer of HTLV-I viral protein expression in long-term cultured cell lines. However, the precise HTLV-I protein(s) and mechanisms by which HS induces its effect remain ill-defined. We initiated these studies by first monitoring the levels of the trans-activator (Tax) protein induced by exposure of the HTLV-I infected cell line to HS. HS treatment at 43 °C for 30 min for 24 h led to marked increases in the level of Tax antigen expression in all HTLV-I-infected T cell lines tested including a number of HTLV-I-naturally infected T cell lines. HS also increased the expression of functional HTLV-I envelope gp46 antigen, as shown by increased syncytium formation activity. Interestingly, the enhancing effect of HS was partially inhibited by the addition of the heat shock protein 70 (HSP70)-inhibitor pifithlin-μ (PFT). In contrast, the HSP 70-inducer zerumbone (ZER) enhanced Tax expression in the absence of HS. These data suggest that HSP 70 is at least partially involved in HS-mediated stimulation of Tax expression. As expected, HS resulted in enhanced expression of the Tax-inducible host antigens, such as CD83 and OX40. Finally, we confirmed that HS enhanced the levels of Tax and gp46 antigen expression in primary human CD4⁺ T cells isolated from HTLV-I-infected humanized NOD/SCID/γc null (NOG) mice and HTLV-I carriers. In summary, the data presented herein indicate that HS is one of the environmental factors involved in the reactivation of HTLV-I in vivo via enhanced Tax expression, which may favor HTLV-I expansion in vivo.

  11. Heat Shock Enhances the Expression of the Human T Cell Leukemia Virus Type-I (HTLV-I) Trans-Activator (Tax) Antigen in Human HTLV-I Infected Primary and Cultured T Cells.

    PubMed

    Kunihiro, Marie; Fujii, Hideki; Miyagi, Takuya; Takahashi, Yoshiaki; Tanaka, Reiko; Fukushima, Takuya; Ansari, Aftab A; Tanaka, Yuetsu

    2016-01-01

    The environmental factors that lead to the reactivation of human T cell leukemia virus type-1 (HTLV-I) in latently infected T cells in vivo remain unknown. It has been previously shown that heat shock (HS) is a potent inducer of HTLV-I viral protein expression in long-term cultured cell lines. However, the precise HTLV-I protein(s) and mechanisms by which HS induces its effect remain ill-defined. We initiated these studies by first monitoring the levels of the trans-activator (Tax) protein induced by exposure of the HTLV-I infected cell line to HS. HS treatment at 43 °C for 30 min for 24 h led to marked increases in the level of Tax antigen expression in all HTLV-I-infected T cell lines tested including a number of HTLV-I-naturally infected T cell lines. HS also increased the expression of functional HTLV-I envelope gp46 antigen, as shown by increased syncytium formation activity. Interestingly, the enhancing effect of HS was partially inhibited by the addition of the heat shock protein 70 (HSP70)-inhibitor pifithlin-μ (PFT). In contrast, the HSP 70-inducer zerumbone (ZER) enhanced Tax expression in the absence of HS. These data suggest that HSP 70 is at least partially involved in HS-mediated stimulation of Tax expression. As expected, HS resulted in enhanced expression of the Tax-inducible host antigens, such as CD83 and OX40. Finally, we confirmed that HS enhanced the levels of Tax and gp46 antigen expression in primary human CD4⁺ T cells isolated from HTLV-I-infected humanized NOD/SCID/γc null (NOG) mice and HTLV-I carriers. In summary, the data presented herein indicate that HS is one of the environmental factors involved in the reactivation of HTLV-I in vivo via enhanced Tax expression, which may favor HTLV-I expansion in vivo. PMID:27409630

  12. Human T-cell lymphotropic virus type 1 (HTLV-1) and lymphoid malignancies in Dominica: a seroprevalence study.

    PubMed

    Adedayo, Olayinka A; Shehu, Sani M

    2004-12-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is endemic in certain regions of the world where it is associated with lymphoid malignancies. Herein we aim to describe the seroprevalence of HTLV-1 in lymphoid malignancies in Dominica. We carried out a 10-year retrospective study of histologically proven hematologic malignancies and HTLV-1 seropositivity at the Princess Margaret Hospital, Dominica. Ninety-eight cases were reviewed (59% males, 41% females), ranging in age from 3 to 91 years. HTLV-1 was seropositive in 38.6% (31/80) of all hematologic malignancies. Three of 6 cases of Hodgkin disease (50%), 16 of 36 (44.4%) of non-Hodgkin lymphoma, and 3 out of 8 unclassified lymphomas (37.5%) were seropositive; all 6 cases (100%) of acute adult T-cell leukemia/lymphoma (ATLL) were seropositive. One case each of chronic lymphocytic leukemia and myeloproliferative disorder was seropositive. HTLV-1-seropositive lymphomas presented at a younger age than did seronegative cases. Thus, HTLV-1 is significantly associated with lymphoid malignancies in Dominica, and further studies are needed before a causal relationship with Hodgkin disease can be established.

  13. Sequence analysis of the new human T cell leukemia/lymphoma virus type I isolate (HTLV-I) in Israel.

    PubMed

    Kilim, Y; Rosenblatt, J D; Danon, Y L

    1994-12-01

    Recent studies have established the presence of human T cell leukemia/lymphoma virus type I (HTLV-I) in Israel. The entire nucleotide sequence of HTLV-I virus from a previously described HE isolate of a Mashadi Jewish Iranian patient was determined. To further characterize the LTR and env genes from the HTLV-I isolate we employed polymerase chain reaction amplification with subsequent cloning and sequencing of the amplified products on both strands. Sequence analyses of amplified LTR regions of this variant showed marked nucleotide homology of 98% compared to Japanese isolates, while African and Indo-Malay (Papua, New Guinea) and Solomon Island isolates showed more divergence with sequence homology of 95% and 91%. Higher homology of 98-99% was conserved in the amplified HTLV-env gene. In this respect the Iranian isolate was most similar to the African and Japanese isolate and divergent from the Melanesian HTLV-I variant, supporting the theory that HTLV-I may have originated in Africa and reached the Far East by overland trade routes.

  14. HSP90 protects the human T-cell leukemia virus type 1 (HTLV-1) tax oncoprotein from proteasomal degradation to support NF-κB activation and HTLV-1 replication.

    PubMed

    Gao, Linlin; Harhaj, Edward William

    2013-12-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 genome encodes the Tax protein that plays essential regulatory roles in HTLV-1 replication and oncogenic transformation of T lymphocytes. Despite intensive study of Tax, how Tax interfaces with host signaling pathways to regulate virus replication and drive T-cell proliferation and immortalization remains poorly understood. To gain new insight into the mechanisms of Tax function and regulation, we used tandem affinity purification and mass spectrometry to identify novel cellular Tax-interacting proteins. This screen identified heat shock protein 90 (HSP90) as a new binding partner of Tax. The interaction between HSP90 and Tax was validated by coimmunoprecipitation assays, and colocalization between the two proteins was observed by confocal microscopy. Treatment of HTLV-1-transformed cells with the HSP90 inhibitor 17-DMAG elicited proteasomal degradation of Tax in the nuclear matrix with concomitant inhibition of NF-κB and HTLV-1 long terminal repeat (LTR) activation. Knockdown of HSP90 by lentiviral shRNAs similarly provoked a loss of Tax protein in HTLV-1-transformed cells. Finally, treatment of HTLV-1-transformed cell lines with 17-DMAG suppressed HTLV-1 replication and promoted apoptotic cell death. Taken together, our results reveal that Tax is a novel HSP90 client protein and HSP90 inhibitors may exert therapeutic benefits for ATL and HAM/TSP patients.

  15. Human T-cell Lymphotropic Virus Type-1 (HTLV-1)-associated Bronchioloalveolar Disorder Presenting with Mosaic Perfusion.

    PubMed

    Yamakawa, Hideaki; Yoshida, Masahiro; Yabe, Masami; Ishikawa, Takeo; Takagi, Masamichi; Tanoue, Susumu; Sano, Koji; Nishiwaki, Kaichi; Sato, Shun; Shimizu, Yoshihiko; Kuwano, Kazuyoshi

    2015-01-01

    Human T-cell lymphotropic virus type-1 (HTLV-1)-associated bronchioloalveolar disorder (HABA) is a specific state with chronic and progressive respiratory symptoms caused by bronchiolar or alveolar disorder characterized by smoldering adult T-cell leukemia or the HTLV-I carrier state. We herein report a rare case of HABA with an initial presentation of mosaic perfusion in the lung. The diagnosis was made according to the results of a flow cytometry analysis of the bronchoalveolar lavage fluid and pathological findings. Clinicians must be careful to recognize that mosaic perfusion may be a radiological finding of HABA. PMID:26631889

  16. Telomere Length, Proviral Load and Neurologic Impairment in HTLV-1 and HTLV-2-Infected Subjects.

    PubMed

    Usadi, Benjamin; Bruhn, Roberta; Lin, Jue; Lee, Tzong-Hae; Blackburn, Elizabeth; Murphy, Edward L

    2016-01-01

    Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45 human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection. PMID:27529270

  17. Telomere Length, Proviral Load and Neurologic Impairment in HTLV-1 and HTLV-2-Infected Subjects

    PubMed Central

    Usadi, Benjamin; Bruhn, Roberta; Lin, Jue; Lee, Tzong-Hae; Blackburn, Elizabeth; Murphy, Edward L.

    2016-01-01

    Short or damaged telomeres have been implicated in degenerative conditions. We hypothesized that analysis of telomere length (TL) in human T-cell lymphotropic virus (HTLV) infection and HTLV-associated neuropathy might provide clues to the etiology of HTLV-associated disease and viral dynamics. A subset of 45 human T-cell lymphotropic virus type 1 (HTLV-1), 45 human T-cell lymphotropic virus type 2 (HTLV-2), and 45 seronegative subjects was selected from the larger HTLV Outcomes Study (HOST) cohort, matched on age, sex and race/ethnicity. Telomere-to-single-copy gene (T/S) ratio (a measure of TL) and HTLV-1 and HTLV-2 proviral loads were measured in peripheral blood mononuclear cells (PBMCs) using quantitative PCR (qPCR). Vibration sensation measured by tuning fork during neurologic examinations performed as part of the HOST study allowed for an assessment of peripheral neuropathy. TL was compared between groups using t-tests, linear and logistic regression. Mean T/S ratio was 1.02 ± 0.16 in HTLV-1, 1.03 ± 0.17 in HTLV-2 and 0.99 ± 0.18 in HTLV seronegative subjects (p = 0.322). TL was not associated with HTLV-1 or -2 proviral load. Shorter TL was significantly associated with impaired vibration sense in the HTLV-2 positive group only. Overall, we found no evidence that telomere length was affected by chronic HTLV-1 and HTLV-2 infection. That TL was only associated with peripheral neuropathy in the HTLV-2-positive group is intriguing, but should be interpreted cautiously. Studies with larger sample size and telomere length measurement in lymphocyte subsets may clarify the relationship between TL and HTLV-infection. PMID:27529270

  18. HTLV-3/4 and simian foamy retroviruses in humans: discovery, epidemiology, cross-species transmission and molecular virology.

    PubMed

    Gessain, Antoine; Rua, Réjane; Betsem, Edouard; Turpin, Jocelyn; Mahieux, Renaud

    2013-01-01

    Non-human primates are considered to be likely sources of viruses that can infect humans and thus pose a significant threat to human population. This is well illustrated by some retroviruses, as the simian immunodeficiency viruses and the simian T lymphotropic viruses, which have the ability to cross-species, adapt to a new host and sometimes spread. This leads to a pandemic situation for HIV-1 or an endemic one for HTLV-1. Here, we present the available data on the discovery, epidemiology, cross-species transmission and molecular virology of the recently discovered HTLV-3 and HTLV-4 deltaretroviruses, as well as the simian foamy retroviruses present in different human populations at risk, especially in central African hunters. We discuss also the natural history in humans of these retroviruses of zoonotic origin (magnitude and geographical distribution, possible inter-human transmission). In Central Africa, the increase of the bushmeat trade during the last decades has opened new possibilities for retroviral emergence in humans, especially in immuno-compromised persons.

  19. HTLV-1-associated infective dermatitis and probable HTLV-1- associated myelopathy in an adolescent female*

    PubMed Central

    Steglich, Raquel Bisacotti; Tonoli, Renata Elise; Souza, Paulo Ricardo Martins; Pinto, Giselle Martins; Riesgo, Rudimar dos Santos

    2015-01-01

    Human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis (ID) is a chronic, severe and recurrent eczema occurring during childhood in patients vertically infected with HTLV-1. HTLV-1-associated myelopathy/tropical spastic paraparesia (HAM/ TSP) is slow and progressive. We report the case of an adolescent female from a non-endemic area for HTLV-1 who presents ID and, most likely, associated HAM/TSP. PMID:26312674

  20. HTLV in the Americas: challenges and perspectives.

    PubMed

    Carneiro-Proietti, Anna Bárbara F; Catalan-Soares, Bernadette C; Castro-Costa, Carlos M; Murphy, Edward L; Sabino, Ester C; Hisada, Michie; Galvão-Castro, Bernardo; Alcantara, Luiz C J; Remondegui, Carlo; Verdonck, Kristien; Proietti, Fernando A

    2006-01-01

    The first description of the human T-lymphotropic virus type 1 (HTLV-1) was made in 1980, followed closely by the discovery of HTLV-2, in 1982. Since then, the main characteristics of these viruses, commonly referred to as HTLV-1/2, have been thoroughly studied. Central and South America and the Caribbean are areas of high prevalence of HTLV-1 and HTVL-2 and have clusters of infected people. The major modes of transmission have been through sexual contact, blood, and mother to child via breast-feeding. HTLV-1 is associated with adult T-cell leukemia/lymphoma (ATL), HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and HTLV-associated uveitis as well as infectious dermatitis of children. More clarification is needed in the possible role of HTLV in rheumatologic, psychiatric, and infectious diseases. Since cures for ATL and HAM/TSP are lacking and no vaccine is available to prevent HTLV-1 and HTLV-2 transmission, these illnesses impose enormous social and financial costs on infected individuals, their families, and health care systems. For this reason, public health interventions aimed at counseling and educating high-risk individuals and populations are of vital importance. In the Americas this is especially important in the areas of high prevalence.

  1. miR-28-3p is a cellular restriction factor that inhibits human T cell leukemia virus, type 1 (HTLV-1) replication and virus infection.

    PubMed

    Bai, Xue Tao; Nicot, Christophe

    2015-02-27

    Human T cell leukemia virus, type 1 (HTLV-1) replication and spread are controlled by different viral and cellular factors. Although several anti-HIV cellular microRNAs have been described, such a regulation for HTLV-1 has not been reported. In this study, we found that miR-28-3p inhibits HTLV-1 virus expression and its replication by targeting a specific site within the genomic gag/pol viral mRNA. Because miR-28-3p is highly expressed in resting T cells, which are resistant to HTLV-1 infection, we investigated a potential protective role of miR-28-3p against de novo HTLV-1 infection. To this end, we developed a new sensitive and quantitative assay on the basis of the detection of products of reverse transcription. We demonstrate that miR-28-3p does not prevent virus receptor interaction or virus entry but, instead, induces a post-entry block at the reverse transcription level. In addition, we found that HTLV-1, subtype 1A isolates corresponding to the Japanese strain ATK-1 present a natural, single-nucleotide polymorphism within the miR-28-3p target site. As a result of this polymorphism, the ATK-1 virus sequence was not inhibited by miR-28. Interestingly, genetic studies on the transmission of the virus has shown that the ATK-1 strain, which carries a Thr-to-Cys transition mutation, is transmitted efficiently between spouses, suggesting that miR-28 may play an important role in HTLV-1 transmission. PMID:25568327

  2. miR-28-3p is a cellular restriction factor that inhibits human T cell leukemia virus, type 1 (HTLV-1) replication and virus infection.

    PubMed

    Bai, Xue Tao; Nicot, Christophe

    2015-02-27

    Human T cell leukemia virus, type 1 (HTLV-1) replication and spread are controlled by different viral and cellular factors. Although several anti-HIV cellular microRNAs have been described, such a regulation for HTLV-1 has not been reported. In this study, we found that miR-28-3p inhibits HTLV-1 virus expression and its replication by targeting a specific site within the genomic gag/pol viral mRNA. Because miR-28-3p is highly expressed in resting T cells, which are resistant to HTLV-1 infection, we investigated a potential protective role of miR-28-3p against de novo HTLV-1 infection. To this end, we developed a new sensitive and quantitative assay on the basis of the detection of products of reverse transcription. We demonstrate that miR-28-3p does not prevent virus receptor interaction or virus entry but, instead, induces a post-entry block at the reverse transcription level. In addition, we found that HTLV-1, subtype 1A isolates corresponding to the Japanese strain ATK-1 present a natural, single-nucleotide polymorphism within the miR-28-3p target site. As a result of this polymorphism, the ATK-1 virus sequence was not inhibited by miR-28. Interestingly, genetic studies on the transmission of the virus has shown that the ATK-1 strain, which carries a Thr-to-Cys transition mutation, is transmitted efficiently between spouses, suggesting that miR-28 may play an important role in HTLV-1 transmission.

  3. Seroprevalence of human T cell leukaemia/lymphoma virus type I (HTLV-I) in pregnant women, patients attending venereological outpatient services and intravenous drug users from Slovenia.

    PubMed

    Poljak, M; Bednarik, J; Rednak, K; Seme, K; Kristancic, L; Celan-Lucu, B

    1998-01-01

    To establish current seroprevalence of human T cell leukaemia/lymphoma virus type I (HTLV-I) infection in some low- and high-risk populations from Slovenia, 10,369 and 869 serum samples collected during Slovenian 1994 unlinked surveys of human immunodeficiency viruses seroprevalence in pregnant women and patients attending venereological outpatient services, respectively, and 219 serum samples collected from Slovenian intravenous drug abusers during 1995 and 1996, were screened for the presence of anti-HTLV-I antibodies using commercial particle agglutination test Serodia HTLV-I (Fujirebio, Tokyo, Japan). Only one sample obtained from a pregnant woman was found repeatedly positive in the screening test. Presence of anti-HTLV-I antibodies in the reactive sample was undoubtedly confirmed with supplemental Western blot test. The prevalence of antibodies to HTLV-I in the Slovenian population might be somewhere between one in 10,000 (0.01%) and one in 15,000 (0.0066%), which is similar or even higher to prevalence rates in other European countries.

  4. Infection with human T-lymphotropic virus types-1 and -2 (HTLV-1 and -2): Implications for blood transfusion safety.

    PubMed

    Murphy, E L

    2016-02-01

    Many countries currently perform antibody screening for HTLV-1 infection in blood donors, and this intervention is likely cost-effective in preventing HTLV-1 related diseases in high prevalence countries. However, a number of high-income countries with low prevalence of HTLV-1 infection also perform universal HTLV-1 screening and debate has arisen regarding the cost-effectiveness of these strategies. Filter-based leukoreduction is likely to substantially reduce HTLV-1 transmission by removing infected lymphocytes, but actual laboratory data on its efficacy is currently lacking. Similarly, cost-effectiveness research on HTLV-1 prevention strategies is limited by poor data on prevalence, transmission efficacy and the cost of treating HTLV1 diseases. PMID:26778839

  5. Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells.

    PubMed Central

    Xu, X; Kang, S H; Heidenreich, O; Okerholm, M; O'Shea, J J; Nerenberg, M I

    1995-01-01

    HTLV-1 infection causes an adult T cell leukemia in humans. The viral encoded protein tax, is thought to play an important role in oncogenesis. Our previous data obtained from a tax transgenic mouse model revealed that tax transforms mouse fibroblasts but not thymocytes, despite comparable levels of tax expression in both tissues. Constitutive tyrosine phosphorylation of a 130-kD protein(s) was observed in the tax transformed fibroblast B line and in HTLV-1 transformed human lymphoid lines, but not in thymocytes from Thy-tax transgenic mice. Phosphotyrosine immunoprecipitation followed by Western blot analysis with a set of Jak kinase specific antibodies, identified p130 as Jak2 in the tax transformed mouse fibroblastic cell line and Jak3 in HTLV-1 transformed human T cell lines. Phosphorylation of Jak2 in tax transformed cells resulted from high expression of IL-6. Tyrosine phosphorylation of this protein could also be induced in Balb/c3T3 cells using a supernatant from the B line, which was associated with induction of cell proliferation. Both phosphorylation and proliferation were inhibited by IL-6 neutralizing antibodies. Constitutive phosphorylation of Jak kinases may facilitate tumor growth in both HTLV-1 infected human T cells and the transgenic mouse model. Images PMID:7657825

  6. Human T-Lymphotropic Virus Type I (HTLV-1) Infection among Iranian Blood Donors: First Case-Control Study on the Risk Factors.

    PubMed

    Hedayati-Moghaddam, Mohammad Reza; Tehranian, Farahnaz; Bayati, Maryam

    2015-11-04

    Human T-cell lymphotropic virus type 1 (HTLV-1) infection is an endemic condition in Northeast Iran and, as such, identification of risk factors associated with the infection in this region seems to be a necessity. All the possible risk factors for HTLV-1 seropositivity among first-time blood donors were evaluated in Mashhad, Iran, during the period of 2011-2012. Blood donation volunteers were interviewed for demographic data, medical history, and behavioral characteristics and the frequencies of risk factors were compared between HTLV-1 positive (case) and HTLV-1 negative (control) donors. The data was analyzed using Chi square and t-tests. Logistic regression analysis was performed to identify independent risk factors for the infection. Assessments were carried out on 246 cases aged 17-60 and 776 controls aged 17-59, who were matched based on their ages, gender, and date and center of donation. Logistic analysis showed low income (OR = 1.53, p = 0.035), low educational level (OR = 1.64, p = 0.049), being born in the cities of either Mashhad (OR = 2.47, p = 0.001) or Neyshabour (OR = 4.30, p < 0001), and a history of blood transfusion (OR = 3.17, p = 0.007) or non-IV drug abuse (OR = 3.77, p < 0.0001) were significant predictors for infection with HTLV-1. Lack of variability or small sample size could be reasons of failure to detect some well-known risk factors for HTLV-1 infection, such as prolonged breastfeeding and sexual promiscuity. Pre-donation screening of possible risk factors for transfusion-transmissible infections should also be considered as an important issue, however, a revision of the screening criteria such as a history of transfusion for more than one year prior to donation is strongly recommended.

  7. HTLV-1, Immune Response and Autoimmunity

    PubMed Central

    Quaresma, Juarez A S; Yoshikawa, Gilberto T; Koyama, Roberta V L; Dias, George A S; Fujihara, Satomi; Fuzii, Hellen T

    2015-01-01

    Human T-lymphotropic virus type-1 (HTLV-1) infection is associated with adult T-cell leukemia/lymphoma (ATL). Tropical spastic paraparesis/HTLV-1-associated myelopathy (PET/HAM) is involved in the development of autoimmune diseases including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), and Sjögren’s Syndrome (SS). The development of HTLV-1-driven autoimmunity is hypothesized to rely on molecular mimicry, because virus-like particles can trigger an inflammatory response. However, HTLV-1 modifies the behavior of CD4+ T cells on infection and alters their cytokine production. A previous study showed that in patients infected with HTLV-1, the activity of regulatory CD4+ T cells and their consequent expression of inflammatory and anti-inflammatory cytokines are altered. In this review, we discuss the mechanisms underlying changes in cytokine release leading to the loss of tolerance and development of autoimmunity. PMID:26712781

  8. Lower numbers of circulating Natural Killer T (NK T) cells in individuals with human T lymphotropic virus type 1 (HTLV-1) associated neurological disease.

    PubMed

    Ndhlovu, L C; Snyder-Cappione, J E; Carvalho, K I; Leal, F E; Loo, C P; Bruno, F R; Jha, A R; Devita, D; Hasenkrug, A M; Barbosa, H M R; Segurado, A C; Nixon, D F; Murphy, E L; Kallas, E G

    2009-12-01

    Human T lymphotropic virus type 1 (HTLV-1) infects 10-20 million people worldwide. The majority of infected individuals are asymptomatic; however, approximately 3% develop the debilitating neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is also currently no cure, vaccine or effective therapy for HTLV-1 infection, and the mechanisms for progression to HAM/TSP remain unclear. NK T cells are an immunoregulatory T cell subset whose frequencies and effector functions are associated critically with immunity against infectious diseases. We hypothesized that NK T cells are associated with HAM/TSP progression. We measured NK T cell frequencies and absolute numbers in individuals with HAM/TSP infection from two cohorts on two continents: São Paulo, Brazil and San Francisco, CA, USA, and found significantly lower levels when compared with healthy subjects and/or asymptomatic carriers. Also, the circulating NK T cell compartment in HAM/TSP subjects is comprised of significantly more CD4(+) and fewer CD8(+) cells than healthy controls. These findings suggest that lower numbers of circulating NK T cells and enrichment of the CD4(+) NK T subset are associated with HTLV-1 disease progression.

  9. Establishment of the milk-borne transmission as a key factor for the peculiar endemicity of human T-lymphotropic virus type 1 (HTLV-1): the ATL Prevention Program Nagasaki

    PubMed Central

    HINO, Shigeo

    2011-01-01

    In late 2010, the nation-wide screening of pregnant women for human T-lymphotropic virus type 1 (HTLV-1) infection was implemented in Japan to prevent milk-borne transmission of HTLV-1. In the late 1970s, recognition of the adult T-cell leukemia (ATL) cluster in Kyushu, Japan, led to the discovery of the first human retrovirus, HTLV-1. In 1980, we started to investigate mother-to-child transmission (MTCT) for explaining the peculiar endemicity of HTLV-1. Retrospective and prospective epidemiological data revealed the MTCT rate at ∼20%. Cell-mediated transmission of HTLV-1 without prenatal infection suggested a possibility of milk-borne transmission. Common marmosets were successfully infected by oral inoculation of HTLV-1 harboring cells. A prefecture-wide intervention study to refrain from breast-feeding by carrier mothers, the ATL Prevention Program Nagasaki, was commenced in July 1987. It revealed a marked reduction of HTLV-1 MTCT by complete bottle-feeding from 20.3% to 2.5%, and a significantly higher risk of short-term breast-feeding (<6 months) than bottle-feeding (7.4% vs. 2.5%, P < 0.001). PMID:21558754

  10. Neurological Manifestations in Human T-Cell Lymphotropic Virus Type 1 (HTLV-1)–Infected Individuals Without HTLV-1–Associated Myelopathy/Tropical Spastic Paraparesis: A Longitudinal Cohort Study

    PubMed Central

    Tanajura, Davi; Castro, Néviton; Oliveira, Paulo; Neto, Abraão; Muniz, André; Carvalho, Natália B.; Orge, Glória; Santos, Silvane; Glesby, Marshall J.; Carvalho, Edgar M.

    2015-01-01

    Background. Human T-cell lymphotropic virus type 1 (HTLV-1) is the agent of HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP), observed in up to 5% of infected individuals. Despite low prevalence, many HTLV-1–infected patients who do not fulfill criteria for HAM/TSP present with neurological complaints related to sensory, motor, urinary, or autonomic manifestations. The aim of this study was to determine the incidence of neurologic manifestations and risk factors associated with these outcomes. Methods. The incidence of HAM/TSP and new signs and neurologic symptoms were computed in a group of patients enrolled in a cohort study. Results. Of 414 subjects, 76 had definite HAM/TSP, 87 had possible or probable HAM/TSP, and 251 subjects had no neurologic manifestation and were selected for analysis. Definite HAM/TSP developed in 5 (1.47%) patients. Follow-up of at least 3 years was achieved in 51% of patients. The incidence rate was computed in 1000 person-years (206 for hand numbness, 187 for feet numbness, 130 for nocturia, and 127 for urgency). Average incidence rate in neurological exam was 76 for leg hyperreflexia, 53 for leg weakness, and 37 for Babinski sign. In the applied Expanded Disability Status Scale, the incidence rate of worsening 1 point was 134 per 1000 person-years. Kaplan–Meier curves stratified by sex and proviral load showed that females and patients with proviral load >50 000 copies/106 peripheral blood mononuclear cells had a higher risk of progression. Conclusions. Development of neurological symptoms or signs occurred in up to 30% of asymptomatic subjects during 8 years of follow-up. PMID:25820277

  11. The lymphotoxin promoter is stimulated by HTLV-I tax activation of NF-kappa B in human T-cell lines.

    PubMed

    Paul, N L; Millet, I; Ruddle, N H

    1993-07-01

    The HTLV-I transcriptional activator tax was used to gain insight into the mechanism of lymphotoxin (LT; TNF-beta) gene induction. Tax-expressing cell lines produce LT biologic activity. An LT promoter (LT-293) CAT construct that contained an NF-kappa B site was active in the LT-producing C81-66-45 cell line, which contains defective HTLV-I but expresses tax. The observation that a mutated LT-kappa B construct (M1-CAT) was inactive in C81-66-45, confirmed the importance of NF-kappa B in LT gene expression. Tax was transfected into HTLV-I-negative human T-cell lines. Jurkat T cells stably expressing tax contained elevated levels of NF-kappa B that directly bound to the LT-kappa B site. Tax co-transfected with reporter constructs into Jurkat cells maximally activated HTLV-I-LTR-CAT and kappa B-fos-CAT and also activated LT-293 to a lesser extent. In JM T cells, tax induced LT-293 activity by two- to four-fold, though there was no induction of M1-CAT. The increase in LT-293 CAT activity mirrored the increase in LT biologic activity seen under these conditions. These studies, the first to demonstrate induction of LT promoter activity over basal levels, indicate that HTLV-I tax causes low-level activation of both endogenous LT and the LT promoter, at least in part through activation of NF-kappa B.

  12. Molecular Studies of HTLV-1 Replication: An Update

    PubMed Central

    Martin, Jessica L.; Maldonado, José O.; Mueller, Joachim D.; Zhang, Wei; Mansky, Louis M.

    2016-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered. Studies on HTLV-1 have been instrumental for our understanding of the molecular pathology of virus-induced cancers. HTLV-1 is the etiological agent of an adult T-cell leukemia (ATL) and can lead to a variety of neurological pathologies, including HTLV-1-associated-myelopathy/tropical spastic paraparesis (HAM/TSP). The ability to treat the aggressive ATL subtypes remains inadequate. HTLV-1 replicates by (1) an infectious cycle involving virus budding and infection of new permissive target cells and (2) mitotic division of cells harboring an integrated provirus. Virus replication initiates host antiviral immunity and the checkpoint control of cell proliferation, but HTLV-1 has evolved elegant strategies to counteract these host defense mechanisms to allow for virus persistence. The study of the molecular biology of HTLV-1 replication has provided crucial information for understanding HTLV-1 replication as well as aspects of viral replication that are shared between HTLV-1 and human immunodeficiency virus type 1 (HIV-1). Here in this review, we discuss the various stages of the virus replication cycle—both foundational knowledge as well as current updates of ongoing research that is important for understanding HTLV-1 molecular pathogenesis as well as in developing novel therapeutic strategies. PMID:26828513

  13. Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-1-regulated protein gp34.

    PubMed Central

    Baum, P R; Gayle, R B; Ramsdell, F; Srinivasan, S; Sorensen, R A; Watson, M L; Seldin, M F; Baker, E; Sutherland, G R; Clifford, K N

    1994-01-01

    A ligand was cloned for murine OX40, a member of the TNF receptor family, using a T cell lymphoma cDNA library. The ligand (muOX40L) is a type II membrane protein with significant identity to human gp34 (gp34), a protein whose expression on HTLV-1-infected human leukemic T cells is regulated by the tax gene. The predicted structures of muOX40L and gp34 are similar to, but more compact than, those of other ligands of the TNF family. Mapping of the muOX40L gene revealed tight linkage to gld, the FasL gene, on chromosome 1. gp34 maps to a homologous region in the human genome, 1q25. cDNAs for human OX40 receptor were cloned by cross-hybridization with muOX40, and gp34 was found to bind the expressed human receptor. Lymphoid expression of muOX40L was detected on activated T cells, with higher levels found on CD4+ rather than CD8+ cells. The cell-bound recombinant ligands are biologically active, co-stimulating T cell proliferation and cytokine production. Strong induction of IL-4 secretion by muOX40L suggests that this ligand may play a role in regulating immune responses. In addition, the HTLV-1 regulation of gp34 suggests a possible connection between virally induced pathogenesis and the OX40 system. Images PMID:8076595

  14. HCV/HTLV coinfection: Does HTLV-1 interfere in the natural history of HCV-related diseases?

    PubMed

    Silva, Marcelo Costa; Silva, Carolina Alves Costa; Machado, Gustavo Uzêda; Atta, Ajax; M Freire, Songeli; Carvalho, Edgar; Schinoni, Maria Isabel; Paraná, Raymundo

    2016-11-01

    Hepatitis C virus (HCV) and human T-lymphotropic virus type 1 (HTLV-1) coinfection occurs in many regions. However, few studies have focused on the natural history of HCV-induced liver disease in coinfected patients. To describe the clinical, epidemiological, and histopathological aspects of HTLV-1/HCV coinfection in Brazil. A cross-sectional study with 23 patients coinfected with HCV/HTLV. The control groups consisted of 21 patients monoinfected with HCV and 20 patients monoinfected with HTLV-1. The cytokine profiles (Th1 and Th2 cell responses), clinical, laboratory features, and histopathological aspects were examined. The control group for cytokine analysis validation consisted of patients monoinfected with HTLV, and a fourth group consisted of healthy blood donors. No anthropometric differences present between the three infected groups. We observed higher serum concentrations of IFN-γ in patients coinfected with HCV/HTLV-1 than those in HCV monoinfected patients. The HCV/HTLV-1 coinfected group also exhibited a higher degree of liver steatosis than the HCV monoinfected patients. Results suggest that HCV/HTLV-1 coinfection may result in a different pattern of HCV infection due to the immunologic disorders likely associated with HTLV-1, but there is no clear evidence of the HTLV role in the natural history of HCV infection. J. Med. Virol. 88:1967-1972, 2016. © 2016 Wiley Periodicals, Inc.

  15. Triple Therapy with Prednisolone, Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load, Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

    PubMed

    Boostani, Reza; Vakili, Rosita; Hosseiny, Samane Sadat; Shoeibi, Ali; Fazeli, Bahare; Etemadi, Mohammad Mehdi; Sabet, Faeze; Valizade, Narges; Rezaee, Seyed Abdolrahim

    2015-10-01

    Considering that there is no effective treatment for human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis, this study aimed to assess the impact of triple combination therapy-interferon-α, valproic acid, and prednisolone-on clinical outcomes, main HTLV-1 viral factors, and host anti-HTLV-1 antibody response. HTLV-1 proviral load (PVL), and HBZ and Tax mRNA expression levels were measured in peripheral blood mononuclear cells of 13 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis before and after treatment with 180 μg pegylated interferon once a week, 10-20 mg/kg/day sodium valproate, and 5 mg/day prednisolone for 25 weeks using a TaqMan real-time polymerase chain reaction assay. Furthermore, anti-HTLV-1 titer, Osame Motor Disability Score, Ashworth spasticity scale, and urinary symptoms (through standard questionnaire and clinical monitoring) were assessed in patients before and after the treatment. HTLV-1 PVL and HBZ expression significantly decreased after the treatment [PVL from 1443 ± 282 to 660 ± 137 copies/10(4) peripheral blood mononuclear cells (p = 0.01); and HBZ from 8.0 ± 1.5 to 3.0 ± 0.66 (p < 0.01)]. Tax mRNA expression decreased after the treatment from 2.26 ± 0.45 to 1.44 ± 0.64, but this reduction was not statistically significant (p = 0.10). Furthermore, anti-HTLV-1 titer reduced dramatically after the treatment, from 3123 ± 395 to 815 ± 239 (p < 0.01). Clinical signs and symptoms, according to Osame Motor Disability Score and Ashworth score, improved significantly (both p < 0.01). Urinary symptoms and sensory disturbances with lower back pain were reduced, though not to a statistically significant degree. Although signs and symptoms of spasticity were improved, frequent urination and urinary incontinence were not significantly affected by the triple therapy. The results provide new insight into the complicated conditions

  16. Triple Therapy with Prednisolone, Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load, Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

    PubMed

    Boostani, Reza; Vakili, Rosita; Hosseiny, Samane Sadat; Shoeibi, Ali; Fazeli, Bahare; Etemadi, Mohammad Mehdi; Sabet, Faeze; Valizade, Narges; Rezaee, Seyed Abdolrahim

    2015-10-01

    Considering that there is no effective treatment for human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis, this study aimed to assess the impact of triple combination therapy-interferon-α, valproic acid, and prednisolone-on clinical outcomes, main HTLV-1 viral factors, and host anti-HTLV-1 antibody response. HTLV-1 proviral load (PVL), and HBZ and Tax mRNA expression levels were measured in peripheral blood mononuclear cells of 13 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis before and after treatment with 180 μg pegylated interferon once a week, 10-20 mg/kg/day sodium valproate, and 5 mg/day prednisolone for 25 weeks using a TaqMan real-time polymerase chain reaction assay. Furthermore, anti-HTLV-1 titer, Osame Motor Disability Score, Ashworth spasticity scale, and urinary symptoms (through standard questionnaire and clinical monitoring) were assessed in patients before and after the treatment. HTLV-1 PVL and HBZ expression significantly decreased after the treatment [PVL from 1443 ± 282 to 660 ± 137 copies/10(4) peripheral blood mononuclear cells (p = 0.01); and HBZ from 8.0 ± 1.5 to 3.0 ± 0.66 (p < 0.01)]. Tax mRNA expression decreased after the treatment from 2.26 ± 0.45 to 1.44 ± 0.64, but this reduction was not statistically significant (p = 0.10). Furthermore, anti-HTLV-1 titer reduced dramatically after the treatment, from 3123 ± 395 to 815 ± 239 (p < 0.01). Clinical signs and symptoms, according to Osame Motor Disability Score and Ashworth score, improved significantly (both p < 0.01). Urinary symptoms and sensory disturbances with lower back pain were reduced, though not to a statistically significant degree. Although signs and symptoms of spasticity were improved, frequent urination and urinary incontinence were not significantly affected by the triple therapy. The results provide new insight into the complicated conditions

  17. Persistence of human T cell lymphotropic virus type 1 (HTLV-1) sequences in peripheral blood mononuclear cells from patients with mycosis fungoides [published erratum appears in J Exp Med 1995 Jan 1;181(1):441

    PubMed Central

    1994-01-01

    Mycosis fungoides (MF) is a rare form of cutaneous T cell lymphoma suspected of having a viral etiology. As in adult T cell leukemia, the virus involved may be human T lymphotropic virus type 1 (HTLV-1). We cultured the peripheral blood mononuclear cells (PBMC) of 29 patients with MF HTLV-1 seronegative by enzyme-linked immunosorbent assay and Western blot. The presence of reverse transcriptase (RT) and p24 antigen was investigated in the concentrate supernatant of the culture. The DNA of all studied patients was submitted to polymerase chain reaction and Southern blot analysis using primers and probes recognizing the tax region of HTLV-1/2 and the pol region of HTLV-1. 10 of 29 patients were found positive to HTLV-1, whereas they were always negative to RT and p24. The same results were confirmed in double blind after 6 mo. Our findings suggest HTLV-1 may be involved in the etiology of MF, at least in certain cases. PMID:7964473

  18. Co-infection by human immunodeficiency virus type 1 (HIV-1) and human T cell leukemia virus type 1 (HTLV-1): does immune activation lead to a faster progression to AIDS?

    PubMed Central

    2009-01-01

    Background Recent data have shown that HTLV-1 is prevalent among HIV positive patients in Mozambique, although the impact of HTLV-1 infection on HIV disease progression remains controversial. Our aim was to determine the phenotypic profile of T lymphocytes subsets among Mozambican patients co-infected by HIV and HTLV-1. Methods We enrolled 29 patients co-infected by HTLV-1 and HIV (co-infected), 59 patients mono-infected by HIV (HIV) and 16 healthy controls (HC), respectively. For phenotypic analysis, cells were stained with the following fluorochrome-labeled anti-human monoclonal antibodies CD4-APC, CD8-PerCP, CD25-PE, CD62L-FITC, CD45RA-FITC. CD45RO-PE, CD38-PE; being analysed by four-colour flow cytometry. Results We initially found that CD4+ T cell counts were significantly higher in co-infected, as compared to HIV groups. Moreover, CD4+ T Lymphocytes from co-infected patients presented significantly higher levels of CD45RO and CD25, but lower levels of CD45RA and CD62L, strongly indicating that CD4+ T cells are more activated under HTLV-1 plus HIV co-infection. Conclusion Our data indicate that HTLV-1/HIV co-infected patients progress with higher CD4+ T cell counts and higher levels of activation markers. In this context, it is conceivable that in co-infected individuals, these higher levels of activation may account for a faster progression to AIDS. PMID:20028500

  19. HTLV-I/II prevalence in different geographic locations.

    PubMed

    Vrielink, Hans; Reesink, Henk W

    2004-01-01

    Human T-cell lymphotropic virus (HTLV) type I (HTLV-I) is the etiological agent of adult T-cell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-II is a closely related virus, and this infection is not clearly associated with clinical disease, although neurologic disorders are observed resembling HAM/TSP. Prevalence rates for HTLV-I infection in the general population are greater than 1% in the Caribbean Basin, Central Africa, and South Japan. In most other areas in the world, as far as we know, HTLV-I/II infections are mainly found in high-risk groups (ie, immigrants from endemic areas, their offspring, their sexual contacts and in patients and intravenous injection users attending sexually transmitted disease clinics). Also, a high rate of infection for both HTLV-I and HTLV-II infection was observed in the native Amerindian population in North America as well as South America. Blood donors are routinely screened for HTLV-I/II in North America, several countries in Europe, Japan, and Taiwan.

  20. High levels of CC-chemokine expression and downregulated levels of CCR5 during HIV-1/HTLV-1 and HIV-1/HTLV-2 coinfections.

    PubMed

    Oo, Z; Barrios, C S; Castillo, L; Beilke, M A

    2015-05-01

    The human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2 are common copathogens among Human Immunodeficiency Virus (HIV)-infected individuals. HTLV-2 may confer a survival benefit among patients with HIV-1/HTLV-2 coinfections, along with lower plasma HIV-1 levels and delayed rates of CD4(+) T-cell decline. These effects have been attributed to the ability of the HTLV-2 viral transactivating Tax2 protein to induce the production of high levels of antiviral CC-chemokines and to downregulate expression of the CCR5 receptor, resulting in impaired entry of HIV-1 into CD4(+) T-cells. This study investigated the innate immunity of coinfected HIV/HTLV individuals by testing the ability of patient PBMCs to produce CC-chemokines in association CCR5 receptor modulation. The cellular proliferative responses of HIV/HTLV coinfected versus HIV monoinfected individuals were also evaluated. Higher levels of MIP-1α, MIP-1β, and RANTES (P < 0.05) were found in HIV-1/HTLV-2 coinfected group compared to HIV-1 monoinfected population. Upregulated levels of RANTES were shown in HIV-1/HTLV-1 after 1 and 3 days of culture (P < 0.05). Lymphocytes from HIV-1/HTLV-2 coinfected individuals showed significant CCR5 downregulation after 1 and 3 days of culture compared to lymphocytes from HIV-1 and uninfected groups (P < 0.05). Lower percentages of CCR5-positive cells were found in HIV-1/HTLV-1 coinfected after 3 days of incubation (P < 0.05). Levels of proliferation were significantly higher in the HIV-1/HTLV-1 group compared to HIV-1 alone (P < 0.05). HTLV-2 and HTLV-1 infections may induce the involvement of innate immunity against HIV-1 via stimulation of CC-chemokines and receptors, potentially modifying CCR5/HIV-1 binding and HIV-1 progression in coinfected individuals.

  1. Activation of the PI3K-Akt pathway by human T cell leukemia virus type 1 (HTLV-1) oncoprotein Tax increases Bcl3 expression, which is associated with enhanced growth of HTLV-1-infected T cells

    SciTech Connect

    Saito, Kousuke; Saito, Mineki; Taniura, Naoko; Okuwa, Takako; Ohara, Yoshiro

    2010-08-01

    Bcl3 is a member of the I{kappa}B family that regulates genes involved in cell proliferation and apoptosis. Recent reports indicated that Bcl3 is overexpressed in HTLV-1-infected T cells via Tax-mediated transactivation, and acts as a negative regulator of viral transcription. However, the role of Bcl3 in cellular signal transduction and the growth of HTLV-1-infected T cells have not been reported. In this study, we showed that the knockdown of Bcl3 by short hairpin RNA inhibited the growth of HTLV-1-infected T cells. Although phosphatidylinositol-3 kinase (PI3K) inhibitor reduced Bcl3 expression, inactivation of glycogen synthase kinase 3 (GSK3), an effector kinase of the PI3K/Akt signaling pathway, restored Bcl3 expression in Tax-negative but not in Tax-positive T cells. Our results indicate that the overexpression of Bcl3 in HTLV-1-infected T cells is regulated not only by transcriptional but also by post-transcriptional mechanisms, and is involved in overgrowth of HTLV-1-infected T cells.

  2. Detection of EBV, HBV, HCV, HIV-1, HTLV-I and -II, and SMRV in Human and Other Primate Cell Lines

    PubMed Central

    Uphoff, Cord C.; Denkmann, Sabine A.; Steube, Klaus G.; Drexler, Hans G.

    2010-01-01

    The high prevalence of contaminated cell cultures suggests that viral contaminations might be distributed among cultures. We investigated more than 460 primate cell lines for Epstein-Barr (EBV), hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus type 1 (HIV-1), human T-cell leukemia/lymphoma virus I and II (HTLV-I/-II), and squirrel monkey retrovirus (SMRV) infections for risk assessment. None of the cell lines were infected with HCV, HIV-1, or HTLV-I/-II. However, one cell line displayed reverse transcriptase activity. Thirty-nine cell lines harbored EBV DNA sequences. Studies on the lytic phase of EBV revealed that five cell lines produce EBV particles and six further cell lines produced EBV upon stimulation. One cell line contained an integrated HBV genome fragment but showed no virus production. Six cell lines were SMRV-infected. Newly established cell lines should be tested for EBV infections to detect B-lymphoblastoid cell lines (B-LCL). B-LCLs established with EBV from cell line B95-8 should be tested for SMRV infections. PMID:20454443

  3. [New form of subcortical dementia: encephalopathy due to infection with human lymphotropic T virus (HTLV-1). Clinical case].

    PubMed

    Cartier, L; Gormaz, A; Kleinsteuber, K; Ramírez, E; Galeno, H

    1997-02-01

    We report a 45 years old female with a HTLV-I associated myelopathy, followed up for 10 years who, five years ago, developed personality changes and intellectual deterioration, assessed with the Wais-Benton test. She also had alterations in the electroencephalogram and a nuclear magnetic resonance imaging of the brain showed hypodensity in T1 and hyperdensity in T2 subcortical regions. The progression of intellectual impairment was related to an increase in proviral DNA, assessed with polymerase chain reaction.

  4. Extracellular matrix-remodeling metalloproteinases and infection of the central nervous system with retrovirus human T-lymphotropic virus type I (HTLV-I).

    PubMed

    Giraudon, P; Buart, S; Bernard, A; Thomasset, N; Belin, M F

    1996-06-01

    Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are involved in physiological processes and contribute to the phenotype of several pathological conditions associated with uncontrolled tissue degradation. In the central nervous system (CNS), MMPs are thought to play a role in cell migration and synaptic plasticity. We have investigated the expression, regulation and possible role of MMPs and TIMPs during infection of glial cells with human T-lymphotropic virus type I (HTLV-I), the causative agent of a progressive chronic myelopathy, TSP/HAM. The major alteration consists in a high increase in MMP-9 secretion and TIMP-2 mRNA expression. Cytokines TNF alpha and IL1 alpha, induced in glial cells during HTLV-I infection, promote the upregulation of MMP-9. In addition, cerebrospinal fluid from TSP/HAM patients contain high MMP-9 level. The exact role of dysregulated MMPs/TIMPs in the pathogenesis of TSP/HAM is not known; however, functions of these proteases in physiological processes should provide valuable clues. MMPs can affect the blood-brain barrier and the intercellular connectivity by degrading the extracellular matrix of endothelial and neural cells. They can be involved in autoimmunity by generating preformed specific peptides from myelin components. Finally, they can direct and prolong TNF activity in the CNS by converting its inactive precursor into active molecules. PMID:8844825

  5. Evidence for exposure to HTLV-III in Uganda before 1973.

    PubMed

    Saxinger, W C; Levine, P H; Dean, A G; de Thé, G; Lange-Wantzin, G; Moghissi, J; Laurent, F; Hoh, M; Sarngadharan, M G; Gallo, R C

    1985-03-01

    Fifty of 75 serum samples collected in the West Nile district of Uganda between August 1972 and July 1973 contained antibodies reactive with human T-cell leukemia (lymphotropic) virus type 3 (HTLV-III; mean titer, 601), while 12 of 75 samples were positive in a similar test for HTLV type 1 (HTLV-1) antibodies (mean titer, 236). The samples were screened by enzyme-linked immunosorbent assay and positive results were confirmed by a newly developed unlabeled antibody-peroxidase procedure with enhanced sensitivity for detection of antibody binding to immunoblots of HTLV-III antigen, demonstrating antibodies to proteins with molecular weights of 24,000, 41,000, and 76,000 in nearly all positive samples. Analysis of titration data indicated enhanced titers of antibody against HTLV-III and HTLV-I when coinfection occurred. The high prevalence and relatively low titers [compared to serum from patients with acquired immune deficiency syndrome (AIDS)] of antibodies recognizing HTLV-III proteins in sera from this population at a time that may predate or coincide with the appearance or spread of the AIDS agent (HTLV-III) suggest that the virus detected may have been a predecessor of HTLV-III or is HTLV-III itself but existing in a population acclimated to its presence. It further suggests an African origin of HTLV-III.

  6. The Tax-Inducible Actin-Bundling Protein Fascin Is Crucial for Release and Cell-to-Cell Transmission of Human T-Cell Leukemia Virus Type 1 (HTLV-1)

    PubMed Central

    Wiesmann, Veit; Millen, Sebastian; Wittenberg, Thomas; Gettemans, Jan; Thoma-Kress, Andrea K.

    2016-01-01

    The delta-retrovirus Human T-cell leukemia virus type 1 (HTLV-1) preferentially infects CD4+ T-cells via cell-to-cell transmission. Viruses are transmitted by polarized budding and by transfer of viral biofilms at the virological synapse (VS). Formation of the VS requires the viral Tax protein and polarization of the host cytoskeleton, however, molecular mechanisms of HTLV-1 cell-to-cell transmission remain incompletely understood. Recently, we could show Tax-dependent upregulation of the actin-bundling protein Fascin (FSCN-1) in HTLV-1-infected T-cells. Here, we report that Fascin contributes to HTLV-1 transmission. Using single-cycle replication-dependent HTLV-1 reporter vectors, we found that repression of endogenous Fascin by short hairpin RNAs and by Fascin-specific nanobodies impaired gag p19 release and cell-to-cell transmission in 293T cells. In Jurkat T-cells, Tax-induced Fascin expression enhanced virus release and Fascin-dependently augmented cell-to-cell transmission to Raji/CD4+ B-cells. Repression of Fascin in HTLV-1-infected T-cells diminished virus release and gag p19 transfer to co-cultured T-cells. Spotting the mechanism, flow cytometry and automatic image analysis showed that Tax-induced T-cell conjugate formation occurred Fascin-independently. However, adhesion of HTLV-1-infected MT-2 cells in co-culture with Jurkat T-cells was reduced upon knockdown of Fascin, suggesting that Fascin contributes to dissemination of infected T-cells. Imaging of chronically infected MS-9 T-cells in co-culture with Jurkat T-cells revealed that Fascin’s localization at tight cell-cell contacts is accompanied by gag polarization suggesting that Fascin directly affects the distribution of gag to budding sites, and therefore, indirectly viral transmission. In detail, we found gag clusters that are interspersed with Fascin clusters, suggesting that Fascin makes room for gag in viral biofilms. Moreover, we observed short, Fascin-containing membrane extensions

  7. Guttate morphoea in human T-cell lymphoma/lymphotrophic virus type-1 (HTLV-1) infection.

    PubMed

    Oiso, N; Fukai, K; Hosomi, N; Ishii, M

    2003-07-01

    A 62-year-old Japanese man presented with multiple small atrophic macules on the trunk and extremities. The lesions were discrete, oval in shape and enclosed by lilac ring. They were distributed in a Christmas tree distribution, reminiscent of pityriasis rosea. Skin biopsy showed increased collagen fibres in the dermis and invading subcutaneous tissue. The clinico-pathological features were consistent with guttate morphoea, a rare variant of localized scleroderma. Serological tests revealed a positive reaction to human T-cell lymphoma/lymphotropic virus type-1 infection.

  8. Polymerase chain reaction (PCR) amplification demonstrates the absence of human T-cell lymphotrophic virus (HTLV)-I specific pol sequences in peripheral T-cell lymphomas.

    PubMed

    Henni, T; Divine, M; Gaulard, P; Haioun, C; Duc Dodon, M; Gourdin, M F; Desforges, L; Goossens, M; Reyes, F; Farcet, J P

    1990-09-01

    HTLV-I seronegative patients in nonendemic areas have been described with T-cell proliferations the DNA of which contains specific HTLV-I viral sequences. We have looked for the presence of HTLV-I DNA sequences in 27 HTLV-I seronegative patients with peripheral T-cell lymphomas, distinct from adult T-cell leukemia (ATL), and four HTLV-I seropositive patients, three with an ATL and one with a tropical spastic paraparesis. Using HTLV-I pol specific primers, the genomic DNA from peripheral blood mononuclear cells and lymph nodes massively infiltrated by tumor cells was analyzed by the enzymatic gene amplification procedure. In contrast to the peripheral blood lymphocytes from the four HTLV-I seropositive patients, the peripheral T-cell lymphoma samples did not harbor HTLV-I pol sequences. The data show that the detection of HTLV-I nucleotide sequences by the polymerase chain reaction correlates with serologic analysis in this series. PMID:2266151

  9. Transcriptional and Epigenetic Regulatory Mechanisms Affecting HTLV-1 Provirus

    PubMed Central

    Miyazato, Paola; Matsuo, Misaki; Katsuya, Hiroo; Satou, Yorifumi

    2016-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with human diseases, such as adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/Tropic spastic paraparesis (HAM/TSP). As a retrovirus, its life cycle includes a step where HTLV-1 is integrated into the host genomic DNA and forms proviral DNA. In the chronic phase of the infection, HTLV‑1 is known to proliferate as a provirus via the mitotic division of the infected host cells. There are generally tens of thousands of infected clones within an infected individual. They exist not only in peripheral blood, but also in various lymphoid organs. Viral proteins encoded in HTLV-1 genome play a role in the proliferation and survival of the infected cells. As is the case with other chronic viral infections, HTLV-1 gene expression induces the activation of the host immunity against the virus. Thus, the transcription from HTLV-1 provirus needs to be controlled in order to evade the host immune surveillance. There should be a dynamic and complex regulation in vivo, where an equilibrium between viral antigen expression and host immune surveillance is achieved. The mechanisms regulating viral gene expression from the provirus are a key to understanding the persistent/latent infection with HTLV-1 and its pathogenesis. In this article, we would like to review our current understanding on this topic. PMID:27322309

  10. Transcriptional and Epigenetic Regulatory Mechanisms Affecting HTLV-1 Provirus.

    PubMed

    Miyazato, Paola; Matsuo, Misaki; Katsuya, Hiroo; Satou, Yorifumi

    2016-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with human diseases, such as adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/Tropic spastic paraparesis (HAM/TSP). As a retrovirus, its life cycle includes a step where HTLV-1 is integrated into the host genomic DNA and forms proviral DNA. In the chronic phase of the infection, HTLV‑1 is known to proliferate as a provirus via the mitotic division of the infected host cells. There are generally tens of thousands of infected clones within an infected individual. They exist not only in peripheral blood, but also in various lymphoid organs. Viral proteins encoded in HTLV-1 genome play a role in the proliferation and survival of the infected cells. As is the case with other chronic viral infections, HTLV-1 gene expression induces the activation of the host immunity against the virus. Thus, the transcription from HTLV-1 provirus needs to be controlled in order to evade the host immune surveillance. There should be a dynamic and complex regulation in vivo, where an equilibrium between viral antigen expression and host immune surveillance is achieved. The mechanisms regulating viral gene expression from the provirus are a key to understanding the persistent/latent infection with HTLV-1 and its pathogenesis. In this article, we would like to review our current understanding on this topic. PMID:27322309

  11. Molecular Mechanisms of HTLV-1 Cell-to-Cell Transmission

    PubMed Central

    Gross, Christine; Thoma-Kress, Andrea K.

    2016-01-01

    The tumorvirus human T-cell lymphotropic virus type 1 (HTLV-1), a member of the delta-retrovirus family, is transmitted via cell-containing body fluids such as blood products, semen, and breast milk. In vivo, HTLV-1 preferentially infects CD4+ T-cells, and to a lesser extent, CD8+ T-cells, dendritic cells, and monocytes. Efficient infection of CD4+ T-cells requires cell-cell contacts while cell-free virus transmission is inefficient. Two types of cell-cell contacts have been described to be critical for HTLV-1 transmission, tight junctions and cellular conduits. Further, two non-exclusive mechanisms of virus transmission at cell-cell contacts have been proposed: (1) polarized budding of HTLV-1 into synaptic clefts; and (2) cell surface transfer of viral biofilms at virological synapses. In contrast to CD4+ T-cells, dendritic cells can be infected cell-free and, to a greater extent, via viral biofilms in vitro. Cell-to-cell transmission of HTLV-1 requires a coordinated action of steps in the virus infectious cycle with events in the cell-cell adhesion process; therefore, virus propagation from cell-to-cell depends on specific interactions between cellular and viral proteins. Here, we review the molecular mechanisms of HTLV-1 transmission with a focus on the HTLV-1-encoded proteins Tax and p8, their impact on host cell factors mediating cell-cell contacts, cytoskeletal remodeling, and thus, virus propagation. PMID:27005656

  12. Prevalence and genetic characterisation of HTLV-1 and 2 dual infections in patients with pulmonary tuberculosis in Central-West Brazil

    PubMed Central

    Kozlowski, Aline Garcia; Carneiro, Megmar Aparecida dos Santos; de Matos, Márcia Alves Dias; Teles, Sheila Araújo; Araújo, João Alves; Otsuki, Koko; Vicente, Ana Carolina Paulo; Martins, Regina Maria Bringel

    2013-01-01

    Human T-cell lymphotropic virus (HTLV) may impact the clinical course of tuberculosis (TB). Both infections are highly endemic in Brazil. The aim of this study was to assess the prevalence of HTLV-1/2 in TB patients in Central-West Brazil and to perform a genetic characterisation of the respective isolates. Of the 402 patients, six (1.49%) were positive for anti-HTLV and five (1.24%; 95% confidence interval: 0.46-3.05) were infected with HTLV-1/2. Genetic characterisation demonstrated that the four HTLV-1 isolates belonged to the Transcontinental subgroup A of the Cosmopolitan subtype a and that the HTLV-2 isolate belonged to subtype a (HTLV-2a/c). The prevalence of HTLV infection observed in this study is higher than that observed in local blood donors and the HTLV-1 and 2 subtypes identified are consistent with those circulating in Brazil. PMID:24141955

  13. Epidemiological Aspects and World Distribution of HTLV-1 Infection

    PubMed Central

    Gessain, Antoine; Cassar, Olivier

    2012-01-01

    The human T-cell leukemia virus type 1 (HTLV-1), identified as the first human oncogenic retrovirus 30 years ago, is not an ubiquitous virus. HTLV-1 is present throughout the world, with clusters of high endemicity located often nearby areas where the virus is nearly absent. The main HTLV-1 highly endemic regions are the Southwestern part of Japan, sub-Saharan Africa and South America, the Caribbean area, and foci in Middle East and Australo-Melanesia. The origin of this puzzling geographical or rather ethnic repartition is probably linked to a founder effect in some groups with the persistence of a high viral transmission rate. Despite different socio-economic and cultural environments, the HTLV-1 prevalence increases gradually with age, especially among women in all highly endemic areas. The three modes of HTLV-1 transmission are mother to child, sexual transmission, and transmission with contaminated blood products. Twenty years ago, de Thé and Bomford estimated the total number of HTLV-1 carriers to be 10–20 millions people. At that time, large regions had not been investigated, few population-based studies were available and the assays used for HTLV-1 serology were not enough specific. Despite the fact that there is still a lot of data lacking in large areas of the world and that most of the HTLV-1 studies concern only blood donors, pregnant women, or different selected patients or high-risk groups, we shall try based on the most recent data, to revisit the world distribution and the estimates of the number of HTLV-1 infected persons. Our best estimates range from 5–10 millions HTLV-1 infected individuals. However, these results were based on only approximately 1.5 billion of individuals originating from known HTLV-1 endemic areas with reliable available epidemiological data. Correct estimates in other highly populated regions, such as China, India, the Maghreb, and East Africa, is currently not possible, thus, the current number of HTLV-1 carriers is

  14. Multifaceted functions and roles of HBZ in HTLV-1 pathogenesis.

    PubMed

    Ma, Guangyong; Yasunaga, Jun-Ichirou; Matsuoka, Masao

    2016-01-01

    Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus responsible for the development of adult T-cell leukemia (ATL). Although HTLV-1 harbors an oncogene, tax, that transforms T cells in vitro and induces leukemia in transgenic mice, tax expression is frequently disrupted in ATL, making the oncogenesis of ATL a bit mysterious. The HTLV-1 bZIP factor (HBZ) gene was discovered in 2002 and has been found to promote T-cell proliferation and cause lymphoma in transgenic mice. Thus HBZ has become a novel hotspot of HTLV-1 research. This review summarizes the current findings on HBZ with a special focus on its potential links to the oncogenesis of ATL. We propose viewing HBZ as a critical contributing factor in ATL development. PMID:26979059

  15. Genome-wide analyses of HTLV-1aD strains from Cape Verde, Africa

    PubMed Central

    Zanella, Louise; de Pina-Araujo I, Isabel; Morgado, Mariza G; Vicente, Ana Carolina

    2016-01-01

    We characterised and reported the first full-length genomes of Human T-cell Lymphotropic Virus Type 1 subgroup HTLV-1aD (CV21 and CV79). This subgroup is one of the major determinants of HTLV-1 infections in North and West Africa, and recombinant strains involving this subgroup have been recently demonstrated. The CV21 and CV79 strains from Cape Verde/Africa were characterised as pure HTLV-1aD genomes, comparative analyses including HTLV-1 subtypes and subgroups revealed HTLV-1aD signatures in the envelope, pol, and pX regions. These genomes provide original information that will contribute to further studies on HTLV-1a epidemiology and evolution.

  16. Genome-wide analyses of HTLV-1aD strains from Cape Verde, Africa.

    PubMed

    Zanella, Louise; Pina-Araujo I, Isabel de; Morgado, Mariza G; Vicente, Ana Carolina

    2016-09-01

    We characterised and reported the first full-length genomes of Human T-cell Lymphotropic Virus Type 1 subgroup HTLV-1aD (CV21 and CV79). This subgroup is one of the major determinants of HTLV-1 infections in North and West Africa, and recombinant strains involving this subgroup have been recently demonstrated. The CV21 and CV79 strains from Cape Verde/Africa were characterised as pure HTLV-1aD genomes, comparative analyses including HTLV-1 subtypes and subgroups revealed HTLV-1aD signatures in the envelope, pol, and pX regions. These genomes provide original information that will contribute to further studies on HTLV-1a epidemiology and evolution.

  17. The Influence of Coinfection on Mood States in HTLV-1-Infected Patients.

    PubMed

    Gascón, Maria Rita Polo; Capitão, Claudio Garcia; Nogueira-Martins, Maria Cezira Fantini; Casseb, Jorge; Penalva Oliveira, Augusto Cesar

    2012-01-01

    The objective of this study was to discuss the influence of coinfection on mood states (depression and anxiety) in Human T Lymphotropic virus type 1 HTLV-1-infected patients. A cross-sectional study was performed with a sample obtained through a nonprobabilistic technique. A total of 130 patients in treatment at the HTLV Ambulatory of Instituto de Infectologia Emílio Ribas participated in the research, of whom 63 had HAM/TS and 67 were asymptomatic. A sociodemographic survey and the Beck Anxiety and Depression Inventories were used. The results indicated a prevalence of 7.2% for HTLV-1/HIV co-infection, 7.2% for HTLV-1/HCV, and 4.0% for HTLV-1/HIV/HCV. It is possible that the presence of a co-infection causes greater fear and concern about the future than asymptomatic HTLV-1 infection, increasing the observed degree of depression and anxiety.

  18. Genome-wide analyses of HTLV-1aD strains from Cape Verde, Africa

    PubMed Central

    Zanella, Louise; de Pina-Araujo I, Isabel; Morgado, Mariza G; Vicente, Ana Carolina

    2016-01-01

    We characterised and reported the first full-length genomes of Human T-cell Lymphotropic Virus Type 1 subgroup HTLV-1aD (CV21 and CV79). This subgroup is one of the major determinants of HTLV-1 infections in North and West Africa, and recombinant strains involving this subgroup have been recently demonstrated. The CV21 and CV79 strains from Cape Verde/Africa were characterised as pure HTLV-1aD genomes, comparative analyses including HTLV-1 subtypes and subgroups revealed HTLV-1aD signatures in the envelope, pol, and pX regions. These genomes provide original information that will contribute to further studies on HTLV-1a epidemiology and evolution. PMID:27653363

  19. Genome-wide analyses of HTLV-1aD strains from Cape Verde, Africa.

    PubMed

    Zanella, Louise; Pina-Araujo I, Isabel de; Morgado, Mariza G; Vicente, Ana Carolina

    2016-09-01

    We characterised and reported the first full-length genomes of Human T-cell Lymphotropic Virus Type 1 subgroup HTLV-1aD (CV21 and CV79). This subgroup is one of the major determinants of HTLV-1 infections in North and West Africa, and recombinant strains involving this subgroup have been recently demonstrated. The CV21 and CV79 strains from Cape Verde/Africa were characterised as pure HTLV-1aD genomes, comparative analyses including HTLV-1 subtypes and subgroups revealed HTLV-1aD signatures in the envelope, pol, and pX regions. These genomes provide original information that will contribute to further studies on HTLV-1a epidemiology and evolution. PMID:27653363

  20. Opportunistic Infections in Patients with HTLV-1 Infection

    PubMed Central

    Tanaka, Toshiki; Sekioka, Toshio; Usui, Masakatsu

    2015-01-01

    As an acquired immunodeficiency, human immunodeficiency virus (HIV) infection is primarily responsible for opportunistic infections in infected patients. However, opportunistic infections also occur in individuals with human T cell lymphotrophic virus type 1 (HTLV-1) infection. Here, we report opportunistic infections in two Japanese HTLV-1-seropositive patients. The first patient was a 67-year-old male, who had cytomegalovirus infection associated with esophagogastritis and terminal ileitis. The patient was HTLV-1-positive and was diagnosed with smoldering adult T cell leukemia (ATL). High levels of serum soluble IL-2 receptor (sIL-2R; 4,304 U/mL) and an increased percentage of CD4+CD25+ T cells (75.5%) in peripheral blood were also detected. The second patient was a 78-year-old female, a known asymptomatic HTLV-1 carrier, who presented with persistent herpes zoster, followed by Pneumocystis jirovecii pneumonia. Disease progression of smoldering ATL along opportunistic infections was observed with very high levels of serum sIL-2R (14,058 U/mL) and an increased percentage of CD4+CD25+ T cells (87.2%) in peripheral blood. In patients with suspected opportunistic infections, both HTLV-1 and HIV should be considered. In HTLV-1-positive patients, an increase in the CD4+CD25+ T cell subset may have its value as a prognostic marker. PMID:26693362

  1. Predictive factors of HTLV1-HIV coinfections in French Guiana.

    PubMed

    Gouhier, Elise; Gaubert-Maréchal, Emilie; Abboud, Philippe; Couppié, Pierre; Nacher, Mathieu

    2013-09-01

    French Guiana, the French territory most affected by human immunodeficiency virus (HIV) (1.3% of pregnant women), is also endemic for human T lymphotropic virus 1 (HTLV1). The objective of this study was to determine if the HTLV1/HIV coinfected patients had particular characteristics. All HIV-infected patients having a computerized medical file containing an HTLV1 serology were included: there were 1,333 HIV monoinfections and 76 HTLV1/VIH coinfections. The prevalence of HTLV1/HIV coinfections was 5.39%. Women (odds ratio [OR] = 1.91[1.13-3.24]), subjects > 40 years of age, and patients of Surinamese origin (OR = 2.65 [1.25-5.61]) were overrepresented among the coinfected. CD4 count at the time of diagnosis and viral loads were higher among coinfected patients. The clinical stage was not significantly different between the two groups. The number of CD4 cells was not higher among the coinfected, unlike most reports from the literature. Prevalence of HTLV1 among HIV-infected patients is high in French Guiana, and physicians seem to omit the prescription of serology for this potentially serious coinfection.

  2. Intracellular Localization and Cellular Factors Interaction of HTLV-1 and HTLV-2 Tax Proteins: Similarities and Functional Differences

    PubMed Central

    Bertazzoni, Umberto; Turci, Marco; Avesani, Francesca; Di Gennaro, Gianfranco; Bidoia, Carlo; Romanelli, Maria Grazia

    2011-01-01

    Human T-lymphotropic viruses type 1 (HTLV-1) and type 2 (HTLV-2) present very similar genomic structures but HTLV-1 is more pathogenic than HTLV-2. Is this difference due to their transactivating Tax proteins, Tax-1 and Tax-2, which are responsible for viral and cellular gene activation? Do Tax-1 and Tax-2 differ in their cellular localization and in their interaction pattern with cellular factors? In this review, we summarize Tax-1 and Tax-2 structural and phenotypic properties, their interaction with factors involved in signal transduction and their localization-related behavior within the cell. Special attention will be given to the distinctions between Tax-1 and Tax-2 that likely play an important role in their transactivation activity. PMID:21994745

  3. [Seroprevalence of HTLV-1/2 in blood donors from Misiones Province].

    PubMed

    Malan, Richard; Berini, Carolina A; Eirin, María E; Delfino, Cecilia M; Pedrozo, Williams; Krupp, Ramón; García Plichta, Atilio; Biglione, Mirna M

    2010-01-01

    Human T-cell Lymphotropic viruses type 1 (HTLV-1), the first human oncoretrovirus to be discovered, is the etiologic agent of Adult T-cell Leukemia (ATL) and HTLV-1 Associated Mielopathy or Tropical Spastic Paraparesis (HAM/TSP). It is endemic worldwide, including the North of Argentina where both associated diseases have also been detected. No etiologic role has been described for HTLV-2, although it has been associated with HAM/TSP-like neurologic syndromes. Both retroviruses are endemic in native populations of The Americas, Africa and at-risk populations. They are transmitted through sex contact, parenterally and from mother to child. The aim of this study was to estimate the seroprevalence of HTLV-1/2 in a blood donor population from Misiones province. A total of 6912 accepted blood donations in 2008 were analyzed. HTLV-1/2 screening was performed with ELISA and particle agglutination, and reactive samples were confirmed by Western Blot. From the total, 5 samples resulted seropositive with a final prevalence of 0.00072. Out of the 5 positive samples, one was an HTLV, three HTLV-1 and one HTLV-2. These blood donors were residents of Posadas, Eldorado and Oberá, with no risk antecedents. This study demonstrates the presence of HTLV-1/2 in a population of Misiones with a prevalence rate similar to those reported among blood donors from non-endemic areas.

  4. Prevalence of HTLV-1/2 infections in Spain: A cross-sectional hospital-based survey.

    PubMed

    Treviño, Ana; García, Juan; de Mendoza, Carmen; Benito, Rafael; Aguilera, Antonio; Ortíz de Lejarazu, Raul; Ramos, José M; Trigo, Matilde; Eirós, Jose M; Rodríguez-Iglesias, Manuel; Torres, Alvaro; Calderón, Enrique; Hernandez, Araceli; Gomez, Cesar; Marcaida, Goizane; Soriano, Vincent

    2010-08-01

    The presence of antibodies to human T-lymphotropic virus (HTLV) types 1 and 2 was examined in 5742 sera belonging to consecutive adult outpatients attended during June 2008 at 13 different hospitals across Spain. Overall, 58.8% were female. Foreigners represented 8% of the study population. Seven individuals were seropositive for HTLV-2 (overall prevalence 0.12%). No cases of HTLV-1 infection were found. All HTLV-2(+) subjects were Spanish natives, of whom six were coinfected with HIV-1 and five with hepatitis C virus (HCV). Moreover, all but one of the HTLV-2(+) subjects had been intravenous drug users. In summary, this cross-sectional survey suggests that the rate of HTLV infection in Spain is low, and is mostly represented by HTLV-2. Infected individuals are generally Spanish natives with a prior history of intravenous drug use and are coinfected with HIV-1 and/or HCV.

  5. Clinical features of HTLV-I associated uveitis.

    PubMed Central

    Nakao, K; Ohba, N

    1993-01-01

    The prevalence of human T cell lymphoma virus type 1 (HTLV-I) was studied among patients with endogenous uveitis. Twelve (15.8%) of 76 uveitis patients with known aetiology or clinical entity were seropositive, the prevalence being comparable with that in the general population of the southwestern area of Japan where HTLV-I is highly endemic. In the comparison, 32 (41.0%) of 78 patients with aetiology or entity undefined uveitis were seropositive for HTLV-I, which indicated a significantly higher seroprevalence than controls matched for sex and age. The 32 cases of clinical entity undefined, HTLV-I positive uveitis were characterised by acute granulomatous or non-granulomatous uveal reactions which were accompanied by vitreous opacities and retinal vasculitis. The uveal inflammatory and retinal vascular changes responded well to topical and/or systemic corticosteroids and resolved in a few weeks in the majority of cases with favourable visual outcome. The disease affected one or both eyes, and eight cases (25%) showed recurrence within a year. The general condition of the patients remained well otherwise during a follow up study (mean follow up time 15.4 months), except for three cases with a possible association of hyperthyroidism. These findings provide additional information favouring an association between HTLV-I and isolated uveitis, a new disease entity which should be termed HTLV-I-associated uveitis. Images PMID:8100446

  6. [A survey of HTLV-1 carrier clinics in Japan].

    PubMed

    Ishitsuka, Kenji; Yamano, Yoshihisa; Utsunomiya, Atae; Uchimaru, Kaoru

    2015-06-01

    Human T-lymphotropic virus type-I (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraparesis. Currently, mother-to-child transmission via breastfeeding and sexual intercourse are considered to be the two major routes for HTLV-1 infection. We surveyed four clinics in Japan (two HTLV-1 carrier clinics in non-endemic areas and one in an endemic area, and one hematology clinic in a highly endemic area) and reviewed the management of carriers. In HTLV-1 carrier clinics, more than half of visitors had learned of their infections based on an examination conducted either for blood donation or pregnancy. Although half of visitors had known of their infection more than 2 years prior to their visit, they became to visit the clinics probably due to recent awareness of HTLV-1 in public and of carrier clinics. They requested a detailed explanation, and check-ups for infection and its related diseases. In contrast, most visitors in highly endemic areas had apparently received good explanations from their primary care physicians. It is noteworthy that neither parent of more than half of the carriers who visited the two clinics in the non-endemic area had been born outside of Kyushu, a highly endemic area, indicating that carriers will disperse from known endemic areas. Configuring an appropriate and efficient system to support carriers is necessary, especially in non-endemic areas. PMID:26256877

  7. Prevalence and phylogenetic analysis of HTLV-1 in a segregated population in Iran.

    PubMed

    Rafatpanah, Houshang; Torkamani, Mahmood; Valizadeh, Narges; Vakili, Rosita; Meshkani, Baratali; Khademi, Hassan; Gerayli, Sina; Mozhgani, Sayed Hamid Reza; Rezaee, Seyed Abdolrahim

    2016-07-01

    Human T-lymphotropic virus type 1 (HTLV-1) infection is an important health issue that affects a variety of endemic areas. The Khorasan province, mainly its capital Mashhad in northeastern Iran, was reported to be as one of these endemic regions. Torbat-e Heydarieh, a large city Southwest border to Mashhad with a segregated population was investigated for the prevalence and associated risk factors of HTLV-1 infection in 400 randomly selected individuals. Blood samples were tested for the presence of HTLV-1 antibodies via the ELISA method and then were confirmed by an Immunoblot test. For the presence of HTLV-1 in lymphocytes of infected subjects, PCR was performed on LTR and TAX regions. DNA sequencing of LTR fragment was also carried out to determine the phylogenetic of HTLV-1, using the Maximum likelihood method. HTLV-1 sero-reactivity (sero-prevalence) among the study population was 2% (8/400), of which 1.25% had HTLV-1 provirus in lymphocytes (actual prevalence). HTLV-1 infection was significantly associated with the age, marital status, and history of blood transfusion (P < 0.05). However, there were no statistical differences between HTLV-1 infection, and gender, surgery, and hospitalization. In regression analysis, age showed the most significant correlation with the infection (P = 0.006, OR = 4.33). Based on our phylogenetic study, the HTLV-1 prevalent sequence type of Torbat-e Heydarieh belongs to the cosmopolitan subtype A. HTLV-1 prevalence in Torbat-e Heydarieh (1.25%) is low comparing to those of both Mashhad (2-3%) and Neishabour (3.5-5%) in the province of Khorasan. Thus, traveling mobility and population mixing such as marriage, bureaucratic affairs, occupation, and economic activities could be the usual routs of HTLV-1 new wave of spreading in this segregated city.

  8. High Prevalence of HTLV-1 Infection among Japanese Immigrants in Non-endemic Area of Brazil

    PubMed Central

    Bandeira, Larissa M.; Uehara, Silvia N. O.; Asato, Marcel A.; Aguena, Gabriela S.; Maedo, Cristiane M.; Benites, Nikolas H.; Puga, Marco A. M.; Rezende, Grazielli R.; Finotti, Carolina M.; Cesar, Gabriela A.; Tanaka, Tayana S. O.; Castro, Vivianne O. L.; Otsuki, Koko; Vicente, Ana C. P.; Fernandes, Carlos E.; Motta-Castro, Ana R. C.

    2015-01-01

    Background Human T-lymphotropic virus type 1 (HTLV-1) has worldwide distribution and is considered endemic in many world regions, including southwestern Japan and Brazil. Japanese immigrants and their descendants have a high risk of acquiring this infection due to intense population exchange between Brazil and Japan. Objective This cross-sectional study aimed to estimate the prevalence of HTLV, analyze the main risk factors associated with this infection, identify the main circulating types and subtypes of HTLV in Japanese immigrants and descendants living in Campo Grande-MS (Middle-West Brazil), as well as analyze the phylogenetic relationship among isolates of HTLV. Study Design A total of 219 individuals were interviewed and submitted to blood collection. All collected blood samples were submitted for detection of anti-HTLV-1/2 using the immunoassay ELISA and confirmed by immunoblot method. The proviral DNA of the 14 samples HTLV- 1 positive were genotyped by nucleotide sequencing. Results The overall prevalence of HTLV-1 was 6.8% (IC 95%: 3,5-10,2). Descriptive analysis of behavioral risk factors showed statistical association between HTLV-1 and age greater than or equal to 45 years. The proviral DNA of HTLV-1 was detected in all HTLV-1 positive samples. Of these, 14 were sequenced and classified as Cosmopolitan subtype, and 50% (7/14) belonged to subgroup A (transcontinental) and 50% (7/14) to the subgroup B (Japanese). Conclusion The high prevalence of HTLV-1 found evidence of the importance of early diagnosis and counseling of individuals infected with HTLV-1 for the control and prevention of the spread of this infection among Japanese immigrants and their descendants in Central Brazil. PMID:25886507

  9. Prevalence and phylogenetic analysis of HTLV-1 in a segregated population in Iran.

    PubMed

    Rafatpanah, Houshang; Torkamani, Mahmood; Valizadeh, Narges; Vakili, Rosita; Meshkani, Baratali; Khademi, Hassan; Gerayli, Sina; Mozhgani, Sayed Hamid Reza; Rezaee, Seyed Abdolrahim

    2016-07-01

    Human T-lymphotropic virus type 1 (HTLV-1) infection is an important health issue that affects a variety of endemic areas. The Khorasan province, mainly its capital Mashhad in northeastern Iran, was reported to be as one of these endemic regions. Torbat-e Heydarieh, a large city Southwest border to Mashhad with a segregated population was investigated for the prevalence and associated risk factors of HTLV-1 infection in 400 randomly selected individuals. Blood samples were tested for the presence of HTLV-1 antibodies via the ELISA method and then were confirmed by an Immunoblot test. For the presence of HTLV-1 in lymphocytes of infected subjects, PCR was performed on LTR and TAX regions. DNA sequencing of LTR fragment was also carried out to determine the phylogenetic of HTLV-1, using the Maximum likelihood method. HTLV-1 sero-reactivity (sero-prevalence) among the study population was 2% (8/400), of which 1.25% had HTLV-1 provirus in lymphocytes (actual prevalence). HTLV-1 infection was significantly associated with the age, marital status, and history of blood transfusion (P < 0.05). However, there were no statistical differences between HTLV-1 infection, and gender, surgery, and hospitalization. In regression analysis, age showed the most significant correlation with the infection (P = 0.006, OR = 4.33). Based on our phylogenetic study, the HTLV-1 prevalent sequence type of Torbat-e Heydarieh belongs to the cosmopolitan subtype A. HTLV-1 prevalence in Torbat-e Heydarieh (1.25%) is low comparing to those of both Mashhad (2-3%) and Neishabour (3.5-5%) in the province of Khorasan. Thus, traveling mobility and population mixing such as marriage, bureaucratic affairs, occupation, and economic activities could be the usual routs of HTLV-1 new wave of spreading in this segregated city. PMID:26680556

  10. Integrating an HTLV-III Screening Program into a Community Based Family Health Service Agency.

    ERIC Educational Resources Information Center

    Klausmeier, Walter W.; Henshaw, Beverly

    Acquired Immune Deficiency Syndrome (AIDS) has become one of the most serious epidemic disease problems in recent years. In 1985 the Public Health Service recommended establishment of test sites where individuals might be tested for Human T Lymphotropic Virus III (HTLV-III) antibody. An HTLV-III antibody screening program was integrated into a…

  11. Evaluation of commercial HTLV-1 test kits by a standard HTLV-1 serum panel.

    PubMed Central

    Fujiyama, C.; Fujiyoshi, T.; Matsumoto, D.; Tamashiro, H.; Sonoda, S.

    1995-01-01

    To evaluate the performance of currently available test kits for human T-cell lymphotropic virus type 1 (HTLV-1), we examined two particle agglutination (PA) tests and nine enzyme immunoassays (EIA) using a standard serum panel consisting of HTLV-1-positive and HTLV-1-negative sera that had been characterized by immunofluorescence and the polymerase chain reaction (PCR). The PA kits exhibited 94.0-100.0% sensitivity and 99.5-100.0% specificity; the sensitivity range was ascribed to the quality of the HTLV-1 antigens coated on the particles. The EIA kits had 99.5-100% sensitivity and 98.5-100% specificity; the 98.5%-99.5% specificity exhibited by five of the EIA kits could have been due to nonspecific reactions that were detected through use of an inadequate cut-off value and the use of recombinant proteins. It can be concluded that the sensitivity of the currently available PA and EIA kits is sufficient to permit their use for screening purposes; however, the specificity of some EIA kits should be optimized. PMID:7554024

  12. Complex role of microRNAs in HTLV-1 infections

    PubMed Central

    Sampey, Gavin C.; Van Duyne, Rachel; Currer, Robert; Das, Ravi; Narayanan, Aarthi; Kashanchi, Fatah

    2012-01-01

    Human T-lymphotropic virus 1 (HTLV-1) was the first human retrovirus to be discovered and is the causative agent of adult T-cell leukemia/lymphoma (ATL) and the neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The importance of microRNA (miRNA) in the replicative cycle of several other viruses, as well as in the progression of associated pathologies, has been well established in the past decade. Moreover, involvement of miRNA alteration in the HTLV-1 life cycle, and in the progression of its related oncogenic and neurodegenerative diseases, has recently come to light. Several HTLV-1 derived proteins alter transcription factor functionalities, interact with chromatin remodelers, or manipulate components of the RNA interference (RNAi) machinery, thereby establishing various routes by which miRNA expression can be up- or down-regulated in the host cell. Furthermore, the mechanism of action through which dysregulation of host miRNAs affects HTLV-1 infected cells can vary substantially and include mRNA silencing via the RNA-induced silencing complex (RISC), transcriptional gene silencing, inhibition of RNAi components, and chromatin remodeling. These miRNA-induced changes can lead to increased cell survival, invasiveness, proliferation, and differentiation, as well as allow for viral latency. While many recent studies have successfully implicated miRNAs in the life cycle and pathogenesis of HTLV-1 infections, there are still significant outstanding questions to be addressed. Here we will review recent discoveries elucidating HTLV-1 mediated manipulation of host cell miRNA profiles and examine the impact on pathogenesis, as well as explore future lines of inquiry that could increase understanding in this field of study. PMID:23251140

  13. CD4+ T cell subsets and Tax expression in HTLV-1 associated diseases

    PubMed Central

    Barros, Nicolas; Risco, Jorge; Rodríguez, Carlos; Sánchez, Cesar; González, Elsa; Tanaka, Yuetsu; Gotuzzo, Eduardo; Clinton White, A; Montes, Martin

    2013-01-01

    Human T lymphotropic virus type 1 (HTLV-1) infection displays variable clinical manifestations. These include inflammatory diseases such as HTLV-1 associated myelopathy (HAM) or immunosuppressive conditions such as Strongyloides stercoralis hyperinfection. The viral protein, Tax causes activation and proliferation of T cells. We hypothesize that the expression of Tax in T cell subsets characterizes the clinical manifestations of HTLV-1. To test this hypothesis, we measured T helper 1 effector cells and regulatory T cells (Tregs) among Tax expressing lymphocytes from peripheral blood mononuclear cells (PBMCs) of 32 HTLV-1 infected patients with HAM, with S. stercoralis co-infection or with asymptomatic infection. We observed increased ratios of Th1/Treg among Tax expressing lymphocytes in HAM patients. These data suggest that the expression of Tax among the different target cells may explain the variable presentation of HTLV-1. PMID:23816512

  14. HTLV-I and Apoptosis: Role in Cellular Transformation and Recent Advances in Therapeutic Approaches

    PubMed Central

    Taylor, John M.; Nicot, Christophe

    2008-01-01

    A universal cellular defense mechanism against viral invasion is the elimination of infected cells through apoptotic cell death. To counteract host defenses many viruses have evolved complex apoptosis evasion strategies. The oncogenic human retrovirus HTLV-I is the etiological agent of adult-T-cell leukemia/lymphoma (ATLL) and the neurodegenerative disease known as HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The poor prognosis in HTLV-I-induced ATLL is linked to the resistance of neoplastic T cells against conventional therapies and the immunocompromised state of patients. Nevertheless, several studies have shown that the apoptotic pathway is largely intact and can be reactivated in ATLL tumor cells to induce specific killing. A better understanding of the molecular mechanisms employed by HTLV-I to counteract cellular death pathways remains an important challenge for future therapies and the treatment of HTLV-I-associated diseases. PMID:18421579

  15. Evaluation of the Microbicidal Activity and Cytokines/Chemokines Profile Released by Neutrophils from HTLV-1-Infected Individuals

    PubMed Central

    Bezerra, Caroline A.; Cardoso, Thiago M.; Giudice, Angela; Porto, Aurélia F.; Santos, Silvane B.; Carvalho, Edgar M.; Bacellar, Olívia

    2011-01-01

    Human T cell lymphotropic virus type-1 (HTLV-1) induces activation and spontaneous proliferation of T cells with production of type-1 pro-inflammatory cytokines. It modifies the immune response to other antigens and increases susceptibility to infectious diseases. However, little is known about innate immunity in HTLV-1 infection. HTLV-1-infected individuals have higher spontaneous neutrophil activation than HTLV-1-seronegative individuals, as shown by the nitroblue tetrazolium (NBT) assay. This study was conducted to evaluate neutrophil function in HTLV-1-infected individuals. Participants in the study included 18 HTLV-1-infected individuals and 14 HTLV-1-seronegative controls. We evaluated the ability of neutrophils (PMNs) to control a parasite infection, to produce peroxynitrite, cytokines and chemokines and to express activation markers in cultures when stimulated with LPS or infected with Leishmania. When compared with the control group, there was no difference in the percentage of PMNs infected with Leishmania or in the number of amastigotes/100 PMNs in HTLV-1-infected individuals. The microbicidal activity of the PMNs and the levels of CXCL8 and CCL4 released by these cells did not show a difference between HTLV-1-infected individuals and the control group. In both the HTLV-1 group and the control group, infection with Leishmania or stimulation of PMNs led to cellular activation. These observations suggest that neutrophils from HTLV-1-infected individuals have preserved their ability to become activated and to produce chemokines and peroxynitrite after stimulation and that the susceptibility to infection by intracellular Leishmania amazonensis in HTLV-1-infected individuals does not depend on impairment of neutrophil function. PMID:21595736

  16. Human T-cell leukemia virus type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the NF-κB inhibitor A20 and constitutive NF-κB signaling.

    PubMed

    Pujari, Rajeshree; Hunte, Richard; Thomas, Remy; van der Weyden, Louise; Rauch, Dan; Ratner, Lee; Nyborg, Jennifer K; Ramos, Juan Carlos; Takai, Yoshimi; Shembade, Noula

    2015-03-01

    Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1) recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells.

  17. Bromodomain and extraterminal (BET) protein inhibition suppresses human T cell leukemia virus 1 (HTLV-1) Tax protein-mediated tumorigenesis by inhibiting nuclear factor κB (NF-κB) signaling.

    PubMed

    Wu, Xuewei; Qi, Jun; Bradner, James E; Xiao, Gutian; Chen, Lin-Feng

    2013-12-13

    The etiology of human T cell leukemia virus 1 (HTLV-1)-mediated adult T cell leukemia is associated with the ability of viral oncoprotein Tax to induce sustained NF-κB activation and the expression of many NF-κB target genes. Acetylation of the RelA subunit of NF-κB and the subsequent recruitment of bromodomain-containing factor Brd4 are important for the expression of NF-κB target genes in response to various stimuli. However, their contributions to Tax-mediated NF-κB target gene expression and tumorigenesis remain unclear. Here we report that Tax induced the acetylation of lysine 310 of RelA and the binding of Brd4 to acetylated RelA to facilitate Tax-mediated transcriptional activation of NF-κB. Depletion of Brd4 down-regulated Tax-mediated NF-κB target gene expression and cell proliferation. Inhibiting the interaction of Brd4 and acetylated RelA with the bromodomain extraterminal protein inhibitor JQ1 suppressed the proliferation of Tax-expressing rat fibroblasts and Tax-positive HTLV-1-infected cells and Tax-mediated cell transformation and tumorigenesis. Moreover, JQ1 attenuated the Tax-mediated transcriptional activation of NF-κB, triggering the polyubiquitination and proteasome-mediated degradation of constitutively active nuclear RelA. Our results identify Brd4 as a key regulator for Tax-mediated NF-κB gene expression and suggest that targeting epigenetic regulators such as Brd4 with the bromodomain extraterminal protein inhibitor might be a potential therapeutic strategy for cancers and other diseases associated with HTLV-1 infection.

  18. Cutaneous Manifestations in HTLV-I Positive Blood Donors

    PubMed Central

    Yazdanpanah, Mohammad Javad; Maleki, Masoud; Joneidi, Nasaibe; Khalighi, Amir Reza; Azarpazhooh, Mahmoud Reza; Khajedaluee, Mohammad; Tehranian, Farahnaz; Shahabi, Majid; Esmaeil Khayami, Mohammad; Livani, Fatemeh

    2013-01-01

    Objective(s): Infection with the human T-cell lymphotrophic virus type-I (HTLV-I) is endemic in Mashhad, Iran. In our research we evaluated the relation between exposure to this infection and the occurrence of dermatologic manifestations. Materials and Methods: 100 blood donors, who were seropositive but asymptomatic for infection with HTLV-I, were selected as case group. They were identified by the Blood Transfusion Organization Mashhad via the ELISA test and documented by PCR. Another 100 blood donors, that were seronegative for HTLV-I via the ELISA test and who were matched to the case group for age, gender, and existence of systemic diseases, were considered as the controls. Dermatologic evaluations and skin biopsies were performed if deemed necessary, and the results were statistically analyzed. Results: 73% of the case and control groups were male, while 27% in each of these groups were female. The mean age in both groups was 40.96±11.94 years. The examination indicated that 58% of the case group and 37% of the control group had cutaneous manifestations (P<0.01). The most common diseases found in the case group were aphthous stomatitis, herpes labialis, and non-genital warts, while common diseases found in the control group were herpes labialis, aphthous stomatitis, and skin tag. The frequency of aphthous stomatitis, eczema, and non-genital warts in the case group were significantly more than the control group (P<0.05). Conclusion : Cutaneous diseases can be found more frequent in asymptomatic carriers of HTLV-I than those who are HTLV-I seronegative. The aphthous stomatitis, eczema, and non-genital warts are more prevalent in those infected by HTLV-I. PMID:24470876

  19. HTLV-1 viral RNA is detected rarely in plasma of HTLV-1 infected subjects.

    PubMed

    Demontis, Maria Antonietta; Sadiq, Maaz Tahir; Golz, Simon; Taylor, Graham P

    2015-12-01

    Plasma of patients infected with HTLV-1 is considered non-infectious but detection of HTLV-1 genomic RNA in plasma has been recently reported. The aim of this project was to detect and quantify HTLV-1 RNA in plasma and assess its potential value in diagnosis and prognosis. RNA from 1 ml of plasma from 65 subjects infected with HTLV-1 (27 asymptomatic carriers [AC]), 17 patients with HTLV-1-associated myelopathy (HAM/TSP), 14 with adult T-cell leukemia/lymphoma (ATLL), two co-infected with HIV, and five with other HTLV-1-associated disease, was extracted and reverse transcribed. HTLV-1 specific nested PCR was performed using primers to amplify the conserved Tax region. All samples were run in quadruplicate, nested PCR products were detected by gel electrophoresis. HTLV-1 RNA was detected in plasma from 18 (28%) patients, always at a very low copy number (3-13 copies viral cDNA per milliliter of plasma). Mean values of HTLV-1 proviral load did not differ between patients in whom HTLV-1 RNA was detected and patients in whom it was not possible to detect HTLV-1 RNA in plasma. HTLV-1 genomic RNA can be detected in the plasma of a minority of patients but not at a level or frequency to be useful clinically or diagnostically. Lack of transmission of HTLV-1 by plasma is due to the rare presence of HTLV-1 virions, regardless of any other factor.

  20. Infection without antibody response in mother-to-child transmission of HTLV-I in rabbits.

    PubMed

    Yamade, I; Ishiguro, T; Seto, A

    1991-04-01

    The presence or absence of the anti-human T-cell leukemia virus type (HTLV-I) antibody and the HTLV-I proviral genome was examined in the offspring of inbred rabbits, which were born to HTLV-I carrier does. The results showed that not all offspring born to the carriers were infected and that not all the infected offspring seroconverted at the age of 10 weeks, which is similar to observations made in human carriers. The anti-HTLV-I antibody was assayed by indirect immunofluorescence in 55 offspring at the age of 10 weeks, which were born to B/J or (B/J x Chbb:HM)F1 seropositive HTLV-I carrier does. Twelve out of 31 offspring born from F1 x F1 mating were seropositive, whereas none of 24 offspring born from B/J x B/J mating, F1 x B/J mating, or F1 x Chbb:HM mating were seropositive. The polymerase chain reaction (PCR) method revealed the presence of the HTLV-I proviral genome in 18 out of 23 offspring born from F1 x F1 mating (F2 hybrids). In these 18 HTLV-I-infected F2 hybrids, 8 were seropositive and 10 were seronegative. The major histocompatibility complex (MHC) of these 23 F2 hybrids was analyzed by restriction fragment length polymorphism (RFLP) in southern hybridization. The results showed no close correlation of MHC with HTLV-I susceptibility or with seroconversion. Natural infection via mother-to-child transmission of virus seems to produce seronegative as well as seropositive carriers. This rabbit model may be useful for the study of seronegative virus carriers via mother-to-child transmission of HTLV-I. PMID:1677415

  1. HTLV-1 and associated adult T-cell leukemia/lymphoma.

    PubMed

    Mahieux, Renaud; Gessain, Antoine

    2003-12-01

    Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infects 15-20 millions individuals worldwide. This oncoretrovirus can be transmitted through 3 ways: horizontally, vertically (mother to child) and via blood transfusion. HTLV-1 causes 2 major diseases: adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-1-associated myelopathy. Tax is a 40-kDa phosphoprotein that is encoded by the pX region of the virus. Several lines of evidence have demonstrated a central role for this protein in the immortalization or transformation of the HTLV-1 infected cells. Apart from its ability to drive transcription from the viral promoter, it also deregulates the cell cycle, inhibits apoptosis, has an effect on the maintenance of the genomic stability and induces the production of several cytokines. In addition, several arguments strongly suggest the existence of host genetic factors, that could be involved in the HTLV-1 infection as well as in the development of ATLL among HTLV-1 infected individuals. ATLL can be classified into 4 major subtypes: a smoldering type, a chronic type, a lymphoma type and a leukemic type. The demonstration by Southern blot analysis of the clonal integration of an HTLV-1 provirus in the tumoral cells represents the gold-standard to define biologically ATLL. The survival rate of ATLL patients, especially those who develop the acute leukemic or lymphomas forms, is very poor, and such clonal malignant CD4 expansion remains one of the most severe lymphoproliferations.

  2. The Burden of Neglected HIV-2 and HTLV-1 Infections in Spain.

    PubMed

    Treviño, Ana; Caballero, Estrella; de Mendoza, Carmen; Aguilera, Antonio; Pirón, Maria; Soriano, Vicente

    2015-01-01

    HIV-2 and HTLV-1 infections are globally less frequent than those produced by HIV-1, the classical AIDS agent. In Spain and up to the end of 2014, a total of 310 cases of HIV-2, 274 of HTLV-1, and 776 of HTLV-2 infections had been reported. No cases of HTLV-3 or HTLV-4 infections have been identified so far in Spain. Most persons infected with HIV-2 or HTLV-1 acknowledge epidemiological risk factors for contagion, such as originating from or living in endemic regions and/or having had sexual partners from those areas. However, risk factors could not be recognized in up to 20-25% of carriers in Spain. Thus, it seems worth keeping a high level of clinical suspicion in order to identify earlier these neglected human retroviral infections, since diagnostic procedures and antiviral treatment are specific for each of these agents. In this article we summarize the major contributions reported at the meeting of the Spanish Group for HIV-2/HTLV held in Madrid in December 2014.

  3. Sensitivity analysis of retrovirus HTLV-1 transactivation.

    PubMed

    Corradin, Alberto; Di Camillo, Barbara; Ciminale, Vincenzo; Toffolo, Gianna; Cobelli, Claudio

    2011-02-01

    Human T-cell leukemia virus type 1 is a human retrovirus endemic in many areas of the world. Although many studies indicated a key role of the viral protein Tax in the control of viral transcription, the mechanisms controlling HTLV-1 expression and its persistence in vivo are still poorly understood. To assess Tax effects on viral kinetics, we developed a HTLV-1 model. Two parameters that capture both its deterministic and stochastic behavior were quantified: Tax signal-to-noise ratio (SNR), which measures the effect of stochastic phenomena on Tax expression as the ratio between the protein steady-state level and the variance of the noise causing fluctuations around this value; t(1/2), a parameter representative of the duration of Tax transient expression pulses, that is, of Tax bursts due to stochastic phenomena. Sensitivity analysis indicates that the major determinant of Tax SNR is the transactivation constant, the system parameter weighting the enhancement of retrovirus transcription due to transactivation. In contrast, t(1/2) is strongly influenced by the degradation rate of the mRNA. In addition to shedding light into the mechanism of Tax transactivation, the obtained results are of potential interest for novel drug development strategies since the two parameters most affecting Tax transactivation can be experimentally tuned, e.g. by perturbing protein phosphorylation and by RNA interference.

  4. Demographic and familial characteristics of HTLV-1 infection among an isolated, highly endemic population of African origin in French Guiana.

    PubMed

    Plancoulaine, S; Buigues, R P; Murphy, E L; van Beveren, M; Pouliquen, J F; Joubert, M; Rémy, F; Tuppin, P; Tortevoye, P; de Thé, G; Moreau, J P; Gessain, A

    1998-05-01

    To determine the epidemiological characteristics of human T cell leukemia/lymphoma virus type I (HTLV-I) infection in the endemic village of Maripasoula, French Guiana, 1,614 persons (83.2% of the population) aged 2 to 91 years (mean age 21) were studied from November 1994 through April 1995. Plasma samples were screened by an HTLV-I ELISA and an IFA test (on MT2 cells), and positive samples were tested by an HTLV-I and -II type-specific Western blot. Overall seropositivity in the village was 6.7%, but HTLV-I infection was restricted to 3 of 6 ethnic groups, including the Noir-Marron (descendants of escaped African slaves, 8%), the Creoles (4.1%) and those of mixed Noir Marron/other ethnicity (3.6%). In the Noir-Marron population of 1,222 persons, including 606 men and 616 women and representing 76% of those tested, HTLV-I seroprevalence increased significantly with age in both sexes, reaching 40% in women older than 50 years. Univariate risk factors for HTLV-I seropositivity in women included older age, more pregnancies, more live births and a history of hospitalization. A cross-sectional analysis of sexual partners demonstrated an excess of discordant female HTLV-I+/male HTLV-I- couples, indicating preferential male-to-female sexual transmission. The demonstration of II HTLV-I-seropositive children aged less than 15 years, of whom 9 had a seropositive mother, suggested maternal-child HTLV-I transmission. Our results demonstrate a very high seroprevalence of HTLV-I in this South American population descended from African slaves, probably due to high rates of mother-to-child and sexual transmission within this rather isolated group.

  5. HLA DRB1*DQB1* haplotype in HTLV-I-associated familial infective dermatitis may predict development of HTLV-I-associated myelopathy/tropical spastic paraparesis

    SciTech Connect

    LaGrenade, L.; Miller, W.; Pate, E.; Rodgers-Johnson, P.

    1996-01-02

    A possible causal association between infective dermatitis and HTLV-I infection was reported in 1990 and confirmed in 1992. We now report familial infective dermatitis (ID) occurring in a 26-year-old mother and her 9-year-old son. The mother was first diagnosed with ID in 1969 at the age of 2 years in Dermatology Unit at the University Hospital of the West Indies (U.H.W.I.) in Jamacia. The elder of her 2 sons was diagnosed with ID at the age of 3 years, also at U.H.W.I. Both mother and son are HTLV-I-seropositive. A second, younger son, currently age 2 years, is also HTLV-I-seropositive, but without clinical evidence of ID. Major histocompatibility complex (MHC), class II, human leucocyte antigen (HLA) genotyping documented a shared class II haplotype, DRB1*DQB1* (1101-0301), in the mother and her 2 sons. This same haplotype has been described among Japanese patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and has been associated with a possible pathologically heightened immune response to HTLV-I infection. The presence of this haplotype in these familial ID cases with clinical signs of HAM/TSP may have contributed to their risk for development of HAM/TSP. The unaffected, HTLV-I-seropositive, younger son requires close clinical follow-up. 20 refs., 1 fig., 1 tab.

  6. Novel interactions between the HTLV antisense proteins HBZ and APH-2 and the NFAR protein family: Implications for the HTLV lifecycles

    PubMed Central

    Murphy, Jane; Hall, William W.; Ratner, Lee; Sheehy, Noreen

    2016-01-01

    The human T-cell leukaemia virus type 1 and type 2 (HTLV-1/HTLV-2) antisense proteins HBZ and APH-2 play key roles in the HTLV lifecycles and persistence in the host. Nuclear Factors Associated with double-stranded RNA (NFAR) proteins NF90/110 function in the lifecycles of several viruses and participate in host innate immunity against infection and oncogenesis. Using GST pulldown and co-immunoprecipitation assays we demonstrate specific novel interactions between HBZ/APH-2 and NF90/110 and characterised the protein domains involved. Moreover we show that NF90/110 significantly enhance Tax mediated LTR activation, an effect that was abolished by HBZ but enhanced by APH-2. Additionally we found that HBZ and APH-2 modulate the promoter activity of survivin and are capable of antagonising NF110-mediated survivin activation. Thus interactions between HTLV antisense proteins and the NFAR protein family have an overall positive impact on HTLV infection. Hence NFARs may represent potential therapeutic targets in HTLV infected cells. PMID:27110706

  7. [Neurologic diseases associated with the HTLV-1 virus in Panama].

    PubMed

    Gracia, F; Castillo, L; de Lao, S L; Archibold, C A; Larreátegui, M; Reeves, W C; Levine, P

    1990-09-01

    Studies of the prevalence of the human T-cell lymphotropic virus (HTLV-1) in 1984 to 1986 in the Republic of Panama revealed a national seroprevalence of 1 to 2%. Since 1985 clinical epidemiological studies of neurological diseases associated to HTLV-1 are being done. Two hundred and fitly six clinical cases of thirty eight different neurological diseases of unknown etiology studied in the Neurology Services of the Santo Tomas Hospital and the Social Security Metropolitan Hospital Complex have been associated in some way to the HTLV-1. Twelve cases of progressive spastic paraparesis were identified and related to HLTV-1 as an etiologic agent. The ratio of men to women was maintained at 1:1 with the average age at onset at 44 years and without racial preference. There are important doubts about the association of this virus to multiple sclerosis. The seroprevalence of the HTLV-1 virus in Panama is found to be similar to that reported in neighboring countries and the association of tropical spastic paraparesis to THLV-1 infection is identified.

  8. HTLV-1 and HTLV-2: highly similar viruses with distinct oncogenic properties

    PubMed Central

    Ciminale, Vincenzo; Rende, Francesca; Bertazzoni, Umberto; Romanelli, Maria G.

    2014-01-01

    HTLV-1 and HTLV-2 share broad similarities in their overall genetic organization and expression pattern, but they differ substantially in their pathogenic properties. This review outlines distinctive features of HTLV-1 and HTLV-2 that might provide clues to explain their distinct clinical outcomes. Differences in the kinetics of viral mRNA expression, functional properties of the regulatory and accessory proteins, and interactions with cellular factors and signal transduction pathways are discussed. PMID:25120538

  9. Aquaporin-4 Antibodies Are Not Related to HTLV-1 Associated Myelopathy

    PubMed Central

    von Glehn, Felipe; Jarius, Sven; Penalva de Oliveira, Augusto C.; Brandão, Carlos Otávio; Farias, Alessandro S.; Damasceno, Alfredo; Casseb, Jorge; Moraes, Adriel S.; Longhini, Ana Leda F.; Wandinger, Klaus-Peter; Damasceno, Benito P.; Wildemann, Brigitte; Santos, Leonilda M. B.

    2012-01-01

    Introduction The seroprevalence of human T-cell leukemia virus type 1 (HTLV-1) is very high among Brazilians (∼1∶200). HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the most common neurological complication of HTLV-1 infection. HAM/TSP can present with an acute/subacute form of longitudinally extensive myelitis, which can be confused with lesions seen in aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorders (NMOSD) on MRI. Moreover, clinical attacks in patients with NMOSD have been shown to be preceded by viral infections in around 30% of cases. Objective To evaluate the frequency of AQP4-Ab in patients with HAM/TSP. To evaluate the frequency of HTLV-1 infection in patients with NMOSD. Patients and Methods 23 Brazilian patients with HAM/TSP, 20 asymptomatic HTLV-1+ serostatus patients, and 34 with NMOSD were tested for AQP4-Ab using a standardized recombinant cell based assay. In addition, all patients were tested for HTLV-1 by ELISA and Western blotting. Results 20/34 NMOSD patients were positive for AQP4-Ab but none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. One patient with HAM/TSP developed optic neuritis in addition to subacute LETM; this patient was AQP4-Ab negative as well. Patients were found to be predominantly female and of African descent both in the NMOSD and in the HAM/TSP group; Osame scale and expanded disability status scale scores did not differ significantly between the two groups. Conclusions Our results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1 seroprevalence

  10. Inhibitory effect of extracts of Brazilian marine algae on human T-cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation in vitro.

    PubMed

    Romanos, MariaTeresaVillela; Andrada-Serpa, Maria José; dos, SantosMartaGonçalvesMatos; Ribeiro, AnaCristinaF; Yoneshigue-Valentin, Yocie; Costa, Sĵnia Soares; Wigg, Marcia Dutra

    2002-01-01

    Extracts from four species of Brazilian marine algae collected from the Rio de Janeiro State coast were screened to determine the inhibitory effect on HTLV-1-induced syncytium formation. Before performing the syncytium inhibition assay the 50% cytotoxic dose (CyD50) of the algal extracts was evaluated. The antiviral test was carried out in HeLa cells co-cultured with HTLV-I infected T-cell line (C91/PL cells) in the presence of marine algal extracts in the concentration inferior to that corresponding to the CyD50. It was observed that co-cultured cells exposed to Ulva fasciata extract showed 60.2% syncytium inhibition at a concentration of 2.5%. At 5% concentration, Sargassum vulgare and Vidalia obtusiloba extracts presented 78.8 and 76% syncytium inhibition, respectively. The best inhibitory activity was observed with Laminaria abyssalis that presented 100% syncytium inhibition at a concentration of 2.5%. This work shows that extracts of marine algae, mainly L. abyssalis extract, are able to inhibit the cell-to-cell contact essential for the spreading of the virus and could be useful to prevent the infection. PMID:11853002

  11. HTLV-I infection: a dynamic struggle between viral persistence and host immunity.

    PubMed

    Lim, Aaron G; Maini, Philip K

    2014-07-01

    Human T-lymphotropic virus type I (HTLV-I) causes chronic infection for which there is no cure or neutralising vaccine. HTLV-I has been clinically linked to the development of adult T-cell leukaemia/lymphoma (ATL), an aggressive blood cancer, and HAM/TSP, a progressive neurological and inflammatory disease. Infected individuals typically mount a large, persistently activated CD8(+) cytotoxic T-lymphocyte (CTL) response against HTLV-I-infected cells, but ultimately fail to effectively eliminate the virus. Moreover, the identification of determinants to disease manifestation has thus far been elusive. A key issue in current HTLV-I research is to better understand the dynamic interaction between persistent infection by HTLV-I and virus-specific host immunity. Recent experimental hypotheses for the persistence of HTLV-I in vivo have led to the development of mathematical models illuminating the balance between proviral latency and activation in the target cell population. We investigate the role of a constantly changing anti-viral immune environment acting in response to the effects of infected T-cell activation and subsequent viral expression. The resulting model is a four-dimensional, non-linear system of ordinary differential equations that describes the dynamic interactions among viral expression, infected target cell activation, and the HTLV-I-specific CTL response. The global dynamics of the model is established through the construction of appropriate Lyapunov functions. Examining the particular roles of viral expression and host immunity during the chronic phase of HTLV-I infection offers important insights regarding the evolution of viral persistence and proposes a hypothesis for pathogenesis. PMID:24583256

  12. Clinical and immunological features of patients with atopy and concomitant HTLV-1 infection.

    PubMed

    Gaspar-Sobrinho, F P; Souza-Machado, A; Santos, S B; Orge, G; Lessa, H A; Cruz, A A; Carvalho, E M

    2010-12-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) induces an exacerbated type 1 immune response characterized by high spontaneous IFN-γ and TNF-α production. Allergic rhinitis and asthma are associated with the type 2 immune response, with elevated secretion of IL-4 and IL-5. The aim of this study was to characterize the immune response in atopic HTLV-1 carriers. The cytokine profile of atopic HTLV-1 carriers (N = 10; all females) was compared with that of non-atopic HTLV-1 carriers (N = 14; 9 females and 5 males). Mean patient age of atopic and non-atopic groups was 45 ± 8 and 38 ± 11 years, respectively. All atopic HTLV-1 carriers had rhinitis with or without asthma and a skin prick test positive for Dermatophagoides pteronyssinus antigen 1 (Derp-1). There was no difference in cytokine levels between the two groups in unstimulated peripheral blood mononuclear cell cultures. In cultures stimulated with Derp-1, IFN-γ levels tended to be higher (P = 0.06) and IL-5 levels were higher (P = 0.02) in atopic HTLV-1 patients than in non-atopic subjects. In contrast, IL-10 was lower (P = 0.004) in atopic than in non-atopic HTLV-1-infected subjects. This study shows that HTLV-1 infection with an exaggerated type 1 immune response does not prevent atopy. In this case, the exacerbated type 1 and type 2 immune responses were due to a lack of IL-10 production, a cytokine that plays an important role in down-modulating type 1 and type 2 immune responses and in preventing the development of chronic inflammatory diseases. PMID:21140101

  13. PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival.

    PubMed

    Panfil, Amanda R; Al-Saleem, Jacob; Howard, Cory M; Mates, Jessica M; Kwiek, Jesse J; Baiocchi, Robert A; Green, Patrick L

    2015-12-30

    Human T-cell leukemia virus type-1 (HTLV-1) is a tumorigenic retrovirus responsible for development of adult T-cell leukemia/lymphoma (ATLL). This disease manifests after a long clinical latency period of up to 2-3 decades. Two viral gene products, Tax and HBZ, have transforming properties and play a role in the pathogenic process. Genetic and epigenetic cellular changes also occur in HTLV-1-infected cells, which contribute to transformation and disease development. However, the role of cellular factors in transformation is not completely understood. Herein, we examined the role of protein arginine methyltransferase 5 (PRMT5) on HTLV-1-mediated cellular transformation and viral gene expression. We found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATLL patient PBMCs. shRNA-mediated reduction in PRMT5 protein levels or its inhibition by a small molecule inhibitor (PRMT5i) in HTLV-1-infected lymphocytes resulted in increased viral gene expression and decreased cellular proliferation. PRMT5i also had selective toxicity in HTLV-1-transformed T-cells. Finally, we demonstrated that PRMT5 and the HTLV-1 p30 protein had an additive inhibitory effect on HTLV-1 gene expression. Our study provides evidence for PRMT5 as a host cell factor important in HTLV-1-mediated T-cell transformation, and a potential target for ATLL treatment.

  14. HTLV-1/2 seroprevalence and coinfection rate in Brazilian first-time blood donors: an 11-year follow-up.

    PubMed

    Pinto, Mariana Tomazini; Rodrigues, Evandra Strazza; Malta, Tathiane Maistro; Azevedo, Rochele; Takayanagui, Osvaldo Massaiti; Valente, Vanderléia Bárbaro; Ubiali, Eugênia Maria Amorim; Covas, Dimas Tadeu; Kashima, Simone

    2012-01-01

    The seroprevalence and geographic distribution of HTLV-1/2 among blood donors are extremely important to transfusion services. We evaluated the seroprevalence of HTLV-1/2 infection among first-time blood donor candidates in Ribeirão Preto city and region. From January 2000 to December 2010, 1,038,489 blood donations were obtained and 301,470 were first-time blood donations. All samples were screened with serological tests for HTLV-1/2 using enzyme immunoassay (EIA). In addition, the frequency of coinfection with hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), Chagas disease (CD) and syphilis was also determined. In-house PCR was used as confirmatory test for HTLV-1/2. A total of 296 (0.1%) first-time donors were serologically reactive for HTLV-1/2. Confirmatory PCR of 63 samples showed that 28 were HTLV-1 positive, 13 HTLV-2 positive, 19 negative and three indeterminate. Regarding HTLV coinfection rates, the most prevalent was with HBV (51.3%) and HCV (35.9%), but coinfection with HIV, CD and syphilis was also detected. The real number of HTLV-infected individual and coinfection rate in the population is underestimated and epidemiological studies like ours are very informative. PMID:22634882

  15. Animal models on HTLV-1 and related viruses: what did we learn?

    PubMed Central

    Hajj, Hiba El; Nasr, Rihab; Kfoury, Youmna; Dassouki, Zeina; Nasser, Roudaina; Kchour, Ghada; Hermine, Olivier; de Thé, Hugues; Bazarbachi, Ali

    2012-01-01

    Retroviruses are associated with a wide variety of diseases, including immunological, neurological disorders, and different forms of cancer. Among retroviruses, Oncovirinae regroup according to their genetic structure and sequence, several related viruses such as human T-cell lymphotropic viruses types 1 and 2 (HTLV-1 and HTLV-2), simian T cell lymphotropic viruses types 1 and 2 (STLV-1 and STLV-2), and bovine leukemia virus (BLV). As in many diseases, animal models provide a useful tool for the studies of pathogenesis, treatment, and prevention. In the current review, an overview on different animal models used in the study of these viruses will be provided. A specific attention will be given to the HTLV-1 virus which is the causative agent of adult T-cell leukemia/lymphoma (ATL) but also of a number of inflammatory diseases regrouping the HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), infective dermatitis and some lung inflammatory diseases. Among these models, rabbits, monkeys but also rats provide an excellent in vivo tool for early HTLV-1 viral infection and transmission as well as the induced host immune response against the virus. But ideally, mice remain the most efficient method of studying human afflictions. Genetically altered mice including both transgenic and knockout mice, offer important models to test the role of specific viral and host genes in the development of HTLV-1-associated leukemia. The development of different strains of immunodeficient mice strains (SCID, NOD, and NOG SCID mice) provide a useful and rapid tool of humanized and xenografted mice models, to test new drugs and targeted therapy against HTLV-1-associated leukemia, to identify leukemia stem cells candidates but also to study the innate immunity mediated by the virus. All together, these animal models have revolutionized the biology of retroviruses, their manipulation of host genes and more importantly the potential ways to either prevent their infection or to

  16. [Dermatomiositis and evans syndrome associated with HTLV-1 infection].

    PubMed

    Loja-Oropeza, David; Zavala-Flores, Ernesto; Vilca-Vasquez, Maricela

    2016-03-01

    A 55-year-old female patient, born in Ayacucho, with a history of dermatomyositis for 3 years, who received irregular treatment with prednisone. Two months prior to admission, she presented with autoinmune hemolytic anemia and idiopathic thrombocytopenic purpura. The patient received methylprednisolone pulse therapy and packed red blood cells transfusions. Upon admission, she was drowsy, with a poor overall status, marked weight loss, dehydration, with presence of livedo reticularis in her lower extremities, and onychodystrophy and onycholysis on the toes of both feet. Western blot test was positive for human T-lymphotropic virus type 1 (HTLV-1). The patient evolved with recurrent hypoglycemia. Therefore, we report a case of dermatomyositis and Evans syndrome in the context of an HTLV-1 infection.

  17. [Dermatomiositis and evans syndrome associated with HTLV-1 infection].

    PubMed

    Loja-Oropeza, David; Zavala-Flores, Ernesto; Vilca-Vasquez, Maricela

    2016-03-01

    A 55-year-old female patient, born in Ayacucho, with a history of dermatomyositis for 3 years, who received irregular treatment with prednisone. Two months prior to admission, she presented with autoinmune hemolytic anemia and idiopathic thrombocytopenic purpura. The patient received methylprednisolone pulse therapy and packed red blood cells transfusions. Upon admission, she was drowsy, with a poor overall status, marked weight loss, dehydration, with presence of livedo reticularis in her lower extremities, and onychodystrophy and onycholysis on the toes of both feet. Western blot test was positive for human T-lymphotropic virus type 1 (HTLV-1). The patient evolved with recurrent hypoglycemia. Therefore, we report a case of dermatomyositis and Evans syndrome in the context of an HTLV-1 infection. PMID:27384637

  18. Immune Compromise in HIV-1/HTLV-1 Coinfection With Paradoxical Resolution of CD4 Lymphocytosis During Antiretroviral Therapy

    PubMed Central

    Rockwood, N.; Cook, L.; Kagdi, H.; Basnayake, S.; Bangham, C.R.M.; Pozniak, A.L.; Taylor, G.P.

    2015-01-01

    Abstract Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity. We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism. Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control. This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity. PMID:26683952

  19. Serological and molecular survey for HTLV-I infection in a high-risk Middle Eastern group.

    PubMed

    Meytes, D; Schochat, B; Lee, H; Nadel, G; Sidi, Y; Cerney, M; Swanson, P; Shaklai, M; Kilim, Y; Elgat, M

    To define the extent of human T-cell leukaemia virus (HTLV-I) infection among a group of Jewish immigrants to Israel with an increased frequency of adult T-cell leukaemia, various serological and molecular screening methods, including enzyme-linked immunosorbent assay (ELISA) for anti-HTLV-I, ELISA for antibody to recombinant HTLV-I p40tax protein, and molecular detection of infection by polymerase chain reaction (PCR) amplification of HTLV-I proviral DNA from peripheral blood mononuclear cell DNA, were used. By HTLV-I ELISA the overall rate of infection was 12% (24 of 208) among immigrants from Khurusan, northeastern Iran; no HTLV-I carriers were detected among 111 unselected Jewish immigrants from other parts of Iran. There was unexplained clustering of HTLV-I infection within a cohort of 32 elderly women of similar geographic origin in a home for old people--14 were seropositive by ELISA and 19 of 29 were positive by PCR. The findings in this newly identified high-risk population suggest that in addition to ELISA, other screening techniques may be required to detect all carriers in high-risk populations.

  20. HTLV type I and HTLV type II infection among Indians and natives from Argentina.

    PubMed

    Bouzas, M B; Zapiola, I; Quiruelas, S; Gorvein, D; Panzita, A; Rey, J; Carnese, F P; Corral, R; Perez, C; Zala, C

    1994-11-01

    Endemic foci for HTLV-II infection have been identified in several Amerindian populations. To determine HTLV-I and/or HTLV-II infection among Amerindians living in Argentina we studied 454 sera or plasmas from Indians and natives from different areas of our country. All samples were tested by the particle agglutination technique, and positive reactions were confirmed by the immunofluorescence assay (IFA). IFA titration was used to differentiate HTLV-I and HTLV-II antibodies. Twenty-three of 222 samples (10.4%) were found positive among the Tobas Indians; 22 samples were typed as HTLV-II and 1 as HTLV-I. Antibodies for HTLV-I were found in the serum and CSF of three natives from Salta with a TSP diagnosis. No positive samples were found among 96 Mapuche Indians and 133 natives from San Luis. Our results indicate that HTLV-II is endemic among the Tobas Indians. In this study, infection by these retroviruses in Argentinian Amerindians seems to have a marked geographic distribution.

  1. Prevalence of antibodies interactive with HTLV-I antigens in selected Solomon Islands populations.

    PubMed

    Armstrong, M Y; Hrdy, D B; Carlson, J R; Friedlaender, J S

    1990-04-01

    Serum samples obtained in 1986 from healthy individuals in three distinct Solomon Islands populations were screened for antibodies to human lymphotropic virus type I (HTLV-I). One of the populations tested lives on the remote Polynesian outlier atoll, Ontong Java. The other two groups, the Baegu and the Lau, are Melanesians living on Malaita, the most populous of the larger Solomon Islands. Eighty-eight of a total of 601 (14.6%) sera tested were repeatably reactive in an enzyme-linked immunosorbent assay (ELISA) that uses as antigen a lysate of HTLV-I viral particles. The prevalence of antibodies interactive with HTLV-I viral particles. The prevalence of antibodies interactive with HTLV-I antigens varied among the three groups, ranging from 8.5% (16/188) in the Baegu, through 13% (7/54) in the Lau, to 18.1% (65/359) among the Ontong Java population. The specificity of the screening ELISA was confirmed by protein immunoblot. No serum samples were obtained from children under 9 years of age. Although 121 of the 601 sera came from children between the ages of 9 and 19, none of these were reactive in the HTLV-I ELISA. Starting in the third decade, the prevalence of HTLV-I seropositivity increased with age, from 8.8% (10/113) between the ages of 20 and 29 to a peak of 25.9% (15/58) and 25% (15/60) in the sixth and seventh decade, respectively. This age-specific prevalence pattern is strikingly similar to that which is seen in populations where HTLV-I infection is endemic. PMID:2333936

  2. Comparison of signal-to-cutoff values in first, second, and third generation enzyme immunoassays for the diagnosis of HTLV-1/2 infection in "at-risk" individuals from São Paulo, Brazil.

    PubMed

    Jacob, Fabrício; Magri, Mariana C; Costa, Emanuela A S; Santos-Fortuna, Elizabeth; Caterino-de-Araujo, Adele

    2009-08-01

    Data obtained during routine diagnosis of human T-cell lymphotropic virus type 1 (HTLV-1) and 2 (HTLV-2) in "at-risk" individuals from São Paulo, Brazil using signal-to-cutoff (S/C) values obtained by first, second, and third generation enzyme immunoassay (EIA) kits, were compared. The highest S/C values were obtained with third generation EIA kits, but no correlation was detected between these values and specific antibody reactivity to HTLV-1, HTLV-2, or untyped HTLV (p=0.302). In addition, use of these third generation kits resulted in HTLV-1/2 false-positive samples. In contrast, first and second generation EIA kits showed high specificity, and the second generation EIA kits showed the highest efficiency, despite lower S/C values. Using first and second generation EIA kits, significant differences in specific antibody detection of HTLV-1, relative to HTLV-2 (p=0.019 for first generation and p<0.001 for second generation EIA kits) and relative to untyped HTLV (p=0.025 for first generation EIA kits), were observed. These results were explained by the composition and format of the assays. In addition, using receiver operating characteristics (ROC) analysis, a slight adjustment in cutoff values for third generation EIA kits improved their specificities and should be used when HTLV "at-risk" populations from this geographic area are to be evaluated.

  3. Risk factors for maternal HTLV-I infection in French Guiana: high HTLV-I prevalence in the Noir Marron population.

    PubMed

    Tuppin, P; Lepère, J F; Carles, G; Ureta-Vidal, A; Gérard, Y; Peneau, C; Tortevoye, P; de Thé, G; Moreau, J P; Gessain, A

    1995-04-01

    The aim of this study was to compare rates of human T-cell lymphotropic virus type I (HTLV-I) seroprevalence in pregnant women belonging to different ethnic groups in French Guiana and to determine the risk factors associated with HTLV-I seropositivity. All 1,873 deliveries between 1 July 1991 and 30 June 1993 in the only gynecologic and obstetric unit at Saint Laurent du Maroni were enrolled. Serologic status could be established for 1,727 women, with 75 (4.3%) being HTLV-I seropositive. The HTLV-I seroprevalence rate differed significantly between ethnic groups: 5.7% for Noir-Marron (70/1,302), 6.3% for Haitian (3/50), and 0% for Creole (126), Amerindians (166), and Hmong (64). In Noir-Marron pregnant women, HTLV-I seropositivity was associated with a maternal age of > 35 years [odds ratio (OR), 3.3; 95% confidence interval (CI), 1.4-7.6], prior miscarriage (OR, 1.7; CI, 1-2.8), prior cesarean section (OR, 2.1; CI, 1.1-4.0), a parity > 4 (OR, 4.0; CI, 1.8-8.8), a gravidity > 6 (OR, 4.2; CI, 2.0-7.2), and a negative Rhesus factor (OR, 2.2; CI, 1.1-4.5). Two separate stepwise logistic regressions were done because gravidity and parity were highly correlated. HTLV-I seropositivity remained associated with a gravidity > 6 (OR, 3.9; CI, 2.1-7.4) and a negative Rhesus factor (OR, 2.6; CI, 1.2-5.3) for the first model and with a parity > 4 (OR, 4.1; CI, 1.9-9.0) and a negative Rhesus factor (OR, 2.5; CI, 1.2-5.1) for the second model.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Laboratory and epidemiologic evaluation of an enzyme immunoassay for antibodies to HTLV-III

    SciTech Connect

    Ward, J.W.; Grindon, A.J.; Feorino, P.M.; Schable, C.; Parvin, M.; Allen, J.R.

    1986-07-18

    The enzyme immunoassays (EIAs) for antibody to human T-cell lymphotropic virus type III (HTLV-III) were rapidly adopted for screening donated blood and plasma. To evaluate the significance of a positive EIA reaction, test performance was examined in a blood bank screening program. Specimens were tested by EIA, Western blot assay, and HTLV-III/lymphadenopathy-associated virus (LAV) culture. The EIA was positive in 0.25% of 67 190 blood donations. Specimens were categorized and 57.3% had low (weak) reactivity, 12.7% had moderate reactivity, and 30.0% had high reactivity. Highly reactive specimens were strongly associated with a positive Western blot or culture (86.7%) in contrast to moderately and weekly reactive specimens (1.9%). Twenty-five of 29 donors interviewed with a highly reactive EIA had risk factors for HTLV-III/LAV infection. Risk factors were not identified for 74 of 75 interviewed donors with specimens of lower reactivity. The minimum calculated specificity was 99.82%. The use of the HTLV-III EIA has virtually eliminated the use of blood and plasma for HTLV-III/LAV infected donors.

  5. I-mfa domain proteins specifically interact with HTLV-1 Tax and repress its transactivating functions.

    PubMed

    Kusano, Shuichi; Yoshimitsu, Makoto; Hachiman, Miho; Ikeda, Masanori

    2015-12-01

    The I-mfa domain proteins HIC (also known as MDFIC) and I-mfa (also known as MDFI) are candidate tumor suppressor genes that are involved in cellular and viral transcriptional regulation. Here, we show that HIC and I-mfa directly interact with human T-cell leukemia virus type-1 (HTLV-1) Tax protein in vitro. In addition, HIC and I-mfa repress Tax-dependent transactivation of an HTLV-1 long terminal repeat (LTR) reporter construct in COS-1, Jurkat and high-Tax-producing HTLV-1-infected T cells. HIC also interacts with Tax through its I-mfa domain in vivo and represses Tax-dependent transactivation of HTLV-1 LTR and NF-κB reporter constructs in an interaction-dependent manner. Furthermore, we show that HIC decreases the nuclear distribution and stimulates the proteasomal degradation of Tax. These data reveal that HIC specifically interacts with HTLV-1 Tax and negatively regulates Tax transactivational activity by altering its subcellular distribution and stability.

  6. Persistent strongyloidiasis complicated by recurrent meningitis in an HTLV seropositive Peruvian migrant resettled in Italy.

    PubMed

    Zammarchi, Lorenzo; Montagnani, Francesca; Tordini, Giacinta; Gotuzzo, Eduardo; Bisoffi, Zeno; Bartoloni, Alessandro; De Luca, Andrea

    2015-06-01

    We describe a case of persistent strongyloidiasis complicated by recurrent meningitis, in a human T cell lymphotropic virus type 1 (HTLV-1) seropositive Peruvian migrant adult resettled in Italy. He was admitted with signs and symptoms of acute bacterial meningitis, reporting four other meningitis episodes in the past 6 years, with an etiological diagnosis of Escherichia coli and Enterococcus faecium in two cases. He had been previously treated with several antihelmintic regimens not including ivermectin, without eradication of strongyloidiasis, and he had never been tested for HTLV before. During the described episode, the patient was treated for meningitis with broad-spectrum antibiotic therapy and 200 μg/kg/dose oral ivermectin once daily on day 1, 2, 15 and 16 with full recovery and no further episodes of meningitis. The presented case underlines several critical points concerning the management of poorly known neglected diseases such as strongyloidiasis and HTLV infection in low-endemic areas. Despite several admissions for meningitis and strongyloidiasis, the parasitic infection was not adequately treated and the patient was not previously tested for HTLV. The supply of ivermectin and the choice of treatment scheme was challenging since ivermectin is not approved in Italy and there are no standardized guidelines for the treatment of severe strongyloidiasis in HTLV seropositive subjects.

  7. HTLV-1-associated arthropathy treated with anti-TNF-alpha agent.

    PubMed

    Frenzel, Laurent; Moura, Bertrand; Marcais, Ambroise; Chapdelaine, Hugo; Hermine, Olivier

    2014-07-01

    Human T cell leukemia virus type 1 or HTLV-1 infection is a public health problem in endemic regions like Japan, Central America or Africa. Although the majority of HTLV-1 carriers remain asymptomatic throughout their lives, some patients could develop neurological disorder, inflammatory arthropathy also called HTLV-1-associated arthropathy or T-cell malignancy, the adult T-cell leukemia/lymphoma or ATL with a very poor prognosis. Described to be very close to rheumatoid arthritis, HTLV-1-associated arthropathy patients have few or no response to the first line therapy with corticosteroids and disease modifying antirheumatic drugs or DMARDs. The use of anti-TNF-α agents in these patients is an interesting alternative but asks the question of risk of developing an adult T-Cell leukemia/lymphoma. We reported an exceptional case of a smoldering ATL patient with an HTLV-1-associated arthropathy, refractory to corticosteroid, DMARDs and rituximab therapy, treated successfully with etanercept, without progression to aggressive ATL after 5 years.

  8. Persistent Strongyloidiasis Complicated by Recurrent Meningitis in an HTLV Seropositive Peruvian Migrant Resettled in Italy

    PubMed Central

    Zammarchi, Lorenzo; Montagnani, Francesca; Tordini, Giacinta; Gotuzzo, Eduardo; Bisoffi, Zeno; Bartoloni, Alessandro; De Luca, Andrea

    2015-01-01

    We describe a case of persistent strongyloidiasis complicated by recurrent meningitis, in a human T cell lymphotropic virus type 1 (HTLV-1) seropositive Peruvian migrant adult resettled in Italy. He was admitted with signs and symptoms of acute bacterial meningitis, reporting four other meningitis episodes in the past 6 years, with an etiological diagnosis of Escherichia coli and Enterococcus faecium in two cases. He had been previously treated with several antihelmintic regimens not including ivermectin, without eradication of strongyloidiasis, and he had never been tested for HTLV before. During the described episode, the patient was treated for meningitis with broad-spectrum antibiotic therapy and 200 μg/kg/dose oral ivermectin once daily on day 1, 2, 15 and 16 with full recovery and no further episodes of meningitis. The presented case underlines several critical points concerning the management of poorly known neglected diseases such as strongyloidiasis and HTLV infection in low-endemic areas. Despite several admissions for meningitis and strongyloidiasis, the parasitic infection was not adequately treated and the patient was not previously tested for HTLV. The supply of ivermectin and the choice of treatment scheme was challenging since ivermectin is not approved in Italy and there are no standardized guidelines for the treatment of severe strongyloidiasis in HTLV seropositive subjects. PMID:25846292

  9. HTLV-1 Rex: the courier of viral messages making use of the host vehicle.

    PubMed

    Nakano, Kazumi; Watanabe, Toshiki

    2012-01-01

    The human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus causing an aggressive T-cell malignancy, adult T-cell leukemia (ATL). Although HTLV-1 has a compact RNA genome, it has evolved elaborate mechanisms to maximize its coding potential. The structural proteins Gag, Pro, and Pol are encoded in the unspliced form of viral mRNA, whereas the Env protein is encoded in singly spliced viral mRNA. Regulatory and accessory proteins, such as Tax, Rex, p30II, p12, and p13, are translated only from fully spliced mRNA. For effective viral replication, translation from all forms of HTLV-1 transcripts has to be achieved in concert, although unspliced mRNA are extremely unstable in mammalian cells. It has been well recognized that HTLV-1 Rex enhances the stability of unspliced and singly spliced HTLV-1 mRNA by promoting nuclear export and thereby removing them from the splicing site. Rex specifically binds to the highly structured Rex responsive element (RxRE) located at the 3' end of all HTLV-1 mRNA. Rex then binds to the cellular nuclear exporter, CRM1, via its nuclear export signal domain and the Rex-viral transcript complex is selectively exported from the nucleus to the cytoplasm for effective translation of the viral proteins. Yet, the mechanisms by which Rex inhibits the cellular splicing machinery and utilizes the cellular pathways beneficial to viral survival in the host cell have not been fully explored. Furthermore, physiological impacts of Rex against homeostasis of the host cell via interactions with numerous cellular proteins have been largely left uninvestigated. In this review, we focus on the biological importance of HTLV-1 Rex in the HTLV-1 life cycle by following the historical path in the literature concerning this viral post-transcriptional regulator from its discovery to this day. In addition, for future studies, we discuss recently discovered aspects of HTLV-1 Rex as a post-transcriptional regulator and its use in host cellular pathways.

  10. Mother-to-Child Transmission of HTLV-1 Epidemiological Aspects, Mechanisms and Determinants of Mother-to-Child Transmission

    PubMed Central

    Percher, Florent; Jeannin, Patricia; Martin-Latil, Sandra; Gessain, Antoine; Afonso, Philippe V.; Vidy-Roche, Aurore; Ceccaldi, Pierre-Emmanuel

    2016-01-01

    Human T-cell Lymphotropic Virus type 1 (HTLV-1) is a human retrovirus that infects at least 5–10 million people worldwide, and is the etiological agent of a lymphoproliferative malignancy; Adult T-cell Leukemia/Lymphoma (ATLL); and a chronic neuromyelopathy, HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), as well as other inflammatory diseases such as infective dermatitis and uveitis. Besides sexual intercourse and intravenous transmission, HTLV-1 can also be transmitted from infected mother to child during prolonged breastfeeding. Some characteristics that are linked to mother-to-child transmission (MTCT) of HTLV-1, such as the role of proviral load, antibody titer of the infected mother, and duration of breastfeeding, have been elucidated; however, most of the mechanisms underlying HTLV-1 transmission during breast feeding remain largely unknown, such as the sites of infection and cellular targets as well as the role of milk factors. The present review focuses on the latest findings and current opinions and perspectives on MTCT of HTLV-1. PMID:26848683

  11. Regulation of the tumor marker Fascin by the viral oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) depends on promoter activation and on a promoter-independent mechanism.

    PubMed

    Mohr, Caroline F; Gross, Christine; Bros, Matthias; Reske-Kunz, Angelika B; Biesinger, Brigitte; Thoma-Kress, Andrea K

    2015-11-01

    Adult T-cell leukemia/lymphoma is a highly infiltrative neoplasia of CD4(+) T-lymphocytes that occurs in about 5% of carriers infected with the deltaretrovirus human T-cell leukemia virus type 1 (HTLV-1). The viral oncoprotein Tax perturbs cellular signaling pathways leading to upregulation of host cell factors, amongst them the actin-bundling protein Fascin, an invasion marker of several types of cancer. However, transcriptional regulation of Fascin by Tax is poorly understood. In this study, we identified a triple mode of transcriptional induction of Fascin by Tax, which requires (1) NF-κB-dependent promoter activation, (2) a Tax-responsive region in the Fascin promoter, and (3) a promoter-independent mechanism sensitive to the Src family kinase inhibitor PP2. Thus, Tax regulates Fascin by a multitude of signals. Beyond, using Tax-expressing and virus-transformed lymphocytes as a model system, our study is the first to identify the invasion marker Fascin as a novel target of PP2, an inhibitor of metastasis.

  12. Cellular transformation by the HTLV-I Tax protein, a jack-of-all-trades.

    PubMed

    Gatza, Michael L; Watt, Julie C; Marriott, Susan J

    2003-08-11

    The human T-cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus that is responsible for adult T-cell leukemia and a neurological disease, HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-I encodes an oncogenic protein, Tax, which affects a variety of cellular functions prompting it to be referred to as a jack-of-all trades. The ability of Tax to both transcriptionally regulate cellular gene expression and to functionally inactivate proteins involved in cell-cycle progression and DNA repair provide the basis for Tax-mediated transformation and leukemogenesis. This review will concentrate on the effects of Tax on the dysregulation of the G(1)/S and G(2)/M checkpoints as well as the suppression of DNA damage repair leading to cellular transformation. PMID:12910251

  13. Neuropsychological assessment in HTLV-1 infection: a comparative study among TSP/HAM, asymptomatic carriers, and healthy controls

    PubMed Central

    Silva, M; Mattos, P; Alfano, A; Araujo, A

    2003-01-01

    Background: Human T cell lymphotropic virus type 1 (HTLV-I) can cause tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) and adult T cell leukaemia/lymphoma. More recently other diseases such as isolated peripheral polyneuropathy, myopathy, artropathy, and uveitis have been associated with this retrovirus. Only a few uncontrolled studies, without necessary exclusion criteria, have described mild cognitive deficits among TSP/HAM patients. To further clarify this the authors evaluated, through neuropsychological testing patients with TSP/HAM and asymptomatic infected carriers, comparing both groups with healthy controls. Objectives: To verify the presence of cognitive deficits among TSP/HAM patients and asymptomatic HTLV-1 infected carriers. In addition, the authors aimed to investigate if these deficits correlated with the degree of motor impairment in TSP/HAM patients. Methods: From a cohort of 501 HTLV-1 infected people the authors selected, according to predefined inclusion and exclusion criteria, 40 asymptomatic HTLV-1 carriers and 37 TSP/HAM patients. Neuropsychological testing was blindly performed in both groups and their scores were compared with those obtained from controls. Results: Both the HTLV-1 carrier group and the group of patients with TSP/HAM exhibited a lower performance in neuropsychological tests when compared with controls. Asymptomatic infected carriers and TSP/HAM patients did not differ in their cognitive results. Also, there was no relation between the degree of motor disability and cognitive deficits in the TSP/HAM group. Psychomotor slowing and deficits in the some domains characterised the neuropsychological impairment in HTLV-1 infection: verbal and visual memory, attention and visuomotor abilities. Conclusions: TSP/HAM as well as asymptomatic infection can be associated with mild cognitive deficits. This finding, if confirmed by further studies, will permit the inclusion of cognitive impairment among the neurological

  14. Tax contributes apoptosis resistance to HTLV-1-infected T cells via suppression of Bid and Bim expression.

    PubMed

    Mühleisen, A; Giaisi, M; Köhler, R; Krammer, P H; Li-Weber, M

    2014-12-18

    The human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). HTLV-1 Tax has been shown to have a prosurvival role in infected T cells by enhancing expression of the Bcl-2 family of antiapoptotic proteins. In this study, we show that the expression of proapoptotic BH3-only proteins Bim (Bcl-2-interacting mediator of cell death) and Bid (BH3-interacting domain death agonist) is diminished in HTLV-1-infected leukemic cells. Using a Tax-inducible system and a transient overexpression approach, we demonstrate that Tax downregulates Bid and Bim expression at the transcriptional level. We show that reinforced expression of Bim and Bid in HTLV-1-infected T-cell lines sensitizes CD95/TRAIL- and anticancer drug-induced apoptosis. Furthermore, we show that Tax suppresses Bid and Bim expression by enhancing hypoxia-inducible factor-1α (HIF-1α) protein expression. siRNA knockdown of HIF-1α or chemical inhibition of the transactivation activity of HIF-1α resulted in an increase in Bid and Bim expression and, consequently, in an increase in CD95/TRAIL- and anticancer drug-induced apoptosis in HTLV-1-infected leukemic T-cell lines. Our study provides evidence that besides upregulation of prosurvival Bcl-2 proteins, Tax may also confer apoptosis resistance to HTLV-1-infected T cells by suppressing the expression of the proapoptotic BH3-only proteins Bim and Bid.

  15. Peridinin, a carotenoid, inhibits proliferation and survival of HTLV-1-infected T-cell lines.

    PubMed

    Ishikawa, Chie; Jomori, Takahiro; Tanaka, Junichi; Senba, Masachika; Mori, Naoki

    2016-10-01

    Human T-cell leukemia virus type 1 (HTLV-1) causes either adult T-cell leukemia (ATL) or chronic inflammatory disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis. These diseases are not curable as yet; therefore new agents for treatment and prevention are needed. Carotenoids are natural plant compounds with anti-carcinogenic activities. Peridinin is one of the most abundant carotenoids found in nature. Based on a series of past experiments, here we investigated the effects of peridinin extracted from Okinawan coral Isis hippuris on the proliferation and survival of HTLV-1-infected T-cell lines. The results of water-soluble tetrazolium-8 assay indicated that peridinin dose-dependently inhibits cell proliferation and viability of HTLV-1-infected T-cell lines. Flow cytometry showed that low concentration of peridinin induced cell cycle arrest at G1 phase, while higher concentration induced apoptosis. Peridinin caused cleavage of caspase-3, -8 and -9. Peridinin significantly reduced the expression of G1 cell cycle regulators, including cyclin D1, cyclin D2, CDK4, CDK6 and c-Myc, and anti-apoptotic proteins, including survivin, XIAP and Bcl-2, in a dose-dependent manner. Peridinin suppressed DNA binding of NF-κB. Peridinin inhibited phosphorylation of IκBα, RelA, Akt and p70 S6 kinase, and reduced protein expression level of 3-phosphoinositide-dependent protein kinase 1. Thus, peridinin exerts its anti-proliferative and pro-apoptotic effects by suppressing NF-κB and Akt signaling in HTLV-1-infected T cells. Peridinin also reduced tumor growth in mice harboring ATL xenograft tumors. The results suggested that peridinin is a potentially suitable therapeutic agent against HTLV-1-associated diseases.

  16. Peridinin, a carotenoid, inhibits proliferation and survival of HTLV-1-infected T-cell lines.

    PubMed

    Ishikawa, Chie; Jomori, Takahiro; Tanaka, Junichi; Senba, Masachika; Mori, Naoki

    2016-10-01

    Human T-cell leukemia virus type 1 (HTLV-1) causes either adult T-cell leukemia (ATL) or chronic inflammatory disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis. These diseases are not curable as yet; therefore new agents for treatment and prevention are needed. Carotenoids are natural plant compounds with anti-carcinogenic activities. Peridinin is one of the most abundant carotenoids found in nature. Based on a series of past experiments, here we investigated the effects of peridinin extracted from Okinawan coral Isis hippuris on the proliferation and survival of HTLV-1-infected T-cell lines. The results of water-soluble tetrazolium-8 assay indicated that peridinin dose-dependently inhibits cell proliferation and viability of HTLV-1-infected T-cell lines. Flow cytometry showed that low concentration of peridinin induced cell cycle arrest at G1 phase, while higher concentration induced apoptosis. Peridinin caused cleavage of caspase-3, -8 and -9. Peridinin significantly reduced the expression of G1 cell cycle regulators, including cyclin D1, cyclin D2, CDK4, CDK6 and c-Myc, and anti-apoptotic proteins, including survivin, XIAP and Bcl-2, in a dose-dependent manner. Peridinin suppressed DNA binding of NF-κB. Peridinin inhibited phosphorylation of IκBα, RelA, Akt and p70 S6 kinase, and reduced protein expression level of 3-phosphoinositide-dependent protein kinase 1. Thus, peridinin exerts its anti-proliferative and pro-apoptotic effects by suppressing NF-κB and Akt signaling in HTLV-1-infected T cells. Peridinin also reduced tumor growth in mice harboring ATL xenograft tumors. The results suggested that peridinin is a potentially suitable therapeutic agent against HTLV-1-associated diseases. PMID:27499015

  17. Characteristic distribution of HTLV type I and HTLV type II carriers among native ethnic groups in South America.

    PubMed

    Fujiyoshi, T; Li, H C; Lou, H; Yashiki, S; Karino, S; Zaninovic, V; Oneegllo, S G; Camacho, M; Andrade, R; Hurtado, L V; Gomez, L H; Damiani, E; Cartier, L; Dipierri, J E; Hayami, M; Sonoda, S; Tajima, K

    1999-09-20

    To confirm the geographic and ethnic segregation of HTLV-I and HTLV-II carriers in native populations in South America, we have conducted a seroepidemiological study of native populations in South America, including HTLV-I carriers distributed among seven ethnic groups in the Andes highlands of Colombia, Peru, Bolivia, Argentina, and Chile, and two ethnic groups on Chiloe Island and Easter Island; and HTLV-II carriers distributed among seven ethnic groups of the lowlands along the Atlantic coast of Colombia, Orinoco, Amazon, and Patagonia, and one ethnic group on Chiloe Island. The incidence rate of HTLV-I and HTLV-II carriers varied among the ethnic groups, ranging from 0.8 to 6.8% for HTLV-I seropositivity and from 1.4 to 57.9% for HTLV-II seropositivity. A new HTLV-I focus was found among the Peruvian Aymara (1.6%), the Bolivian Aymara (5.3%) and Quechua (4.5%), the Argentine Puna (2.3%), and the Chilean Atacama (4.1%), while on HTLV-II focus was found among the Brazilian Kayapo (57.9%), the Paraguayan Chaco (16.4%), and the Chilean Alacalf (34.8%) and Yahgan (9.1%). The distribution of HTLV-I/II foci showed a geographic clustering of HTLV-I foci in the Andes highlands and of HTLV-II foci in the lowlands of South America. It was thus suggested that South American natives might be divided into two major ethnic groups by HTLV-I and HTLV-II carrier state.

  18. Genetic Markers of the Host in Persons Living with HTLV-1, HIV and HCV Infections

    PubMed Central

    Assone, Tatiane; Paiva, Arthur; Fonseca, Luiz Augusto M.; Casseb, Jorge

    2016-01-01

    Human T-cell leukemia virus type 1 (HTLV-1), hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) are prevalent worldwide, and share similar means of transmission. These infections may influence each other in evolution and outcome, including cancer or immunodeficiency. Many studies have reported the influence of genetic markers on the host immune response against different persistent viral infections, such as HTLV-1 infection, pointing to the importance of the individual genetic background on their outcomes. However, despite recent advances on the knowledge of the pathogenesis of HTLV-1 infection, gaps in the understanding of the role of the individual genetic background on the progress to disease clinically manifested still remain. In this scenario, much less is known regarding the influence of genetic factors in the context of dual or triple infections or their influence on the underlying mechanisms that lead to outcomes that differ from those observed in monoinfection. This review describes the main factors involved in the virus–host balance, especially for some particular human leukocyte antigen (HLA) haplotypes, and other important genetic markers in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other persistent viruses, such as HIV and HCV. PMID:26848682

  19. Evidence for HTLV-III infection in prostitutes in Tamil Nadu (India).

    PubMed

    Simoes, E A; Babu, P G; John, T J; Nirmala, S; Solomon, S; Lakshminarayana, C S; Quinn, T C

    1987-04-01

    Blood samples were collected from 102 female prostitutes housed in a custodial care institution in Tamil Nadu, India, to determine the presence of antibodies to human T-lymphotropic virus type III (HTLV-III). Both social and sexual histories were taken from 101 of the 102 women. Commercial test kits were used to test sera for antibody to HTLV-III. Reactive sera were tested for a 2nd time by the enzyme-linked immunoabsorbent assay (ELISA). Those repeatedly reactive sera were transported to the US, the National Institutes of Health, for western blot analysis. The sera from 11 of the study subjects were found to be repeatedly reactive in ELISA, and 10 were confirmed to have specific antibody to the virus by western blot analysis. Both infected and uninfected women were similar in age and of low socioeconomic status. The risk ratio for HTLV-III antibody was 8.2 in those women who had had sexual exposure to foreigners. None of the women were intravenous drug abusers, and all denied oral or rectal intercourse. On the basis of the stringent criteria used in the western blot analysis, it is believed that the 10 women have HTLV-III antibody. This emerges as the 1st report of evidence for HTLV-III infection in India. 10-40% of prostitutes in North America and Europe have HTLV-III antibody; the risk factors for infection appear to be intravenous drug use and penis-rectal intercourse. 54-88% of prostitutes in Central Africa have HTLV-III antibody, and the frequency of sexual contact with different partners is more important here as a risk-factor than the type of intercourse. As the prostitutes in this study in Indian did not use intravenous drugs and did not practice penis-rectal or penis-oral intercourse and had been prostitutes for shorter periods of time than the noninfected women and had fewer contacts, it is believed that HTLV-III infection has been introduced only recently into prostitutes in India. Sexual exposure to foreigners was a significant factor in the infected

  20. Immune Compromise in HIV-1/HTLV-1 Coinfection With Paradoxical Resolution of CD4 Lymphocytosis During Antiretroviral Therapy: A Case Report.

    PubMed

    Rockwood, N; Cook, L; Kagdi, H; Basnayake, S; Bangham, C R M; Pozniak, A L; Taylor, G P

    2015-12-01

    Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity. We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism. Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control. This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity.

  1. Immune Compromise in HIV-1/HTLV-1 Coinfection With Paradoxical Resolution of CD4 Lymphocytosis During Antiretroviral Therapy: A Case Report.

    PubMed

    Rockwood, N; Cook, L; Kagdi, H; Basnayake, S; Bangham, C R M; Pozniak, A L; Taylor, G P

    2015-12-01

    Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity. We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism. Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control. This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity. PMID:26683952

  2. Human T-cell leukemia virus types I and II exhibit different DNase I protection patterns.

    PubMed

    Altman, R; Harrich, D; Garcia, J A; Gaynor, R B

    1988-04-01

    Human T-cell leukemia virus types I (HTLV-I) and II (HTLV-II) are human retroviruses which normally infect T-lymphoid cells. HTLV-I infection is associated with adult T-cell leukemia-lymphoma, and HTLV-II is associated with an indolent form of hairy-cell leukemia. To identify potential transcriptional regulatory elements of these two related human retroviruses, we performed DNase I footprinting of both the HTLV-I and HTLV-II long terminal repeats (LTRs) by using extracts prepared from uninfected T cells, HTLV-I and HTLV-II transformed T cells, and HeLa cells. Five regions of the HTLV-I LTR and three regions of the HTLV-II LTR showed protection by DNase I footprinting. All three of the 21-base-pair repeats previously shown to be important in HTLV transcriptional regulation were protected in the HTLV-I LTR, whereas only one of these repeats was protected in the HTLV-II LTR. Several regions exhibited altered protection in extracts prepared from lymphoid cells as compared with HeLa cells, but there were minimal differences in the protection patterns between HTLV-infected and uninfected lymphoid extracts. A number of HTLV-I and HTLV-II LTR fragments which contained regions showing protection in DNase I footprinting were able to function as inducible enhancer elements in transient CAT gene expression assays in the presence of the HTLV-II tat protein. The alterations in the pattern of the cellular proteins which bind to the HTLV-I and HTLV-II LTRs may in part be responsible for differences in the transcriptional regulation of these two related viruses.

  3. The transcription elongation factor ELL2 is specifically upregulated in HTLV-1-infected T-cells and is dependent on the viral oncoprotein Tax

    SciTech Connect

    Mann, Melanie C. Strobel, Sarah Fleckenstein, Bernhard Kress, Andrea K.

    2014-09-15

    The oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation. - Highlights: • ELL2, a transcription elongation factor, is upregulated in HTLV-1-positive T-cells. • Tax transactivates the ELL2 promoter. • Tax and ELL2 synergistically activate the HTLV-1 promoter. • Tax and ELL2 interact in vivo.

  4. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ

    PubMed Central

    Giam, Chou-Zen; Semmes, Oliver John

    2016-01-01

    HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10–20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%–5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling—the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)—to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided. PMID:27322308

  5. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ.

    PubMed

    Giam, Chou-Zen; Semmes, Oliver John

    2016-01-01

    HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10-20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%-5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling-the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)-to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided. PMID:27322308

  6. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ.

    PubMed

    Giam, Chou-Zen; Semmes, Oliver John

    2016-06-16

    HTLV-1 (Human T-cell lymphotropic virus type 1) is a complex human delta retrovirus that currently infects 10-20 million people worldwide. While HTLV-1 infection is generally asymptomatic, 3%-5% of infected individuals develop a highly malignant and intractable T-cell neoplasm known as adult T-cell leukemia/lymphoma (ATL) decades after infection. How HTLV-1 infection progresses to ATL is not well understood. Two viral regulatory proteins, Tax and HTLV-1 basic zipper protein (HBZ), encoded by the sense and antisense viral transcripts, respectively, are thought to play indispensable roles in the oncogenic process of ATL. This review focuses on the roles of Tax and HBZ in viral replication, persistence, and oncogenesis. Special emphasis is directed towards recent literature on the mechanisms of action of these two proteins and the roles of Tax and HBZ in influencing the outcomes of HTLV-1 infection including senescence induction, viral latency and persistence, genome instability, cell proliferation, and ATL development. Attempts are made to integrate results from cell-based studies of HTLV-1 infection and studies of HTLV-1 proviral integration site preference, clonality, and clonal expansion based on high throughput DNA sequencing. Recent data showing that Tax hijacks key mediators of DNA double-strand break repair signaling-the ubiquitin E3 ligase, ring finger protein 8 (RNF8) and the ubiquitin E2 conjugating enzyme (UBC13)-to activate the canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and other signaling pathways will be discussed. A perspective on how the Tax-RNF8 signaling axis might impact genomic instability and how Tax may collaborate with HBZ to drive oncogenesis is provided.

  7. Biology and treatment of HTLV-1 associated T-cell lymphomas.

    PubMed

    Tsukasaki, Kunihiro; Tobinai, Kensei

    2013-03-01

    Adult T-cell leukemia-lymphoma (ATL) is a distinct peripheral T-lymphocytic malignancy associated with human T-cell lymphotropic virus type I (HTLV-1) endemics in several regions of the world including the south-west Japan. The three major routes of HTLV-1 transmission are mother-to-child infections via breast milk, sexual intercourse, and blood transfusions. A HTLV-1 infection early in life, presumably from breast feeding, is crucial to the development of ATL. The estimated cumulative risk of developing ATL among HTLV-1-positive individuals is about 3% after transmission from the mother. The diversity in clinical features and prognosis of patients with this disease has led to its subtype-classification into acute, lymphoma, chronic, and smoldering types defined by organ involvement, lactate dehydrogenase (LDH) and calcium values. For the acute, lymphoma and unfavorable chronic subtypes (aggressive ATL), and the favorable chronic and smoldering subtypes (indolent ATL), intensive chemotherapy followed by allogeneic stem cell transplantation and watchful waiting until disease progression has been recommended, respectively, in Japan. A retrospective analysis suggested that the combination of interferon alpha and zidovudine was promising for the treatment of ATL, especially for leukemic subtypes. There are several new trials for ATL, including a defucosylated humanized anti-CC chemokine receptor 4 monoclonal antibody, histone deacetylase inhibitors, a purine nucleoside phosphorylase inhibitor, a proteasome inhibitor and lenalidomide. PMID:23768636

  8. A seroepidemiological survey of HTLV-I/II carriers in the Puna Jujeña.

    PubMed

    Dipierri, J E; Tajima, K; Cartier Robirosa, L; Sonoda, S

    1999-01-01

    Human T-cell leukemia virus type I (HTLV-I) carriers are clustered in limited groups in the world. One of these groups is the Andean native population of South America. As part of an international collaborative study devoted to explore the clustering of HTVL-I carriers in different countries, the aim of this paper was to evaluate the seroprevalence of HTLV-I/II virus in the native population of Puna Argentina in Jujuy. Blood samples of individuals of three populations of Puna Jujeña (Susques, Rinconada, Cochinoca) were screened with particle agglutination (PA), immunofluorescence (IF) and western immunoblotting analysis (WB) tests. Two out 86 (2.32%) individuals examined in the Puna Jujeña showed positive results for HTLV-I antibodies. It is concluded that the Province of Jujuy, in particular its less miscegenated highest altitude areas, constitute the northern and southern Andean natural geographical clustering of HTLV-I. This distribution is probably linked both to a history of prehistoric human dispersal in the Andes and to high mother- to-child transmission of the virus under close conditions of each group.

  9. Bcl-3, induced by Tax and HTLV-1, inhibits NF-κB activation and promotes autophagy.

    PubMed

    Wang, Jinheng; Niu, Zhiguo; Shi, Ying; Gao, Cai; Wang, Xia; Han, Jingxian; Li, Junying; Gao, Zhitao; Zhu, Xiaofei; Song, Xiangfeng; Qin, Zhihai; Wang, Hui

    2013-12-01

    The human T cell leukemia virus type 1 (HTLV-1) is a complex human retrovirus that causes an aggressive leukemia known as adult T cell leukemia (ATL). The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway, which is perceived as the primary cause of ATL. Bcl-3, a member of the NF-κB inhibitor (IκB) family, is highly expressed in many HTLV-1-infected T cell lines and ATL cells. However, the role of Bcl-3 in Tax-induced NF-κB activation has not been fully elucidated. Here, we show that Tax induces Bcl-3 expression, which in turn negatively regulates the Tax-induced NF-κB activation. Interestingly, both Bcl-3 up-regulation and NF-κB inhibition promote the autophagy process in HTLV-1-infected cells. Consistent with this, over-expression of Bcl-3 also results in enhancement of rapamycin-, pifithrin-α- or starvation-induced autophagy in control cells. Together, these data demonstrate that Bcl-3 acts as a negative regulator of NF-κB activation and promotes autophagy in HTLV-1-infected cells.

  10. A tax on luxury: HTLV-I infection of CD4+CD25+ Tregs.

    PubMed

    Fujinami, Robert S

    2005-05-01

    Almost a quarter of a century ago, Oldstone and colleagues proposed that infection of cells by noncytopathic viruses may lead to an alteration of the cells' ability to produce certain products or perform certain tasks, i.e., inhibition of "luxury function." In this issue of the JCI, this topic has been revisited by Yamano et al., who demonstrate that human T cell lymphotropic virus type I (HTLV-I) infection of CD4(+)CD25(+) Tregs in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) results in a decrease in FOXP3 mRNA and protein expression. This leads to the inability of HTLV-I-infected CD4(+)CD25(+) Tregs to inhibit the proliferation of CD4(+)CD25(-) Tregs, due to the effect of the HTLV-I tax gene. Defects in the Treg population could be responsible for the large numbers of virus-specific T cells and occurrence of lymphoproliferation and inflammatory autoimmune disease in HAM/TSP patients.

  11. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells.

    PubMed

    Swaims, Alison Y; Khani, Francesca; Zhang, Yingyu; Roberts, Arthur I; Devadas, Satish; Shi, Yufang; Rabson, Arnold B

    2010-10-21

    Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4(+) T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4(+)CD25(+)CD3(-) phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4(+) T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax(+), CD4(+) lymphocytes. We suggest that immune activation of infected CD4(+) T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals. PMID:20634377

  12. HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains.

    PubMed

    Ren, T; Takahashi, Y; Liu, X; Loughran, T P; Sun, S-C; Wang, H-G; Cheng, H

    2015-01-15

    The retroviral oncoprotein Tax from human T-cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T-cell leukemia and lymphoma, has a crucial role in initiating T-lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating inhibitor of κB (IκB) kinase (IKK) complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IKK complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells.

  13. TCF1 and LEF1 act as T-cell intrinsic HTLV-1 antagonists by targeting Tax.

    PubMed

    Ma, Guangyong; Yasunaga, Jun-ichirou; Akari, Hirofumi; Matsuoka, Masao

    2015-02-17

    Human T-cell leukemia virus type 1 (HTLV-1) is a delta-type retrovirus that induces malignant and inflammatory diseases during its long persistence in vivo. HTLV-1 can infect various kinds of cells; however, HTLV-1 provirus is predominantly found in peripheral CD4 T cells in vivo. Here we find that TCF1 and LEF1, two Wnt transcription factors that are specifically expressed in T cells, inhibit viral replication through antagonizing Tax functions. TCF1 and LEF1 can each interact with Tax and inhibit Tax-dependent viral expression and activation of NF-κB and AP-1. As a result, HTLV-1 replication is suppressed in the presence of either TCF1 or LEF1. On the other hand, T-cell activation suppresses the expression of both TCF1 and LEF1, and this suppression enables Tax to function as an activator. We analyzed the thymus of a simian T-cell leukemia virus type 1 (STLV-1) infected Japanese macaque, and found a negative correlation between proviral load and TCF1/LEF1 expression in various T-cell subsets, supporting the idea that TCF1 and LEF1 negatively regulate HTLV-1 replication and the proliferation of infected cells. Thus, this study identified TCF1 and LEF1 as Tax antagonistic factors in vivo, a fact which may critically influence the peripheral T-cell tropism of this virus.

  14. Development of T cell lymphoma in HTLV-1 bZIP factor and Tax double transgenic mice.

    PubMed

    Zhao, Tiejun; Satou, Yorifumi; Matsuoka, Masao

    2014-07-01

    Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL cells possess a CD4+ CD25+ phenotype, similar to that of regulatory T cells (Tregs). Tax has been reported to play a crucial role in the leukemogenesis of HTLV-1. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the viral genomic RNA, is expressed in all ATL cases and induces neoplastic and inflammatory disease in vivo. To test whether HBZ and Tax are both required for T cell malignancy, we generated HBZ/Tax double transgenic mice in which HBZ and Tax are expressed exclusively in CD4+ T cells. Survival was much reduced in HBZ/Tax double-transgenic mice compared with wild type littermates. Transgenic expression of HBZ and Tax induced skin lesions and T-cell lymphoma in mice, resembling diseases observed in HTLV-1 infected individuals. However, Tax single transgenic mice did not develop major health problems. In addition, memory CD4+ T cells and Foxp3+ Treg cells counts were increased in HBZ/Tax double transgenic mice, and their proliferation was enhanced. There was very little difference between HBZ single and HBZ/Tax double transgenic mice. Taken together, these results show that HBZ, in addition to Tax, plays a critical role in T-cell lymphoma arising from HTLV-1 infection.

  15. Localization and Sub-Cellular Shuttling of HTLV-1 Tax with the miRNA Machinery

    PubMed Central

    Van Duyne, Rachel; Guendel, Irene; Klase, Zachary; Narayanan, Aarthi; Coley, William; Jaworski, Elizabeth; Roman, Jessica; Popratiloff, Anastas; Mahieux, Renaud; Kehn-Hall, Kylene; Kashanchi, Fatah

    2012-01-01

    The innate ability of the human cell to silence endogenous retroviruses through RNA sequences encoding microRNAs, suggests that the cellular RNAi machinery is a major means by which the host mounts a defense response against present day retroviruses. Indeed, cellular miRNAs target and hybridize to specific sequences of both HTLV-1 and HIV-1 viral transcripts. However, much like the variety of host immune responses to retroviral infection, the virus itself contains mechanisms that assist in the evasion of viral inhibition through control of the cellular RNAi pathway. Retroviruses can hijack both the enzymatic and catalytic components of the RNAi pathway, in some cases to produce novel viral miRNAs that can either assist in active viral infection or promote a latent state. Here, we show that HTLV-1 Tax contributes to the dysregulation of the RNAi pathway by altering the expression of key components of this pathway. A survey of uninfected and HTLV-1 infected cells revealed that Drosha protein is present at lower levels in all HTLV-1 infected cell lines and in infected primary cells, while other components such as DGCR8 were not dramatically altered. We show colocalization of Tax and Drosha in the nucleus in vitro as well as coimmunoprecipitation in the presence of proteasome inhibitors, indicating that Tax interacts with Drosha and may target it to specific areas of the cell, namely, the proteasome. In the presence of Tax we observed a prevention of primary miRNA cleavage by Drosha. Finally, the changes in cellular miRNA expression in HTLV-1 infected cells can be mimicked by the add back of Drosha or the addition of antagomiRs against the cellular miRNAs which are downregulated by the virus. PMID:22808228

  16. Infective Dermatitis in an Adult Patient With HTLV-1

    PubMed Central

    Riveros, Rosalba; Medina, Raquel; Morel, Maida

    2015-01-01

    Abstract: Infective dermatitis is a chronic exudative eczematous eruption presenting in human T-lymphotropic virus type 1 (HTLV-1)–infected people. It presents with relapsing erythematous, scaly, and crusted lesions affecting simultaneously the scalp, external ear, retroauricular area, eyelid, paranasal skin, neck axilla, and groin. Superimposed Staphylococcus and Streptococcus infection are common. It mainly affects children and exceptionally adults, and there are only a few published cases. The authors present the first reported case in Paraguay of an adult patient who had symptoms of human T-lymphotropic virus type 1–associated progressive tropical spastic paraparesis, and 6 years after the onset of the neurological symptoms, the patient developed infective dermatitis lesions on the skin, with frequent exacerbations since then. PMID:26588341

  17. A critical role for IL-17RB signaling in HTLV-1 tax-induced NF-κB activation and T-cell transformation.

    PubMed

    Lavorgna, Alfonso; Matsuoka, Masao; Harhaj, Edward William

    2014-10-01

    Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia (ATL) and the neuroinflammatory disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein functions as a potent viral oncogene that constitutively activates the NF-κB transcription factor to transform T cells; however, the underlying mechanisms remain obscure. Here, using next-generation RNA sequencing we identified the IL-25 receptor subunit IL-17RB as an aberrantly overexpressed gene in HTLV-1 immortalized T cells. Tax induced the expression of IL-17RB in an IκB kinase (IKK) and NF-κB-dependent manner. Remarkably, Tax activation of the canonical NF-κB pathway in T cells was critically dependent on IL-17RB expression. IL-17RB and IL-25 were required for HTLV-1-induced immortalization of primary T cells, and the constitutive NF-κB activation and survival of HTLV-1 transformed T cells. IL-9 was identified as an important downstream target gene of the IL-17RB pathway that drives the proliferation of HTLV-1 transformed cells. Furthermore, IL-17RB was overexpressed in leukemic cells from a subset of ATL patients and also regulated NF-κB activation in some, but not all, Tax-negative ATL cell lines. Together, our results support a model whereby Tax instigates an IL-17RB-NF-κB feed-forward autocrine loop that is obligatory for HTLV-1 leukemogenesis.

  18. Molecular Detection and Clinical Implications of HTLV-1 Infections among Antiretroviral Therapy-Naïve HIV-1-Infected Individuals in Abuja, Nigeria

    PubMed Central

    Nasir, Idris Abdullahi; Ahmad, Abdurrahman Elfulaty; Emeribe, Anthony Uchenna; Shehu, Muhammad Sagir; Medugu, Jessy Thomas; Babayo, Adamu

    2015-01-01

    BACKGROUND Individuals with human T-cell lymphotrophic virus type-1 (HTLV-1)/HIV-1 coinfection have been demonstrated to undergo CD4+ lymphocytosis even in the face of immunodeficiency and increased vulnerability to opportunistic pathogens that can lead to poor prognosis. OBJECTIVE This study investigated the prevalence as well as the effects of HIV-1/HTLV-1 coinfection on CD4+ cell counts, routine hematology, and biochemical parameters of study participants. MATERIALS AND METHODS This prospective cross-sectional study involved 184 blood samples collected from HIV-1-seropositive individuals attending HIV-special clinic of the University of Abuja Teaching Hospital, Gwagwalada, Nigeria. These samples were analyzed for anti-HTLV-1/2 IgM antibodies using enzyme-linked immunosorbent assay, CD4+ cell counts, and some routine hematological and biochemical parameters. All samples were also tested for HTLV-1 provirus DNA using real-time polymerase chain reaction (PCR) assay. RESULTS Of the 184 subjects studied, 9 (4.9%) were anti-HTLV-1/2 IgM seropositive; however, upon real-time PCR testing, 12 (6.5%) had detectable HTLV-1 provirus DNA. The CD4+ cell count was significantly high in HTLV-1-positive (742 ± 40.2) subjects compared to their HTLV-1-negative (380 ± 28.5) counterpart (P-value = 0.025). However, there was no significant association between HTLV-1 positivity with other hematology and biochemical parameters studied (P > 0.05). CONCLUSION All subjects (100%) who were HTLV-1/HIV-1-coinfected had normal CD4+ counts. This gives contrasting finding on the true extent of immunodeficiency of subjects. So it is suggested to be very careful in using only CD4+ counts to monitor disease progression and as indicators for antiretroviral therapy (ART) in resource-limited settings. In such conditions, there may be a need to test for HTLV-1 alongside HIV viral loads in order to begin appropriate ART regimens that contain both pathogens. PMID:26688662

  19. Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes

    SciTech Connect

    Xiang, Di; Yuan, Yunsheng; Chen, Li; Liu, Xin; Belani, Chandra; Cheng, Hua

    2015-08-14

    Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IκB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells. - Highlights: • Niclosamide is a promising therapeutic candidate for adult T cell leukemia. • Niclosamide employs a novel mechanism through proteasomal degradation of Tax. • Niclosamide downregulates certain cellular pro-survival molecules.

  20. Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes.

    PubMed

    Xiang, Di; Yuan, Yunsheng; Chen, Li; Liu, Xin; Belani, Chandra; Cheng, Hua

    2015-08-14

    Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IκB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells.

  1. Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes

    PubMed Central

    Chen, Li; Liu, Xin; Belani, Chandra; Cheng, Hua

    2015-01-01

    Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IκB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells. PMID:26116531

  2. Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes.

    PubMed

    Xiang, Di; Yuan, Yunsheng; Chen, Li; Liu, Xin; Belani, Chandra; Cheng, Hua

    2015-08-14

    Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1-transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IκB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1-associated leukemia cells. PMID:26116531

  3. CADM1/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis

    PubMed Central

    Tanaka, Yuetsu; Taylor, Graham P.; Bangham, Charles R. M.

    2016-01-01

    Human T cell lymphotropic virus-1 (HTLV-1) primarily infects CD4+ T cells, causing inflammatory disorders or a T cell malignancy in 5% to 10% of carriers. The cytotoxic T lymphocyte (CTL) response is a key factor that controls the viral load and thus the risk of disease. The ability to detect the viral protein Tax in primary cells has made it possible to estimate the rate at which Tax-expressing infected cells are eliminated by CTLs in persistently infected people. However, most HTLV-1-infected cells are Tax–at a given time, and their immunophenotype is poorly defined. Here, we aimed to identify a cell-surface molecule expressed by both Tax+ and Tax–HTLV-1-infected cells and use it to analyse the CTL response in fresh peripheral blood mononuclear cells. Cell adhesion molecule 1 (CADM1/TSLC1) was the best single marker of HTLV-1 infection, identifying HTLV-1-infected cells with greater sensitivity and specificity than CD25, CCR4 or ICAM-1. CADM1+CD4+ T cells carried a median of 65% of proviral copies in peripheral blood. In a cohort of 23 individuals, we quantified the rate of CTL-mediated killing of Tax+ and Tax−CADM1+ cells. We show that CADM1 expression is associated with enhanced susceptibility of infected cells to CTL lysis: despite the immunodominance of Tax in the CTL response, Tax+CADM1– cells were inefficiently lysed by CTLs. Upregulation of the CADM1 ligand CRTAM on CD8+ T cells correlated with efficient lysis of infected cells. Tax–CADM1+ cells were lysed at a very low rate by autologous CTLs, however, were efficiently killed when loaded with exogenous peptide antigen. High expression of CADM1 on most HTLV-1-infected cells in the face of enhanced CTL counterselection implies that CADM1 confers a strong benefit on the virus. PMID:27105228

  4. Human T-lymphotropic virus and transfusion safety: does one size fit all?

    PubMed

    Marano, Giuseppe; Vaglio, Stefania; Pupella, Simonetta; Facco, Giuseppina; Catalano, Liviana; Piccinini, Vanessa; Liumbruno, Giancarlo Maria; Grazzini, Giuliano

    2016-01-01

    Human T-cell leukemia viruses (HTLV-1 and HTLV-2) are associated with a variety of human diseases, including some severe ones. Transfusion transmission of HTLV through cellular blood components is undeniable. HTLV screening of blood donations became mandatory in different countries to improve the safety of blood supplies. In Japan and Europe, most HTLV-infected donors are HTLV-1 positive, whereas in the United States a higher prevalence of HTLV-2 is reported. Many industrialized countries have also introduced universal leukoreduction of blood components, and pathogen inactivation technologies might be another effective preventive strategy, especially if and when generalized to all blood cellular products. Considering all measures available to minimize HTLV blood transmission, the question is what would be the most suitable and cost-effective strategy to ensure a high level of blood safety regarding these viruses, considering that there is no solution that can be deemed optimal for all countries. PMID:26388300

  5. Analysis of the Prevalence of HTLV-1 Proviral DNA in Cervical Smears and Carcinomas from HIV Positive and Negative Kenyan Women.

    PubMed

    He, Xiaotong; Maranga, Innocent O; Oliver, Anthony W; Gichangi, Peter; Hampson, Lynne; Hampson, Ian N

    2016-01-01

    The oncogenic retrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is endemic in some countries although its prevalence and relationship with other sexually transmitted infections in Sub-Saharan Africa is largely unknown. A novel endpoint PCR method was used to analyse the prevalence of HTLV-1 proviral DNA in genomic DNA extracted from liquid based cytology (LBC) cervical smears and invasive cervical carcinomas (ICCs) obtained from human immunodeficiency virus-positive (HIV+ve) and HIV-negative (HIV-ve) Kenyan women. Patient sociodemographic details were recorded by structured questionnaire and these data analysed with respect to HIV status, human papillomavirus (HPV) type (Papilocheck(®)) and cytology. This showed 22/113 (19.5%) of LBC's from HIV+ve patients were positive for HTLV-1 compared to 4/111 (3.6%) of those from HIV-ve women (p = 0.0002; odds ratio (OR) = 6.42 (2.07-26.56)). Only 1/37 (2.7%) of HIV+ve and none of the 44 HIV-ve ICC samples were positive for HTLV-1. There was also a significant correlation between HTLV-1 infection, numbers of sexual partners (p < 0.05) and smoking (p < 0.01). Using this unique method, these data suggest an unexpectedly high prevalence of HTLV-1 DNA in HIV+ve women in this geographical location. However, the low level of HTLV-1 detected in HIV+ve ICC samples was unexpected and the reasons for this are unclear. PMID:27608036

  6. Analysis of the Prevalence of HTLV-1 Proviral DNA in Cervical Smears and Carcinomas from HIV Positive and Negative Kenyan Women

    PubMed Central

    He, Xiaotong; Maranga, Innocent O.; Oliver, Anthony W.; Gichangi, Peter; Hampson, Lynne; Hampson, Ian N.

    2016-01-01

    The oncogenic retrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is endemic in some countries although its prevalence and relationship with other sexually transmitted infections in Sub-Saharan Africa is largely unknown. A novel endpoint PCR method was used to analyse the prevalence of HTLV-1 proviral DNA in genomic DNA extracted from liquid based cytology (LBC) cervical smears and invasive cervical carcinomas (ICCs) obtained from human immunodeficiency virus-positive (HIV+ve) and HIV-negative (HIV−ve) Kenyan women. Patient sociodemographic details were recorded by structured questionnaire and these data analysed with respect to HIV status, human papillomavirus (HPV) type (Papilocheck®) and cytology. This showed 22/113 (19.5%) of LBC’s from HIV+ve patients were positive for HTLV-1 compared to 4/111 (3.6%) of those from HIV−ve women (p = 0.0002; odds ratio (OR) = 6.42 (2.07–26.56)). Only 1/37 (2.7%) of HIV+ve and none of the 44 HIV−ve ICC samples were positive for HTLV-1. There was also a significant correlation between HTLV-1 infection, numbers of sexual partners (p < 0.05) and smoking (p < 0.01). Using this unique method, these data suggest an unexpectedly high prevalence of HTLV-1 DNA in HIV+ve women in this geographical location. However, the low level of HTLV-1 detected in HIV+ve ICC samples was unexpected and the reasons for this are unclear. PMID:27608036

  7. Preventive and Therapeutic Strategies for Bovine Leukemia Virus: Lessons for HTLV

    PubMed Central

    Rodríguez, Sabrina M.; Florins, Arnaud; Gillet, Nicolas; de Brogniez, Alix; Sánchez-Alcaraz, María Teresa; Boxus, Mathieu; Boulanger, Fanny; Gutiérrez, Gerónimo; Trono, Karina; Alvarez, Irene; Vagnoni, Lucas; Willems, Luc

    2011-01-01

    Bovine leukemia virus (BLV) is a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1). BLV is a major animal health problem worldwide causing important economic losses. A series of attempts were developed to reduce prevalence, chiefly by eradication of infected cattle, segregation of BLV-free animals and vaccination. Although having been instrumental in regions such as the EU, these strategies were unsuccessful elsewhere mainly due to economic costs, management restrictions and lack of an efficient vaccine. This review, which summarizes the different attempts previously developed to decrease seroprevalence of BLV, may be informative for management of HTLV-1 infection. We also propose a new approach based on competitive infection with virus deletants aiming at reducing proviral loads. PMID:21994777

  8. HTLV-1 Tax Protein Stimulation of DNA Binding of bZIP Proteins by Enhancing Dimerization

    NASA Astrophysics Data System (ADS)

    Wagner, Susanne; Green, Michael R.

    1993-10-01

    The Tax protein of human T cell leukemia virus type-1 (HTLV-I) transcriptionally activates the HTLV-I promoter. This activation requires binding sites for activating transcription factor (ATF) proteins, a family of cellular proteins that contain basic region-leucine zipper (bZIP) DNA binding domains. Data are presented showing that Tax increases the in vitro DNA binding activity of multiple ATF proteins. Tax also stimulated DNA binding by other bZIP proteins, but did not affect DNA binding proteins that lack a bZIP domain. The increase in DNA binding occurred because Tax promotes dimerization of the bZIP domain in the absence of DNA, and the elevated concentration of the bZIP homodimer then facilitates the DNA binding reaction. These results help explain how Tax activates viral transcription and transforms cells.

  9. HTLV-1 Tax oncoprotein stimulates ROS production and apoptosis in T cells by interacting with USP10.

    PubMed

    Takahashi, Masahiko; Higuchi, Masaya; Makokha, Grace Naswa; Matsuki, Hideaki; Yoshita, Manami; Tanaka, Yuetsu; Fujii, Masahiro

    2013-08-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL), and the viral oncoprotein Tax plays key roles in the immortalization of human T cells, lifelong persistent infection, and leukemogenesis. We herein identify the ubiquitin-specific protease 10 (USP10) as a Tax-interactor in HTLV-1-infected T cells. USP10 is an antistress factor against various environmental stresses, including viral infections and oxidative stress. On exposure to arsenic, an oxidative stress inducer, USP10 is recruited into stress granules (SGs), and USP10-containing SGs reduce reactive oxygen species (ROS) production and inhibit ROS-dependent apoptosis. We found that interaction of Tax with USP10 inhibits arsenic-induced SG formation, stimulates ROS production, and augments ROS-dependent apoptosis in HTLV-1-infected T cells. These findings suggest that USP10 is a host factor that inhibits stress-induced ROS production and apoptosis in HTLV-1-infected T cells; however, its activities are attenuated by Tax. A clinical study showed that combination therapy containing arsenic is effective against some forms of ATL. Therefore, these findings may be relevant to chemotherapy against ATL.

  10. [Anti HTLV-I antibody titers in seropositive infected individuals].

    PubMed

    Galeno, H; Ramírez, E; Mora, J; Ojeda, M; Cartier, L

    1994-09-01

    The aim of this study was to determine anti HTLV-I antibody titers in seropositive symptomatic and asymptomatic infected subjects. One hundred seven infected subjects (47 with spastic paraparesis and 60 asymptomatic) were studied. HTLV-I antibodies were determined using indirect immunofluorescence in cells infected with the retrovirus. The mean titer was 1/234 in asymptomatic subjects and 1/2138 in symptomatic patients (p < 0.001). These results suggest an association between HTLV-I antibody titers and clinical stage of infected subjects.

  11. Effect of Pulsed Methylprednisolone on Pain, in Patients with HTLV-1-Associated Myelopathy

    PubMed Central

    Buell, Kevin G.; Puri, Aiysha; Demontis, Maria Antonietta; Short, Charlotte L.; Adonis, Adine; Haddow, Jana; Martin, Fabiola; Dhasmana, Divya

    2016-01-01

    HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immune mediated myelopathy caused by the human T-lymphotropic virus type 1 (HTLV-1). The efficacy of treatments used for patients with HAM/TSP is uncertain. The aim of this study is to document the efficacy of pulsed methylprednisolone in patients with HAM/TSP. Data from an open cohort of 26 patients with HAM/TSP was retrospectively analysed. 1g IV methylprednisolone was infused on three consecutive days. The outcomes were pain, gait, urinary frequency and nocturia, a range of inflammatory markers and HTLV-1 proviral load. Treatment was well tolerated in all but one patient. Significant improvements in pain were: observed immediately, unrelated to duration of disease and maintained for three months. Improvement in gait was only seen on Day 3 of treatment. Baseline cytokine concentrations did not correlate to baseline pain or gait impairment but a decrease in tumour necrosis factor-alpha (TNF-α) concentration after pulsed methylprednisolone was associated with improvements in both. Until compared with placebo, treatment with pulsed methylprednisolone should be offered to patients with HAM/TSP for the treatment of pain present despite regular analgesia. PMID:27077747

  12. The HTLV-1-encoded protein HBZ directly inhibits the acetyl transferase activity of p300/CBP

    PubMed Central

    Wurm, Torsten; Wright, Diana G.; Polakowski, Nicholas; Mesnard, Jean-Michel; Lemasson, Isabelle

    2012-01-01

    The homologous cellular coactivators p300 and CBP contain intrinsic lysine acetyl transferase (termed HAT) activity. This activity is responsible for acetylation of several sites on the histones as well as modification of transcription factors. In a previous study, we found that HBZ, encoded by the Human T-cell Leukemia Virus type 1 (HTLV-1), binds to multiple domains of p300/CBP, including the HAT domain. In this study, we found that HBZ inhibits the HAT activity of p300/CBP through the bZIP domain of the viral protein. This effect correlated with a reduction of H3K18 acetylation, a specific target of p300/CBP, in cells expressing HBZ. Interestingly, lower levels of H3K18 acetylation were detected in HTLV-1 infected cells compared to non-infected cells. The inhibitory effect of HBZ was not limited to histones, as HBZ also inhibited acetylation of the NF-κB subunit, p65, and the tumor suppressor, p53. Recent studies reported that mutations in the HAT domain of p300/CBP that cause a defect in acetylation are found in certain types of leukemia. These observations suggest that inhibition of the HAT activity by HBZ is important for the development of adult T-cell leukemia associated with HTLV-1 infection. PMID:22434882

  13. Detection and differentiation of antibodies to human T-cell lymphotropic virus types I and II by the immunofluorescence method.

    PubMed

    Gallo, D; Penning, L M; Hanson, C V

    1991-10-01

    We compared the sensitivities of the prototype human T-cell lymphotropic virus type I (HTLV-I)- and HTLV-II-transformed cell lines, MT2 and Mo-T, with that of an HTLV-II-infected cell line, clone 19, established in our laboratory, in the immunofluorescence (IF) test for detection of antibody to HTLV-I and HTLV-II. In addition, IF antibody titers with the three antigens were determined, and the results were compared with HTLV-I and HTLV-II typing by polymerase chain reaction (PCR). The MT2 cell line was more sensitive than the two HTLV-II cell lines for detecting HTLV-I antibody by IF, and clone 19 was more sensitive than Mo-T or MT2 for measuring HTLV-II antibody. In the titration study, the antigen that gave the highest titer correlated completely with the HTLV type determined by PCR, indicating that the relatively simple IF titration method can be used for differentiating HTLV-I and HTLV-II antibody in sera and plasmas.

  14. A unique seroepidemiological pattern of HBV, HCV and HTLV-I in Nenets and Komi in northwestern Russia.

    PubMed

    Dobrodeeva, Liliya K; Kornienko, Elena B; Petrenya, Nataliya N; Lutfalieva, Gulnara T; Schegoleva, Lyubov S; Demeneva, Ludmila V; Duberman, Boris L; Tkachev, Anatolij V; Chiba, Hitoshi; Senoo, Haruki; Ito, Keiko; Mizoguchi, Emi; Yoshida, Shigeru; Tajima, Kazuo

    2005-01-01

    An epidemiological study of hepatitis viruses type B (HBV) and type C (HCV) and human T-cell leukemia virus type I (HTLV-I) was carried out among 105 residents (male:female=19:86) regarded as Nenets partly mixed with Komi, in the region of Krasnoe, the Nenets Autonomous District of the Arkhangelsk Region, in northwestern Russia in 2004. Blood was drawn from apparently healthy volunteers at ages of 41.6+/-16.5 (range 14-85) years. HBsAg, HBsAb, HBcAb, HBeAb and HCV Ab were measured by microparticle enzyme-immunoassay, and HTLV-I Ab was measured by particle agglutination. Prevalences of HBsAg(+), HBsAb(+), HBcAb(+) and HBeAb(+) were 0.0%, 29.5.%, 20.0% and 7.6%, respectively. The overall HBV infection rate (positive HBsAb or HBcAb) was 34.3%, while no positive HCV or HTLV-I Abs could be detected. A serological subgroup with positive HBsAb and negative HBcAb, consisting of 15(14.3%) females, contrasted sharply to other serological subgroups in sex, age, parent's ethnicity, positive HBeAb rate, and HBcAb inhibition%. We conclude that HBV is prevalent with unique serological patterns among the Nenets, while HCV and HTLV-I infections are negligible.

  15. The HTLV-1 Tax interactome

    PubMed Central

    Boxus, Mathieu; Twizere, Jean-Claude; Legros, Sébastien; Dewulf, Jean-François; Kettmann, Richard; Willems, Luc

    2008-01-01

    The Tax1 oncoprotein encoded by Human T-lymphotropic virus type I is a major determinant of viral persistence and pathogenesis. Tax1 affects a wide variety of cellular signalling pathways leading to transcriptional activation, proliferation and ultimately transformation. To carry out these functions, Tax1 interacts with and modulates activity of a number of cellular proteins. In this review, we summarize the present knowledge of the Tax1 interactome and propose a rationale for the broad range of cellular proteins identified so far. PMID:18702816

  16. Neutralizing human monoclonal antibodies to conformational epitopes of human T-cell lymphotropic virus type 1 and 2 gp46.

    PubMed Central

    Hadlock, K G; Rowe, J; Perkins, S; Bradshaw, P; Song, G Y; Cheng, C; Yang, J; Gascon, R; Halmos, J; Rehman, S M; McGrath, M S; Foung, S K

    1997-01-01

    Ten human monoclonal antibodies derived from peripheral B cells of a patient with human T-cell lymphotropic virus (HTLV)-associated myelopathy are described. One monoclonal antibody recognized a linear epitope within the carboxy-terminal 43 amino acids of HTLV gp21, and two monoclonal antibodies recognized linear epitopes within HTLV type 1 (HTLV-1) gp46. The remaining seven monoclonal antibodies recognized denaturation-sensitive epitopes within HTLV-1 gp46 that were expressed on the surfaces of infected cells. Two of these antibodies also bound to viable HTLV-2 infected cells and immunoprecipitated HTLV-2 gp46. Virus neutralization was determined by syncytium inhibition assays. Eight monoclonal antibodies, including all seven that recognized denaturation-sensitive epitopes within HTLV-1 gp46, possessed significant virus neutralization activity. By competitive inhibition analysis it was determined that these antibodies recognized at least four distinct conformational epitopes within HTLV-1 gp46. These findings indicate the importance of conformational epitopes within HTLV-1 gp46 in mediating a neutralizing antibody response to HTLV infection. PMID:9223472

  17. Bcl-3 suppresses Tax-induced NF-κB activation through p65 nuclear translocation blockage in HTLV-1-infected cells.

    PubMed

    Wang, Jinheng; Li, Junying; Huang, Yanmei; Song, Xiangfeng; Niu, Zhiguo; Gao, Zhitao; Wang, Hui

    2013-01-01

    Human T cell leukemia virus type 1 (HTLV-1) Tax-induced persistent activation of the NF-κB pathway is perceived as the primary cause of adult T cell leukemia (ATL), an aggressive leukemia caused by HTLV-1. Although elevated oncoprotein Bcl-3 levels are found in many HTLV-1-infected T cell lines and ATL cells, the role of Bcl-3 in the malignant progression caused by HTLV-1 retrovirus remains poorly understood. We confirmed, in the present study, that the Tax-induced NF-κB activation involves the regulation of Bcl-3. Both knockdown and overexpression of Bcl-3 inhibit the Tax-induced NF-κB activation. Similarly, excessive Bcl-3 inhibits the NF-κB/DNA binding activity and significantly decreases Tax-induced p65 nuclear translocation. The present results demonstrate the pleiotropic roles of Bcl-3 in Tax-induced NF-κB activation and indicate that a balance in the aberrant Bcl-3 expression may be established to play an important role in the maintenance of proliferation and inhibition of apoptosis in HTLV-1-infected and ATL cells.

  18. Sexual practices and prevalence of HIV, HTLV-I/II, and Treponema pallidum among clandestine female sex workers in Lima, Peru.

    PubMed

    Trujillo, L; Muñoz, D; Gotuzzo, E; Yi, A; Watts, D M

    1999-02-01

    A survey was conducted to determine the prevalence of HIV-I, human T cell leukemia virus I and II (HTLV-I/II), and Treponema pallidum infection and the associated risk factors for the transmission of these sexually transmitted diseases (STDs) among unlicensed female sex workers (FSWs) in Lima, Peru, to further define their role as a potential source of infection. Unlicensed FSWs from 15 brothels were enrolled in this study from March to June 1994. Serum samples were collected and tested for antibodies to HIV-I, HTLV-I, HTLV-II, and Treponema pallidum. Results revealed that of the 158 FSWs studied, all were negative for HIV-I; 6 were positive for HTLV-I, and 5 had T. pallidum antibodies. Of their male clients, 75% had used condoms for the past 6 months, whereas only 3% reported condom use with their steady partners. Among the workers who stated that condoms were always used, the frequency of a history of STDs, including genital ulcers and inguinal adenopathies, was lower compared to occasional users. Similarly, the prevalence of HTLV-I infection and syphilis was lower among these workers. In conclusion, the study results suggested that the low rate of STDs among FSWs reflected a high rate of condom use.

  19. Lack of evidence to support the association of a single IL28B genotype SNP rs12979860 with the HTLV-1 clinical outcomes and proviral load

    PubMed Central

    2012-01-01

    Background The Interleukin 28B (IL28B) rs12979860 polymorphisms was recently reported to be associated with the human T-cell leukemia virus type 1 (HTLV-1) proviral load (PvL) and the development of the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Methods In an attempt to examine this hypothesis, we assessed the association of the rs12979860 genotypes with HTLV-1 PvL levels and clinical status in 112 unrelated Brazilian subjects (81 HTLV-1 asymptomatic carriers, 24 individuals with HAM/TSP and 7 with Adult T cell Leukemia/Lymphoma (ATLL)). Results All 112 samples were successfully genotyped and their PvLs compared. Neither the homozygote TT nor the heterozygote CT mutations nor the combination genotypes (TT/CT) were associated with a greater PvL. We also observed no significant difference in allele distribution between asymptomatic carriers and patients with HTLV-1 associated HAM/TSP. Conclusions Our study failed to support the previously reported positive association between the IL28B rs12979860 polymorphisms and an increased risk of developing HAM/TSP in the Brazilian population. PMID:23259930

  20. The transcription elongation factor ELL2 is specifically upregulated in HTLV-1-infected T-cells and is dependent on the viral oncoprotein Tax.

    PubMed

    Mann, Melanie C; Strobel, Sarah; Fleckenstein, Bernhard; Kress, Andrea K

    2014-09-01

    The oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation.

  1. Infection of human endothelial cells by human T-lymphotropic virus type I.

    PubMed Central

    Ho, D D; Rota, T R; Hirsch, M S

    1984-01-01

    We studied the effects of human T-lymphotropic virus type I (HTLV-I) on human endothelial cells in vitro. During cocultivation with an HTLV-I producer cell line (C91/PL), endothelial cells formed characteristic multinucleated syncytial giant cells. Inoculation with concentrated cell-free supernatant fluid from C91/PL cultures produced similar cytopathic effects, which were neutralized by pretreatment with HTLV-I specific human serum. HTLV-I antigens were detected in the cytoplasm of the multinucleated cells by indirect immunofluorescence. When endothelial cells showed maximal cytopathic changes, reverse transcriptase activity was demonstrated in the supernatant fluid and HTLV-I was isolated by cocultivation with peripheral blood mononuclear cells. This study demonstrates that HTLV-I tropism is not limited to lymphoid cells but extends to human endothelial cells as well. Images PMID:6095308

  2. Phosphatidylglycerol participates in syncytium formation induced by HTLV type 1-bearing cells.

    PubMed

    Sagara, Y; Inoue, Y; Kojima, E; Ishida, C; Shiraki, H; Maeda, Y

    2001-01-20

    We previously reported that 71-kDa heat shock cognate protein (HSC70) was expressed on the cell surface of human T cell lymphotropic virus type 1 (HTLV-1)-susceptible cells and that HSC70, beta-actin, and a lipid-like component on the target cell membrane participated in syncytium formation by HTLV-1. We have now identified this lipid-like component to be palmitoyl (16:0)-oleoyl (18:1)-phosphatidylglycerol (POPG), using preparative thin-layer chromatographic fractionation and tandem mass spectrometric analysis. In the syncytium formation assay, exogenously added PG inhibited cell-to-cell transmission of HTLV-1 in a dose-dependent manner. Other phospholipids showed less (PE) or no effect (PC, PS, PI, PA, lysoPC, lysoPE, and CL). Binding experiments showed that PG interacted with three synthetic peptides, gp46--111, gp46--197, and gp21--400, which correspond to regions Lys111--Asp138 and Asp197--Leu216 on the gp46 surface glycoprotein, and to region Cys400--Leu429 on the gp21 transmembrane glycoprotein, respectively, as well as with intact gp46 and gp21 proteins of HTLV-1. On the other hand, HSC70 and beta-actin interacted with gp46--197 and gp46, not with gp46--111. However, the eluate from an affinity column coupled with gp46--111 contained not only PG but also HSC70 and beta-actin, despite the lack of direct interaction between gp46--111 and these proteins. In the in vitro binding assay, HSC70 showed interaction with both PG and beta-actin, while there was no evidence of any interaction between PG and beta-actin. These results suggest that HSC70 molecules on target cell surface interact with both PG in lipid bilayers and intracellular beta-actin and that these three cellular components form a receptor complex that plays a critical role in syncytium formation induced by HTLV-1-bearing cells. PMID:11177392

  3. Long-term increases in lymphocytes and platelets in human T-lymphotropic virus type II infection.

    PubMed

    Bartman, Melissa T; Kaidarova, Zhanna; Hirschkorn, Dale; Sacher, Ronald A; Fridey, Joy; Garratty, George; Gibble, Joan; Smith, James W; Newman, Bruce; Yeo, Anthony E; Murphy, Edward L

    2008-11-15

    Human T-lymphotropic viruses types I and II (HTLV-I and HTLV-II) cause chronic infections of T lymphocytes that may lead to leukemia and myelopathy. However, their long-term effects on blood counts and hematopoiesis are poorly understood. We followed 151 HTLV-I-seropositive, 387 HTLV-II-seropositive, and 799 HTLV-seronegative former blood donors from 5 U.S. blood centers for a median of 14.0 years. Complete blood counts were performed every 2 years. Multivariable repeated measures analyses were conducted to evaluate the independent effect of HTLV infection and potential confounders on 9 hematologic measurements. Participants with HTLV-II had significant (P < .05) increases in their adjusted lymphocyte counts (+126 cells/mm(3); approximately +7%), hemoglobin (+2 g/L [+0.2 g/dL]) and mean corpuscular volume (MCV; 1.0 fL) compared with seronegative participants. Participants with HTLV-I and HTLV-II had higher adjusted platelet counts (+16 544 and +21 657 cells/mm(3); P < .05) than seronegatives. Among all participants, time led to decreases in platelet count and lymphocyte counts, and to increases in MCV and monocytes. Sex, race, smoking, and alcohol consumption all had significant effects on blood counts. The HTLV-II effect on lymphocytes is novel and may be related to viral transactivation or immune response. HTLV-I and HTLV-II associations with higher platelet counts suggest viral effects on hematopoietic growth factors or cytokines.

  4. Evaluation of a combined lysate/recombinant antigen anti-HTLV-I/II ELISA in high and low endemic areas of HTLV-I/II infection.

    PubMed

    Vrielink, H; Sisay, Y; Reesink, H W; Woerdeman, M; Winkel, C; de Leeuw, S J; Lelie, P N; van der Poel, C L

    1995-06-01

    The Wellcozyme HTLV-I/II ELISA (Murex Diagnostics) was evaluated in 7800 samples of various serum panels. Repeat activity was found by Wellcozyme in (A) 1/2181 (0.05%) Dutch blood donors, (B) 44/3036 (1.4%) Curaçao (Caribbean area) blood donors, (C) 46/2533 (1.8%) individuals of different Ethiopian population subsets, (D) 30/30 (100%) confirmed anti-HTLV-I positive samples and (E) 20/20 (100%) HTLV-II PCR-positive samples. All 91 Wellcozyme-positive samples were tested for confirmation by Western blot (WB, Diagnostic Biotechnology). Among Wellcozyme HTLV-I/II ELISA-positive individuals, HTLV-I/II WB positivity was found in 0/1 Dutch blood donors, 40/44 (88.9%) Curaçao blood donors and 20/46 (43.5%) Ethiopian individuals. HTLV-I positivity was found in 40 (1.3%) WB-positive Curaçao blood donors and in 9 (0.35%) Ethiopian individuals. HTLV-II positivity was found in 11 (0.43%) WB-positive Ethiopian individuals. The Wellcozyme HTLV-I/II ELISA had a specificity of 99.95% in Dutch blood donors and a sensitivity of 100% on confirmed HTLV-I- and HTLV-II-positive samples. In Ethiopia 55% of the HTLV-I/II WB-positive individuals were exclusively HTLV-II positive, whereas in Curaçao no HTLV-II infections were found. PMID:7655577

  5. Isolation of human T-cell lymphotropic virus type 2 from Guaymi Indians in Panama.

    PubMed Central

    Lairmore, M D; Jacobson, S; Gracia, F; De, B K; Castillo, L; Larreategui, M; Roberts, B D; Levine, P H; Blattner, W A; Kaplan, J E

    1990-01-01

    Human T-lymphotropic virus type I (HTLV-I) is associated with adult T-cell leukemia/lymphoma and with a chronic degenerative myelopathy. However, another major type of HTLV, HTLV-II, has been isolated only sporadically, and little is known of disease associations, transmission routes, and risk factors for HTLV-II infection. Recent studies indicate that a high percentage of certain groups of i.v. drug users and blood donors are infected with HTLV-II. Seroepidemiologic studies have found an elevated rate of seroreactivity to HTLV among Guaymi Indians from Bocas del Toro Province, Panama. To identify the cause of seroreactivity among this unique population we used HTLV-II-specific polymerase chain reaction techniques to detect HTLV genetic sequences from blood leukocytes of three seropositive Guaymi Indians. The HTLV-II primer-amplified polymerase chain reaction products from two of these subjects were partially sequenced and matched published HTLV-II nucleotide sequences in both p24 gag (94% of 107 bases) and pol (98% of 112 bases) regions. A CD4+ T-lymphocyte line established from one of these same subjects produced HTLV-II-specific proteins when tested in antigen-capture and immunoblot assays, as well as mature HTLV particles. The demonstration of HTLV-II infection in this geographically and culturally isolated Central American Indian population without typical risk factors for HTLV infection suggests that HTLV-II infection is endemic in this population and provides an important clue to potential natural reservoir for this virus. Images PMID:2247455

  6. Identification of TBK1 and IKKε, the non-canonical IκB kinases, as crucial pro-survival factors in HTLV-1-transformed T lymphocytes.

    PubMed

    Zhang, Huan; Chen, Li; Cai, Shao-Hui; Cheng, Hua

    2016-07-01

    Persistent activation of NF-κB is a prerequisite for development of adult T cell leukemia-lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). HTLV-1 genome encodes a viral transforming protein named Tax, which constitutively activates the canonical IκB kinases (IKK), the central regulator of NF-κB signaling. However, the role of the non-canonical IκB kinases, TBK1 and IKKε, in the pathogenesis of HTLV-1-associated leukemia has not been evaluated. We here show that TBK1/IKKε are crucial pro-survival molecules by maintaining persistent activity of Stat3. Consistent with this finding, silencing Stat3 by the specific shRNA or by the chemical inhibitor ruxolitinib results in drastic impediment of leukemia cell growth. We further find that in HTLV-1-transformed T cells expressing Tax, TBK1 co-localizes with the canonical IκB kinases and Tax in the lipid raft microdomains. The wild type Tax, but not the Tax mutant defective in activating the canonical IKK, promotes the lipid raft translocation of TBK1. This phenomenon correlates with Tax activation of both NF-κB and Stat3. Tax does not interact directly with TBK1/IKKε, and it rather engages a molecular crosstalk between the canonical IKKs and TBK1/IKKε. Our data, therefore, demonstrate a key role of TBK1/IKKε in the survival and proliferation of HTLV-1-transformed T cells and implicate a potential therapy targeting TBK1/IKKε and Stat3 in controlling HTLV-1-mediated oncogenesis. PMID:27123832

  7. Interferon-γ Promotes Inflammation and Development of T-Cell Lymphoma in HTLV-1 bZIP Factor Transgenic Mice

    PubMed Central

    Mitagami, Yu; Yasunaga, Jun-ichirou; Kinosada, Haruka; Ohshima, Koichi; Matsuoka, Masao

    2015-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) is an etiological agent of several inflammatory diseases and a T-cell malignancy, adult T-cell leukemia (ATL). HTLV-1 bZIP factor (HBZ) is the only viral gene that is constitutively expressed in HTLV-1-infected cells, and it has multiple functions on T-cell signaling pathways. HBZ has important roles in HTLV-1-mediated pathogenesis, since HBZ transgenic (HBZ-Tg) mice develop systemic inflammation and T-cell lymphomas, which are similar phenotypes to HTLV-1-associated diseases. We showed previously that in HBZ-Tg mice, HBZ causes unstable Foxp3 expression, leading to an increase in regulatory T cells (Tregs) and the consequent induction of IFN-γ-producing cells, which in turn leads to the development of inflammation in the mice. In this study, we show that the severity of inflammation is correlated with the development of lymphomas in HBZ-Tg mice, suggesting that HBZ-mediated inflammation is closely linked to oncogenesis in CD4+ T cells. In addition, we found that IFN-γ-producing cells enhance HBZ-mediated inflammation, since knocking out IFN-γ significantly reduced the incidence of dermatitis as well as lymphoma. Recent studies show the critical roles of the intestinal microbiota in the development of Tregs in vivo. We found that even germ-free HBZ-Tg mice still had an increased number of Tregs and IFN-γ-producing cells, and developed dermatitis, indicating that an intrinsic activity of HBZ evokes aberrant T-cell differentiation and consequently causes inflammation. These results show that immunomodulation by HBZ is implicated in both inflammation and oncogenesis, and suggest a causal connection between HTLV-1-associated inflammation and ATL. PMID:26296091

  8. Highly divergent molecular variants of human T-lymphotropic virus type I from isolated populations in Papua New Guinea and the Solomon Islands.

    PubMed Central

    Gessian, A; Yanagihara, R; Franchini, G; Garruto, R M; Jenkins, C L; Ajdukiewicz, A B; Gallo, R C; Gajdusek, D C

    1991-01-01

    To determine the molecular genetic relationship between Melanesian strains of human T-lymphotropic virus type I (HTLV-I) and cosmopolitan prototype HTLV-I, we amplified by PCR, then cloned, and sequenced a 522-base-pair region of the HTLV-I env gene in DNA extracted from uncultured (fresh) and cultured peripheral blood mononuclear cells obtained from six seropositive Melanesian Papua New Guineans and Solomon Islanders, including a Solomon Islander with HTLV-I myeloneuropathy. Unlike isolates of HTLV-I from Japan, the West Indies, the Americas, and Africa, which share greater than or equal to 97% sequence homology, the Melanesian strains of HTLV-I were only 91.8%-92.5% identical with a prototype Japanese HTLV-IATK-1. The nucleotide sequence of proviral DNA from the Solomon Islander with HTLV-I myeloneuropathy also diverged markedly from that of HTLV-I isolated from Japanese patients with HTLV-I-associated myelopathy and from Jamaican patients with tropical spastic paraparesis, suggesting that these variant viruses are capable of causing disease. The HTLV-I variants from Papua New Guineans, in turn, differed by nearly 4% from the Melanesian variants from Solomon Islanders, indicating the existence of another HTLV-I quasi-species. By contrast, HTLV-I strains from two residents of Bellona Island, a Polynesian Outlier within the Solomon Islands, were closely related to cosmopolitan prototype HTLV-I (greater than or equal to 97% sequence identity), suggesting recent introduction, possibly during this century. These findings are consistent with a proto-Melanesian HTLV-I strain of archaic presence, which evolved independently of contemporary cosmopolitan strains, and pose new questions about the origin and global dissemination of HTLV-I. Images PMID:1881912

  9. Universal cytotoxic activity of a HTLV-1 Tax-specific T cell clone from an HLA-A*24:02⁺ patient with adult T-cell leukemia against a variety of HTLV-I-infected T-cells.

    PubMed

    Tanaka, Yukie; Yamazaki, Rie; Terasako-Saito, Kiriko; Nakasone, Hideki; Akahoshi, Yu; Nakano, Hirofumi; Ugai, Tomotaka; Wada, Hidenori; Yamasaki, Ryoko; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Ashizawa, Masahiro; Sato, Miki; Kimura, Shun-ichi; Kikuchi, Misato; Kako, Shinichi; Kanda, Junya; Tanihara, Aki; Nishida, Junji; Kanda, Yoshinobu

    2014-01-01

    Adult T cell leukemia/lymphoma (ATL) is an aggressive mature T cell malignancy that is causally associated with human T cell lymphotropic virus type 1 (HTLV-1) infection. The HTLV-1 regulatory protein Tax aggressively accelerates the proliferation of host cells and is also an important target antigen for CD8(+) cytotoxic T cells (CTLs). We previously reported that several predominant HLA-A*24:02-restricted HTLV-1 Tax301-309-specific CTL clones commonly expressed a particular amino acid sequence motif (P-D-R) in complementarity-determining region 3 of T-cell receptor (TCR)-β chain among unrelated ATL patients who underwent allogeneic stem cell transplantation (allo-HSCT). Furthermore, a PDR-motif(+) CTL clone persistently existed in a long-term survivor as a central CTL clone with strong CTL activities after HSCT. Although a larger analysis of the relationship between PDR-motif(+) CTLs and the clinical course is required, the expression of PDR-motif(+) TCR on CD8(+) T cells may play a critical role in the management of anti-HTLV-1 activities for HLA-A24:02(+) ATL patients. Therefore, in this study, we prepared an HTLV-1 Tax301-309 peptide-specific CTL clone (HT-9) expressing PDR-motif(+) TCR isolated from a long-term survivor after HSCT, and evaluated its CTL activity against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients. Before the assay of CTL function, we confirmed that HT-9 expressed less-differentiated effector-memory phenotypes (CD45RA(-)CCR7(-)CD27(+)CD28(+/-)CD57(+/-)) and T-cell exhaustion marker PD-1(+). In assays of CTL function, HT-9 recognized HTLV-1 Tax in an HLA-restricted fashion and demonstrated strong CTL activities against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients regardless of whether the sources were autologous or allogeneic, but not normal cells. These data indicate that PDR-motif(+) TCR could be an important TCR candidate for TCR-gene immunotherapy for HLA-A24:02(+) ATL patients, provided

  10. Human T Cell Lymphotropic Virus Type 2a Strains Among HIV Type 1-Coinfected Patients from Brazil Have Originated Mostly from Brazilian Amerindians

    PubMed Central

    Magri, Mariana Cavalheiro; Brigido, Luis Fernando de Macedo; Morimoto, Helena Kaminami

    2013-01-01

    Abstract The human T cell lymphotropic virus type 2 (HTLV-2) is found mainly in Amerindians and in intravenous drug users (IDUs) from urban areas of the United States, Europe, and Latin America. Worldwide, HTLV-2a and HTLV-2b subtypes are the most prevalent. Phylogenetic analysis of HTLV-2 isolates from Brazil showed the HTLV-2a subtype, variant -2c, which spread from Indians to the general population and IDUs. The present study searched for the types of HTLV-2 that predominate among HIV-1-coinfected patients from southern and southeastern Brazil. Molecular characterization of the LTR, env, and tax regions of 38 isolates confirmed the HTLV-2c variant in 37 patients, and one HTLV-2b in a patient from Paraguay. Phylogenetic analysis of sequences showed different clades of HTLV-2 associated with risk factors and geographic region. These clades could represent different routes of virus transmission and/or little diverse evolutionary rates of virus. Taking into account the results obtained in the present study and the lack of the prototypic North American HTLV-2a strain and HTLV-2b subtypes commonly detected among HIV-coinfected individuals worldwide, we could speculate on the introduction of Brazilian HTLV-2 strains in such populations before the introduction of HIV. PMID:23484539

  11. Human T cell lymphotropic virus type 2a strains among HIV type 1-coinfected patients from Brazil have originated mostly from Brazilian Amerindians.

    PubMed

    Magri, Mariana Cavalheiro; Brigido, Luis Fernando de Macedo; Morimoto, Helena Kaminami; Caterino-de-Araujo, Adele

    2013-07-01

    The human T cell lymphotropic virus type 2 (HTLV-2) is found mainly in Amerindians and in intravenous drug users (IDUs) from urban areas of the United States, Europe, and Latin America. Worldwide, HTLV-2a and HTLV-2b subtypes are the most prevalent. Phylogenetic analysis of HTLV-2 isolates from Brazil showed the HTLV-2a subtype, variant -2c, which spread from Indians to the general population and IDUs. The present study searched for the types of HTLV-2 that predominate among HIV-1-coinfected patients from southern and southeastern Brazil. Molecular characterization of the LTR, env, and tax regions of 38 isolates confirmed the HTLV-2c variant in 37 patients, and one HTLV-2b in a patient from Paraguay. Phylogenetic analysis of sequences showed different clades of HTLV-2 associated with risk factors and geographic region. These clades could represent different routes of virus transmission and/or little diverse evolutionary rates of virus. Taking into account the results obtained in the present study and the lack of the prototypic North American HTLV-2a strain and HTLV-2b subtypes commonly detected among HIV-coinfected individuals worldwide, we could speculate on the introduction of Brazilian HTLV-2 strains in such populations before the introduction of HIV.

  12. Tumours derived from HTLV-I tax transgenic mice are characterized by enhanced levels of apoptosis and oncogene expression.

    PubMed

    Hall, A P; Irvine, J; Blyth, K; Cameron, E R; Onions, D E; Campbell, M E

    1998-10-01

    In order to investigate the role that the human T-lymphotropic virus type I (HTLV-I) tax oncogene plays in apoptosis and transformation in vivo, four lines of HTLV-I tax transgenic mice were generated under the regulatory control of the CD3-epsilon promoter-enhancer sequence. These mice develop a variety of phenotypes including mesenchymal tumours, which develop at wound sites, and salivary and mammary adenomas. In situ DNA fragment labelling and immunocytochemical analysis of these tumours reveals that they display enhanced levels of apoptosis, which is associated with elevated levels of Myc, Fos, Jun, and p53 protein expression. Furthermore, double immunofluorescent staining shows that Tax expression and apoptosis co-localize, indicating that Tax expression is closely associated with apoptosis in vivo. PMID:9924438

  13. HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT).

    PubMed

    Yasuma, Keiko; Yasunaga, Jun-ichirou; Takemoto, Keiko; Sugata, Kenji; Mitobe, Yuichi; Takenouchi, Norihiro; Nakagawa, Masanori; Suzuki, Yutaka; Matsuoka, Masao

    2016-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL) in some infected individuals. The HTLV-1 bZIP factor (HBZ) gene, which is encoded in the minus strand of HTLV-1, plays critical roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT), in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg) mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT-CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT's ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1. PMID:26735971

  14. HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT)

    PubMed Central

    Yasuma, Keiko; Yasunaga, Jun-ichirou; Takemoto, Keiko; Sugata, Kenji; Mitobe, Yuichi; Takenouchi, Norihiro; Nakagawa, Masanori; Suzuki, Yutaka; Matsuoka, Masao

    2016-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL) in some infected individuals. The HTLV-1 bZIP factor (HBZ) gene, which is encoded in the minus strand of HTLV-1, plays critical roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT), in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg) mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT-CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT’s ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1. PMID:26735971

  15. Enhancement of anti-STLV-1/HTLV-1 immune responses through multimodal effects of anti-CCR4 antibody.

    PubMed

    Sugata, Kenji; Yasunaga, Jun-Ichirou; Miura, Michi; Akari, Hirofumi; Utsunomiya, Atae; Nosaka, Kisato; Watanabe, Yuko; Suzushima, Hitoshi; Koh, Ki-Ryang; Nakagawa, Masanori; Kohara, Michinori; Matsuoka, Masao

    2016-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia and inflammatory diseases. Because anti-HTLV-1 immune responses are critical for suppressing infected cells, enhancing cellular immunity is beneficial for the treatment of HTLV-1-associated diseases. Using simian T-cell leukemia virus type 1 (STLV-1) infected Japanese macaques, we analyzed the immune responses to viral antigens and the dynamics of virus-infected cells. The chemokine receptor CCR4 is expressed on STLV-1 infected cells, and administration of humanized monoclonal antibody to CCR4, mogamulizumab, dramatically decreased the number of STLV-1-infected cells in vivo. Concurrently, mogamulizumab treatment enhanced STLV-1 specific CD4(+) and CD8(+) T cell responses by simultaneously targeting CCR4(+) effector regulatory T (Treg) cells and infected cells. Mogamulizumab promoted the phagocytosis of CCR4(+) infected cells by macrophages, which likely enhanced antigen presentation. Vaccination with recombinant vaccinia virus (rVV) expressing viral antigens suppressed the proviral load and the number of Tax-expressing cells. Enhanced T-cell responses were also observed in some ATL patients who were treated with mogamulizumab. This study shows that mogamulizumab works not only by killing CCR4(+) infected cells directly, but also by enhancing T cell responses by increasing the phagocytosis of infected cells by antigen-presenting cells and suppressing CCR4(+) effector Treg cells. PMID:27250643

  16. Enhancement of anti-STLV-1/HTLV-1 immune responses through multimodal effects of anti-CCR4 antibody

    PubMed Central

    Sugata, Kenji; Yasunaga, Jun-ichirou; Miura, Michi; Akari, Hirofumi; Utsunomiya, Atae; Nosaka, Kisato; Watanabe, Yuko; Suzushima, Hitoshi; Koh, Ki-Ryang; Nakagawa, Masanori; Kohara, Michinori; Matsuoka, Masao

    2016-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia and inflammatory diseases. Because anti-HTLV-1 immune responses are critical for suppressing infected cells, enhancing cellular immunity is beneficial for the treatment of HTLV-1-associated diseases. Using simian T-cell leukemia virus type 1 (STLV-1) infected Japanese macaques, we analyzed the immune responses to viral antigens and the dynamics of virus-infected cells. The chemokine receptor CCR4 is expressed on STLV-1 infected cells, and administration of humanized monoclonal antibody to CCR4, mogamulizumab, dramatically decreased the number of STLV-1-infected cells in vivo. Concurrently, mogamulizumab treatment enhanced STLV-1 specific CD4+ and CD8+ T cell responses by simultaneously targeting CCR4+ effector regulatory T (Treg) cells and infected cells. Mogamulizumab promoted the phagocytosis of CCR4+ infected cells by macrophages, which likely enhanced antigen presentation. Vaccination with recombinant vaccinia virus (rVV) expressing viral antigens suppressed the proviral load and the number of Tax-expressing cells. Enhanced T-cell responses were also observed in some ATL patients who were treated with mogamulizumab. This study shows that mogamulizumab works not only by killing CCR4+ infected cells directly, but also by enhancing T cell responses by increasing the phagocytosis of infected cells by antigen-presenting cells and suppressing CCR4+ effector Treg cells. PMID:27250643

  17. SIRT1 Suppresses Human T-Cell Leukemia Virus Type 1 Transcription

    PubMed Central

    Tang, Hei-Man Vincent; Gao, Wei-Wei; Chan, Chi-Ping; Cheng, Yun; Deng, Jian-Jun; Yuen, Kit-San; Iha, Hidekatsu

    2015-01-01

    ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1)-associated diseases are poorly treatable, and HTLV-1 vaccines are not available. High proviral load is one major risk factor for disease development. HTLV-1 encodes Tax oncoprotein, which activates transcription from viral long terminal repeats (LTR) and various types of cellular promoters. Counteracting Tax function might have prophylactic and therapeutic benefits. In this work, we report on the suppression of Tax activation of HTLV-1 LTR by SIRT1 deacetylase. The transcriptional activity of Tax on the LTR was largely ablated when SIRT1 was overexpressed, but Tax activation of NF-κB was unaffected. On the contrary, the activation of the LTR by Tax was boosted when SIRT1 was depleted. Treatment of cells with resveratrol shunted Tax activity in a SIRT1-dependent manner. The activation of SIRT1 in HTLV-1-transformed T cells by resveratrol potently inhibited HTLV-1 proviral transcription and Tax expression, whereas compromising SIRT1 by specific inhibitors augmented HTLV-1 mRNA expression. The administration of resveratrol also decreased the production of cell-free HTLV-1 virions from MT2 cells and the transmission of HTLV-1 from MT2 cells to uninfected Jurkat cells in coculture. SIRT1 associated with Tax in HTLV-1-transformed T cells. Treatment with resveratrol prevented the interaction of Tax with CREB and the recruitment of CREB, CRTC1, and p300 to Tax-responsive elements in the LTR. Our work demonstrates the negative regulatory function of SIRT1 in Tax activation of HTLV-1 transcription. Small-molecule activators of SIRT1 such as resveratrol might be considered new prophylactic and therapeutic agents in HTLV-1-associated diseases. IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) causes a highly lethal blood cancer or a chronic debilitating disease of the spinal cord. Treatments are unsatisfactory, and vaccines are not available. Disease progression is associated with robust expression of HTLV-1 genes

  18. TRANSMISIÓN VERTICAL DE HTLV-1 EN EL PERÚ

    PubMed Central

    Villaverde, Jorge Alarcón; Romaní, Franco Romaní; Torres, Silvia Montano; Zunt, Joseph R.

    2012-01-01

    La infección por el virus linfotrópico humano de células T tipo 1 (HTLV-1) ha sido descrita en muchas áreas del mundo, como en los países del Caribe, Japón, África, Oceanía y en Sudamérica. En la presente revisión definimos la endemicidad del HTLV-1 en el país, planteando cuatro criterios epidemiológicos. Luego discutimos el tema central de la revisión: la transmisión vertical del HTLV-1, que en nuestro país sería uno de los principales mecanismos de transmisión. Dentro del desarrollo de este aspecto en particular, presentamos una estimación de la tasa de transmisión vertical y los factores de riesgo asociados con la transmisión vertical sobre la base de una revisión exhaustiva de estudios nacionales y extranjeros. Con esta revisión pretendemos dar una primera aproximación al estudio de la trasmisión vertical de HTLV-1, un aspecto poco estudiado en nuestro medio. PMID:21537777

  19. Human T cell lymphotropic virus type 1 infection among U.S. thalassemia patients.

    PubMed

    Switzer, William M; Shankar, Anupama; Trimble, Sean R; Thompson, Alexis A; Giardina, Patricia J; Cohen, Alan R; Coates, Thomas D; Vichinsky, Elliott; Neufeld, Ellis J; Boudreaux, Jeanne M; Heneine, Walid

    2013-07-01

    Thalassemia is an inherited genetic disorder requiring multiple transfusions to treat anemia caused by low hemoglobin levels. Thus, thalassemia patients are at risk for infection with blood-borne pathogens, including human T cell lymphotropic viruses (HTLV) that are transmitted by transfusion of cellular blood products. Here, we examined the prevalence of HTLV among 234 U.S. thalassemia patients using sera collected in 2008. Sera were tested for antibodies to HTLV-1/2 using enzyme immunoassay (EIA) and a confirmatory western blot (WB) that differentiates between HTLV-1 and HTLV-2. Demographic information and clinical information were collected at study enrollment, including HIV and hepatitis C virus (HCV) status. Three patients (1.3%) were WB positive; two were HTLV-1 and one could not be serotyped as HTLV-1/2. All three HTLV-positive persons were HIV-1 negative and one was HCV seropositive. The HTLV seroprevalence was higher than that of HIV-1 (0.85%) and lower than HCV (18.8%) in this population. All three patients (ages 26-46 years) were diagnosed with β-thalassemia shortly after birth and have since been receiving multiple transfusions annually. Two of the HTLV-positive patients confirmed receiving transfusions before HTLV blood screening was implemented in 1988. We identified a substantial HTLV-1 seroprevalence in U.S. thalassemia patients that is much greater than that seen in blood donors. Our findings highlight the importance of HTLV testing of patients with thalassemia and other diseases requiring multiple transfusions, especially in recipients of unscreened transfusions. In addition, appropriate counseling and follow-up of HTLV-infected patients are warranted. PMID:23409829

  20. Dermatological Manifestations of Individuals Infected with Human T-cell Lymphotropic Virus type 1

    PubMed Central

    Dantas, Lorena; Netto, Eduardo; Glesby, Marshall; Carvalho, Edgar; Machado, Paulo

    2013-01-01

    Background Human T-cell lymphotropic virus - type 1 (HTLV-1) is associated with specific manifestations such as adult T-cell lymphoma/leukemia (ATLL), HTLV-1-associated myelopathy / tropical spastic paraparesis (HAM/TSP), HTLV-1-associated uveitis and infective dermatitis associated with HTLV-1 (IDH). Although ATLL and IDH are considered specific manifestations of HTLV-1 infection, several dermatological manifestations have been described in HTLV-1-infected patients. Methods A prevalence study was conducted between 2008 and 2010 with two groups of individuals, 179 HTLV-1 seropositive (positive ELISA and positive Western Blot) and 193 seronegative individuals (ELISA negative). The subjects were selected at a random basis and evaluated using a questionnaire to obtain epidemiological and clinical data. A physical examination was performed to verify the presence of skin lesions. Results Superficial mycoses were found in 54 HTLV-1-positive subjects (30.2%) and in 26 (13.5%) of the seronegative group (p<0.001). Xerosis was found in 39.1% of HTLV-1 infected subjects and in 9.3% of seronegative controls (p<0.001). Ichthyosis was diagnosed in 9 HTLV-1 positive cases (5%) whereas absent in the control group (p=0.001). A seborrheic dermatitis diagnosis was made in 43 HTLV-1 infected subjects (24%) and in 24 seronegative controls (12.4%) (p=0.004). Furthermore, the dermatological manifestations were more intense in the HTLV-1 group. Conclusions Several dermatological manifestations are more common and more severe in HTLV-1 subjects. The presence of these manifestations in an endemic area for HTLV- 1 infection may be a clue for the investigation of this infection. PMID:24111739

  1. HTLV-1 Tax Stabilizes MCL-1 via TRAF6-Dependent K63-Linked Polyubiquitination to Promote Cell Survival and Transformation

    PubMed Central

    Choi, Young Bong; Harhaj, Edward William

    2014-01-01

    The human T-cell leukemia virus type 1 (HTLV-1) Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs) and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63)-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation. PMID:25340740

  2. HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation.

    PubMed

    Choi, Young Bong; Harhaj, Edward William

    2014-10-01

    The human T-cell leukemia virus type 1 (HTLV-1) Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs) and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63)-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation.

  3. The tax gene of human T-cell leukemia virus type 2 is essential for transformation of human T lymphocytes.

    PubMed Central

    Ross, T M; Pettiford, S M; Green, P L

    1996-01-01

    The mechanism of human T-cell leukemia virus (HTLV)-mediated transformation and induction of malignancy is unknown; however, several studies have implicated the viral gene product, Tax. Conclusive evidence for the role of Tax in the HTLV malignant process has been impeded by the inability to mutate tax in the context of an infectious virus and dissociate viral replication from cellular transformation. To circumvent this problem we constructed a mutant of HTLV type 2 (HTLV-2) that replicates by a Tax-independent mechanism. For these studies, the Tax response element in the viral long terminal repeat was replaced with the cytomegalovirus immediate-early promoter enhancer (C-enh). Transcription of the chimeric HTLV-2 (HTLVC-enh) was efficiently directed by this heterologous promoter. Also, the chimeric virus transformed primary human T lymphocytes with an efficiency similar to that of wild-type HTLV-2. A tax-knockout virus, termed HTLVC-enhDeltaTax, was constructed to directly assess the importance of Tax in cellular transformation. Transfection and infection studies indicated that HTLVC-enhDeltaTax was replication competent; however, HTLVC-enhDeltaTax failed to transform primary human T lymphocytes. We conclude that Tax is essential for HTLV-mediated transformation of human T lymphocytes. Furthermore, this chimeric HTLV, that replicates in the absence of Tax, should facilitate studies to determine the precise mechanism of T-lymphocyte transformation by HTLV. PMID:8764028

  4. HTLV-1 subgroups associated with the risk of HAM/TSP are related to viral and host gene expression in peripheral blood mononuclear cells, independent of the transactivation functions of the viral factors.

    PubMed

    Yasuma, Keiko; Matsuzaki, Toshio; Yamano, Yoshihisa; Takashima, Hiroshi; Matsuoka, Masao; Saito, Mineki

    2016-08-01

    Among human T cell leukemia virus type 1 (HTLV-1)-infected individuals, the risk of developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) across lifetime differs between ethnic groups. There is an association between HTLV-1 tax gene subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. In this study, we investigated the full-length proviral genome sequences of various HTLV-1-infected cell lines and patient samples. The functional differences in the viral transcriptional regulators Tax and HTLV-1 bZIP factor (HBZ) between each subgroup and the relationships between subgroups and the clinical and laboratory characteristics of HAM/TSP patients were evaluated. The results of these analyses indicated the following: (1) distinct nucleotide substitutions corresponding to each subgroup were associated with nucleotide substitutions in viral structural, regulatory, and accessory genes; (2) the HBZ messenger RNA (mRNA) expression in HTLV-1-infected cells was significantly higher in HAM/TSP patients with subgroup-B than in those with subgroup-A; (3) a positive correlation was observed between the expression of HBZ mRNA and its target Foxp3 mRNA in HAM/TSP patients with subgroup-B, but not in patients with subgroup-A; (4) no clear differences were noted in clinical and laboratory characteristics between HAM/TSP patients with subgroup-A and subgroup-B; and (5) no functional differences were observed in Tax and HBZ between each subgroup based on reporter gene assays. Our results indicate that although different HTLV-1 subgroups are characterized by different patterns of viral and host gene expression in HAM/TSP patients via independent mechanisms of direct transcriptional regulation, these differences do not significantly affect the clinical and laboratory characteristics of HAM/TSP patients. PMID:26635027

  5. Bay 11-7082 inhibits transcription factor NF-kappaB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells.

    PubMed

    Mori, Naoki; Yamada, Yasuaki; Ikeda, Shuichi; Yamasaki, Yoshihiro; Tsukasaki, Kunihiro; Tanaka, Yuetsu; Tomonaga, Masao; Yamamoto, Naoki; Fujii, Masahiro

    2002-09-01

    Human T-cell leukemia virus type I (HTLV-I) is the causative agent of an aggressive form of leukemia designated adult T-cell leukemia (ATL). We have previously demonstrated that all T-cell lines infected with HTLV-I and primary leukemic cells from ATL patients display constitutively high activity of transcription factor NF-kappaB. In this study we showed that Bay 11-7082, an inhibitor of NF-kappaB, induced apoptosis of HTLV-I-infected T-cell lines but only negligible apoptosis of HTLV-I-negative T cells. Bay 11-7082 rapidly and efficiently reduced the DNA binding of NF-kappaB in HTLV-I-infected T-cell lines and down-regulated the expression of the antiapoptotic gene, Bcl-x(L), regulated by NF-kappaB, whereas it had little effect on the DNA binding of another transcription factor, AP-1. Although the viral protein Tax is an activator of NF-kappaB, Bay 11-7082-induced apoptosis of HTLV-I-infected cells was not associated with reduced expression of Tax. Furthermore, Bay 11-7082- induced apoptosis of primary ATL cells was more prominent than that of normal peripheral blood mononuclear cells, and apoptosis of these cells was also associated with down-regulation of NF-kappaB activity. Our results indicate that NF-kappaB plays a crucial role in the pathogenesis and survival of HTLV-I-infected leukemic cells and that it is a suitable target for the prevention and treatment of ATL.

  6. Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30{sup II} accessory protein and the induction of oncogenic cellular transformation by p30{sup II}/c-MYC

    SciTech Connect

    Romeo, Megan M.; Ko, Bookyung; Kim, Janice; Brady, Rebecca; Heatley, Hayley C.; He, Jeffrey; Harrod, Carolyn K.; Barnett, Braden; Ratner, Lee; Lairmore, Michael D.; Martinez, Ernest; Lüscher, Bernhard; Robson, Craig N.; Henriksson, Marie; Harrod, Robert

    2015-02-15

    The human T-cell leukemia retrovirus type-1 (HTLV-1) p30{sup II} protein is a multifunctional latency-maintenance factor that negatively regulates viral gene expression and deregulates host signaling pathways involved in aberrant T-cell growth and proliferation. We have previously demonstrated that p30{sup II} interacts with the c-MYC oncoprotein and enhances c-MYC-dependent transcriptional and oncogenic functions. However, the molecular and biochemical events that mediate the cooperation between p30{sup II} and c-MYC remain to be completely understood. Herein we demonstrate that p30{sup II} induces lysine-acetylation of the c-MYC oncoprotein. Acetylation-defective c-MYC Lys→Arg substitution mutants are impaired for oncogenic transformation with p30{sup II} in c-myc{sup −/−} HO15.19 fibroblasts. Using dual-chromatin-immunoprecipitations (dual-ChIPs), we further demonstrate that p30{sup II} is present in c-MYC-containing nucleoprotein complexes in HTLV-1-transformed HuT-102 T-lymphocytes. Moreover, p30{sup II} inhibits apoptosis in proliferating cells expressing c-MYC under conditions of genotoxic stress. These findings suggest that c-MYC-acetylation is required for the cooperation between p30{sup II}/c-MYC which could promote proviral replication and contribute to HTLV-1-induced carcinogenesis. - Highlights: • Acetylation of c-MYC is required for oncogenic transformation by HTLV-1 p30{sup II}/c-MYC. • Acetylation-defective c-MYC mutants are impaired for foci-formation by p30{sup II}/c-MYC. • The HTLV-1 p30{sup II} protein induces lysine-acetylation of c-MYC. • p30{sup II} is present in c-MYC nucleoprotein complexes in HTLV-1-transformed T-cells. • HTLV-1 p30{sup II} inhibits apoptosis in c-MYC-expressing proliferating cells.

  7. Human T-cell leukemia virus infection of human hematopoietic progenitor cells: maintenance of virus infection during differentiation in vitro and in vivo.

    PubMed Central

    Feuer, G; Fraser, J K; Zack, J A; Lee, F; Feuer, R; Chen, I S

    1996-01-01

    Human T-cell leukemia virus type I (HTLV-1) is the etiologic agent of adult T-cell leukemia and lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. We examined whether HTLV could productively infect human hematopoietic progenitor cells. CD34+ cells were enriched from human fetal liver cells and cocultivated with cell lines transformed with HTLV-1 and -2. HTLV-1 infection was established in between 10 and >95% of the enriched CD34+ cell population, as demonstrated by quantitative PCR analysis. HTLV-1 p19 Gag expression was also detected in infected hematopoietic progenitor cells. HTLV-1-infected hematopoietic progenitor cells were cultured in semisolid medium permissive for the development of erythbroid (BFU-E), myeloid (CFU-GM), and primitive progenitor (CFU-GEMM, HPP-CFC, or CFU-A) colonies. HTLV-1 sequences were detected in colonies of all hematopoietic lineages; furthermore, the ratio of HTLV genomes to the number of human cells in each infected colony was 1:1, consistent with each colony arising from a single infected hematopoietic progenitor cell. Severe combined immunodeficient mice engrafted with human fetal thymus and liver tissues (SCID-hu) develop a conjoint organ which supports human thymocyte differentiation and maturation. Inoculation of SCID-hu mice with HTLV-1-infected T cells or enriched populations of CD34+ cells established viral infection of thymocytes 4 to 6 weeks postreconstitution. Thymocytes from two mice with the greatest HTLV-1 proviral burdens showed increased expression of the CD25 marker and the interleukin 2 receptor alpha chain and perturbation of CD4+ and CD8+ thymocyte subset distribution profiles. Hematopoietic progenitor cells and thymuses may be targets for HTLV infection in humans, and these events may play a role in the pathogenesis associated with infection. PMID:8648741

  8. HTLV-I Tax-Mediated Inactivation of Cell Cycle Checkpoints and DNA Repair Pathways Contribute to Cellular Transformation: “A Random Mutagenesis Model”

    PubMed Central

    Nicot, Christophe

    2015-01-01

    To achieve cellular transformation, most oncogenic retroviruses use transduction by proto-oncogene capture or insertional mutagenesis, whereby provirus integration disrupts expression of tumor suppressors or proto-oncogenes. In contrast, the Human T-cell leukemia virus type 1 (HTLV-I) has been classified in a separate class referred to as “transactivating retroviruses”. Current views suggest that the viral encoded Tax protein transactivates expression of cellular genes leading to deregulated growth and transformation. However, if Tax-mediated transactivation was indeed sufficient for cellular transformation, a fairly high frequency of infected cells would eventually become transformed. In contrast, the frequency of transformation by HTLV-I is very low, likely less than 5%. This review will discuss the current understanding and recent discoveries highlighting critical functions of Tax in cellular transformation. HTLV-I Tax carries out essential functions in order to override cell cycle checkpoints and deregulate cellular division. In addition, Tax expression is associated with increased DNA damage and genome instability. Since Tax can inhibit multiple DNA repair pathways and stimulate unfaithful DNA repair or bypass checkpoints, these processes allow accumulation of genetic mutations in the host genome. Given this, a “Random Mutagenesis” transformation model seems more suitable to characterize the oncogenic activities of HTLV-I. PMID:26835512

  9. Prevalence of HIV, HTLV-I and HTLV-II among female sex workers in Spain, 2000-2001.

    PubMed

    Belza, María José

    2004-01-01

    Using an unlinked anonymous survey the seroprevalence of HIV, HTLV-I and HTLV-II was analysed among female sex workers. They were surveyed when they attended sexually transmitted disease clinics in six Spanish cities during the period 2000-2001. Fifty-eight percent of the 3149 women analysed came from Latin America or sub-Saharan Africa. The total prevalence of HIV was 0.7%, rising to 15.9% amongst injecting drug users (IDUs). When this group was not included, the prevalence amongst the Latin-Americans or sub-Saharan Africans was 0.8% and amongst the women from other origins 0.3% (p = 0.148). 33.3% of the women infected with HIV already knew about their infection. The prevalences of HTLV-I and HTLV-II were 0.3% and 0.2%, respectively. The prevalences of these three infections in this collective were low if evaluated without the IDUs.

  10. HTLV-1 Rex Tunes the Cellular Environment Favorable for Viral Replication.

    PubMed

    Nakano, Kazumi; Watanabe, Toshiki

    2016-02-24

    Human T-cell leukemia virus type-1 (HTLV-1) Rex is a viral RNA binding protein. The most important and well-known function of Rex is stabilizing and exporting viral mRNAs from the nucleus, particularly for unspliced/partially-spliced mRNAs encoding the structural proteins essential for viral replication. Without Rex, these unspliced viral mRNAs would otherwise be completely spliced. Therefore, Rex is vital for the translation of structural proteins and the stabilization of viral genomic RNA and, thus, for viral replication. Rex schedules the period of extensive viral replication and suppression to enter latency. Although the importance of Rex in the viral life-cycle is well understood, the underlying molecular mechanism of how Rex achieves its function has not been clarified. For example, how does Rex protect unspliced/partially-spliced viral mRNAs from the host cellular splicing machinery? How does Rex protect viral mRNAs, antigenic to eukaryotic cells, from cellular mRNA surveillance mechanisms? Here we will discuss these mechanisms, which explain the function of Rex as an organizer of HTLV-1 expression based on previously and recently discovered aspects of Rex. We also focus on the potential influence of Rex on the homeostasis of the infected cell and how it can exert its function.

  11. HTLV-1 Rex Tunes the Cellular Environment Favorable for Viral Replication.

    PubMed

    Nakano, Kazumi; Watanabe, Toshiki

    2016-03-01

    Human T-cell leukemia virus type-1 (HTLV-1) Rex is a viral RNA binding protein. The most important and well-known function of Rex is stabilizing and exporting viral mRNAs from the nucleus, particularly for unspliced/partially-spliced mRNAs encoding the structural proteins essential for viral replication. Without Rex, these unspliced viral mRNAs would otherwise be completely spliced. Therefore, Rex is vital for the translation of structural proteins and the stabilization of viral genomic RNA and, thus, for viral replication. Rex schedules the period of extensive viral replication and suppression to enter latency. Although the importance of Rex in the viral life-cycle is well understood, the underlying molecular mechanism of how Rex achieves its function has not been clarified. For example, how does Rex protect unspliced/partially-spliced viral mRNAs from the host cellular splicing machinery? How does Rex protect viral mRNAs, antigenic to eukaryotic cells, from cellular mRNA surveillance mechanisms? Here we will discuss these mechanisms, which explain the function of Rex as an organizer of HTLV-1 expression based on previously and recently discovered aspects of Rex. We also focus on the potential influence of Rex on the homeostasis of the infected cell and how it can exert its function. PMID:26927155

  12. Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice.

    PubMed

    Fujisawa, K; Asahara, H; Okamoto, K; Aono, H; Hasunuma, T; Kobata, T; Iwakura, Y; Yonehara, S; Sumida, T; Nishioka, K

    1996-07-15

    We have recently demonstrated Fas-mediated apoptosis in the synovium, of patients with rheumatoid arthritis (RA) and suggested that it may be one factor responsible for the regression of RA. To examine whether the induction of apoptosis caused by anti-Fas mAb may play a potential role as a new therapeutic strategy for RA, we investigated the effect of anti-Fas mAb (RK-8) on synovitis in an animal model of RA, the human T cell leukemia virus type I (HTLV-1) tax transgenic mice. We report here that administration of anti-Fas mAb into mice intra-articularly improved the paw swelling and arthritis within 48 h. Immunohistochemical study and in vitro culture studies showed that 35% of synovial fibroblasts, 75% of mononuclear cells, and some of polymorphonuclear leukocytes infiltrating in synovium underwent apoptosis by anti-Fas mAb. In situ nick end labeling analysis and electron microscope analysis clearly showed that many cells in synovium were induced apoptosis by anti-Fas mAb administration. However, local administration of anti-Fas mAb did not produce systemic side effects. Results demonstrated that administration of anti-Fas mAb in arthritic joints of the HTLV-1 tax transgenic mice produced improvement of arthritis. These findings suggest that local administration of anti-Fas mAb may represent a useful therapeutic strategy for proliferative synovitis such as RA.

  13. Can thymic epithelial cells be infected by human T-lymphotropic virus type 1?

    PubMed

    Moreira-Ramos, Klaysa; Castro, Flávia Madeira Monteiro de; Linhares-Lacerda, Leandra; Savino, Wilson

    2011-09-01

    The human T-lymphotropic virus type-1 (HTLV-1) is the cause of adult T cell leukaemias/lymphoma. Because thymic epithelial cells (TEC) express recently defined receptors for the virus, it seemed conceivable that these cells might be a target for HTLV-1 infection. We developed an in vitro co-culture system comprising HTLV-1+-infected T cells and human TECs. Infected T cells did adhere to TECs and, after 24 h, the viral proteins gp46 and p19 were observed in TECs. After incubating TECs with culture supernatants from HTLV-1+-infected T cells, we detected gp46 on TEC membranes and the HTLV-1 tax gene integrated in the TEC genome. In conclusion, the human thymic epithelium can be infected in vitro by HTLV-1, not only via cell-cell contact, but also via exposure to virus-containing medium. PMID:22012233

  14. Inability to detect human T cell lymphotropic virus type 2-specific antibodies in a patient coinfected with HIV-1, human T cell lymphotropic virus type 1, human T cell lymphotropic virus type 2, and hepatitis C virus.

    PubMed

    Caterino-de-Araujo, Adele; Magri, Mariana Cavalheiro; Sato, Neuza Satomi; Morimoto, Helena Kaminami; Brigido, Luis Fernando de Macedo; Morimoto, Arilson Akira

    2014-01-01

    HIV-1, human T cell lymphotropic virus type 1 and type 2 (HTLV-1 and HTLV-2) and hepatitis C virus (HCV) are common among intravenous drug users (IDUs) and can cause chronic infections in the host. Usually, the diagnosis of such viruses employs serological assays; however, some difficulties in confirming HTLV-2 infection have been reported in high-risk populations in Brazil. We present data of an unusual case of coinfection with HIV-1, HTLV-1, HTLV-2, and HCV in a male IDU in which HTLV-2 was detected only by molecular assays. Comparative analysis of retroviruses from 2002 and 2012 showed identical HTLV-1 and HTLV-2 sequences (LTR, env, and tax), and a change in HIV-1 tropism from CXCR4 to CCR5. No mutation was detected in the hot points of the env region of the HTLV-2 isolate that justified the lack of rgp46-II-specific antibodies. These data emphasize the need for molecular assays to diagnose HTLV-2 in high-risk populations in Brazil.

  15. Inability to Detect Human T Cell Lymphotropic Virus Type 2-Specific Antibodies in a Patient Coinfected with HIV-1, Human T Cell Lymphotropic Virus Type 1, Human T Cell Lymphotropic Virus Type 2, and Hepatitis C Virus

    PubMed Central

    Magri, Mariana Cavalheiro; Sato, Neuza Satomi; Morimoto, Helena Kaminami; Brigido, Luis Fernando de Macedo; Morimoto, Arilson Akira

    2014-01-01

    Abstract HIV-1, human T cell lymphotropic virus type 1 and type 2 (HTLV-1 and HTLV-2) and hepatitis C virus (HCV) are common among intravenous drug users (IDUs) and can cause chronic infections in the host. Usually, the diagnosis of such viruses employs serological assays; however, some difficulties in confirming HTLV-2 infection have been reported in high-risk populations in Brazil. We present data of an unusual case of coinfection with HIV-1, HTLV-1, HTLV-2, and HCV in a male IDU in which HTLV-2 was detected only by molecular assays. Comparative analysis of retroviruses from 2002 and 2012 showed identical HTLV-1 and HTLV-2 sequences (LTR, env, and tax), and a change in HIV-1 tropism from CXCR4 to CCR5. No mutation was detected in the hot points of the env region of the HTLV-2 isolate that justified the lack of rgp46-II-specific antibodies. These data emphasize the need for molecular assays to diagnose HTLV-2 in high-risk populations in Brazil. PMID:23875602

  16. Infection of human synovial cells by human T cell lymphotropic virus type I. Proliferation and granulocyte/macrophage colony-stimulating factor production by synovial cells.

    PubMed Central

    Sakai, M; Eguchi, K; Terada, K; Nakashima, M; Yamashita, I; Ida, H; Kawabe, Y; Aoyagi, T; Takino, H; Nakamura, T

    1993-01-01

    The present study was performed to clarify the relationship between human T cell lymphotropic virus type I (HTLV-I) infection and chronic inflammatory arthropathy. To determine the ability of HTLV-I to infect synovial cells and the effect on synovial cell proliferation, synovial cells were cocultured with the HTLV-I-producing T cell lines (MT-2 or HCT-1). After coculture with HTLV-I-infected T cells, the synovial cells expressed HTLV-I-specific core antigens, and HTLV-I proviral DNA was detected from the synovial cells by polymerase chain reaction. These cocultured synovial cells with HTLV-I-infected T cells proliferated more actively than the synovial cells cocultured with uninfected T cells. This stimulatory effect of HTLV-I-infected T cells on synovial cell proliferation seems necessary to contact each other. After being cocultured with MT-2 cells, synovial cells proliferated more actively than control cells even after several passages. Furthermore, HTLV-I-infected synovial cells produced significant amounts of granulocyte/macrophage colony-stimulating factor. These results suggest that HTLV-I can infect synovial cells, resulting their active proliferation and may be involved in the pathogenesis of proliferative synovitis similar to that found in rheumatoid arthritis. Images PMID:8408648

  17. Plasma Soluble CD30 as a Possible Marker of Adult T-cell Leukemia in HTLV-1 Carriers: a Nested Case-Control Study.

    PubMed

    Takemoto, Shigeki; Iwanaga, Masako; Sagara, Yasuko; Watanabe, Toshiki

    2015-01-01

    Elevated levels of soluble CD30 (sCD30) are linked with various T-cell neoplasms. However, the relationship between sCD30 levels and the development of adult T-cell leukemia (ATL) in human T-cell leukemia virus type 1 (HTLV-1) carriers remains to be clarified. We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case-control study within a cohort of HTLV-1 carriers. We compared sCD30 levels between 11 cases (i.e., HTLV-1 carriers who later progressed to ATL) and 22 age-, sex- and institution-matched control HTLV-1 carriers (i.e., those with no progression). The sCD30 concentration at baseline was significantly higher in cases than in controls (median 65.8, range 27.2-134.5 U/mL vs. median 22.2, range 8.4-63.1 U/mL, P=0.001). In the univariate logistic regression analysis, a higher sCD30 (≥30.2 U/mL) was significantly associated with ATL development (odds ratio 7.88 and the 95% confidence intervals 1.35-45.8, P = 0.02). Among cases, sCD30 concentration tended to increase at the time of diagnosis of aggressive-type ATL, but the concentration was stable in those developing the smoldering-type. This suggests that sCD30 may serve as a predictive marker for the onset of aggressive-type ATL in HTLV-1 carriers.

  18. The Prevalence of Human T-Lymphotropic Virus Infection among Blood Donors in Southeast China, 2004-2013

    PubMed Central

    Xie, Jinzhen; Ge, Shengxiang; Zhang, Yali; Lin, Yongcai; Ni, Hongying; Zhang, Jun; Chen, Changrong

    2015-01-01

    Background The human T-lymphotropic virus type 1 (HTLV-1) which is associated with the diseases of adult T-cell leukemia/lymphoma, HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP) and HTLV-associated uveitis, can cause transfusion-transmitted infections. Although HTLV screening of blood donors was already routinely performed in developed countries, little is know about the HTLV prevalence among blood donors in developing countries which do not perform HTLV screening, such as China. Objectives &Aims To systematically characterize the prevalence of HTLV infection among bloods in southeast China. Methods A 10-year survey for HTLV prevalence in blood donors was performed in Xiamen, southeast China, during 2004-2013. The HTLV-1/2 of blood donations were screened by enzyme-linked immunosorbent assay, following with confirmation by western blot assay and 9nucleic acid testing. The HTLV-1 prevalences in donors from different cities were calculated. Viral sequences derived from identified HTLV-positive cases were sequenced and analyzed. Results Among 253,855 blood donors, 43 were confirmed to be seropositive for HTLV-1 (16.9 per 100,000 95% CI: 12.3-22.8) and none HTLV-2 infection was found. The HTLV-1 prevalence varied significantly in donors from different cities. Donors from cities in Fujian province (24.3 per 100,000, 95%CI: 17.4-33.1) had a significantly higher (p=0.001) HTLV-1 seroprevalence than those who were born in non-Fujian cities (3.4 per 100,000, 95%CI: 0.7-9.8). Among nine cities in Fujian province, the highest prevalence was found in blood donors from Ningde (171.3 per 100,000, 95%CI: 91.3-292.8) which is a coastal city in the northeast of Fujian. Molecular characterization of viral sequences from 27 HTLV-1 carriers revealed 25 were Transcontinental subtype of genotype A and 2 were Japanese subtype of genotype A. Interestingly, 12 of 25 Transcontinental subtype sequences harbored a characteristic L55P mutation in viral gp46 protein

  19. Association between Human Papillomavirus and Human T-Lymphotropic Virus in Indigenous Women from the Peruvian Amazon

    PubMed Central

    Garcia, Patricia J.; Carcamo, Cesar; Montano, Silvia M.; Muñante, Ricardo; Zunt, Joseph R.

    2012-01-01

    Background No association between the Human T-cell lymphotropic virus (HTLV), an oncogenic virus that alters host immunity, and the Human Papillomavirus (HPV) has previously been reported. Examining the association between these two viruses may permit the identification of a population at increased risk for developing cervical cancer. Methods and Findings Between July 2010 and February 2011, we conducted a cross-sectional study among indigenous Amazonian Peruvian women from the Shipibo-Konibo ethnic group, a group with endemic HTLV infection. We recruited women between 15 and 39 years of age who were living in the cities of Lima and Ucayali. Our objectives were to determine the association between HTLV and: (i) HPV infection of any type, and (ii) high-risk HPV type infection. Sexually active Shipibo-Konibo women were screened for HTLV-1 and HTLV-2 infections. All HTLV-1 or -2 positive women, along with two community-matched HTLV negative sexually active Shipibo-Konibo controls were later tested for the presence of HPV DNA, conventional cytology, and HIV. We screened 1,253 Shipibo-Konibo women, observing a prevalence of 5.9% (n = 74) for HTLV-1 and 3.8% (n = 47) for HTLV-2 infections. We enrolled 62 (60.8%) HTLV-1 positive women, 40 (39.2%) HTLV-2 positive women, and 205 community-matched HTLV negative controls. HTLV-1 infection was strongly associated with HPV infection of any type (43.6% vs. 29.3%; Prevalence Ratio (PR): 2.10, 95% CI: 1.53–2.87), and with high-risk HPV infection (32.3% vs. 22.4%; PR: 1.93, 95% CI: 1.04–3.59). HTLV-2 was not significantly associated with either of these HPV infections. Conclusions HTLV-1 infection was associated with HPV infection of any type and with high-risk HPV infection. Future longitudinal studies are needed to evaluate the incidence of high-risk HPV infection as well as the incidence of cervical neoplasia among HTLV-1 positive women. PMID:22952937

  20. Human T-cell leukemia virus type 2 produces a spliced antisense transcript encoding a protein that lacks a classic bZIP domain but still inhibits Tax2-mediated transcription

    PubMed Central

    Halin, Marilène; Douceron, Estelle; Clerc, Isabelle; Journo, Chloé; Ko, Nga Ling; Landry, Sébastien; Murphy, Edward L.; Gessain, Antoine; Lemasson, Isabelle; Mesnard, Jean-Michel

    2009-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) retroviruses infect T lymphocytes. The minus strand of the HTLV-1 genome encodes HBZ, a protein that could play a role in the development of leukemia in infected patients. Herein, we demonstrate that the complementary strand of the HTLV-2 genome also encodes a protein that we named APH-2 for “antisense protein of HTLV-2.” APH-2 mRNA is spliced, polyadenylated, and initiates in the 3′-long terminal repeat at different positions. This transcript was detected in all HTLV-2–infected cell lines and short-term culture of lymphocytes obtained from HTLV-2 African patients tested and in 4 of 15 HTLV-2–infected blood donors. The APH-2 protein is 183 amino acids long, is localized in the cell nucleus, and is detected in vivo. Despite the lack of a consensus basic leucine zipper domain, APH-2 interacts with cyclic adenosine monophosphate-response element binding protein (CREB) and represses Tax2-mediated transcription in Tax2-expressing cells and in cells transfected with an HTLV-2 molecular clone. Altogether, our results demonstrate the existence of an antisense strand–encoded protein in HTLV-2, which could represent an important player in the development of disorders, such as lymphocytosis, which is frequently observed in HTLV-2 patients. PMID:19602711

  1. Multiple isolates and characteristics of human T-cell leukemia virus type II.

    PubMed Central

    Hall, W W; Takahashi, H; Liu, C; Kaplan, M H; Scheewind, O; Ijichi, S; Nagashima, K; Gallo, R C

    1992-01-01

    Human T-cell leukemia (or lymphotropic) virus type II (HTLV-II) was isolated from eight HTLV-seropositive patients, six of whom were also infected with human immunodeficiency virus, by cocultivation of peripheral blood mononuclear cells (PBMCs) with BJAB, a continuous B-cell line. Restriction endonuclease mapping of the proviruses demonstrated consistent differences among isolates, and two distinct physical map patterns were observed. The results suggest the existence of two closely related molecular subtypes of HTLV-II, which are tentatively designated HTLV-IIa and HTLV-IIb. This finding was supported by preliminary nucleotide sequence analysis of the env gene region encoding the transmembrane glycoprotein gp21, which showed consistent differences between the two proposed virus subtypes. Exploitation of differences in restriction endonuclease sites allowed polymerase chain reaction amplification to detect and differentiate the two subtypes in fresh PBMCs of HTLV-seropositive intravenous drug abusers (IVDAs). The results of these studies confirm that HTLV-II infection is the prominent HTLV infection in seropositive IVDAs and also show that infection with both subtypes occurs. The finding of genetic heterogeneity in the HTLV-II group of viruses may have important implications for studies on its role in human disease and will be useful in characterizing the viruses present in newly discovered endemic foci in New World indigenous populations. Images PMID:1347796

  2. HTLV-1 and -2 Infections among 10 Indigenous Groups in the Peruvian Amazon

    PubMed Central

    Alva, Isaac E.; Orellana, E. Roberto; Blas, Magaly M.; Bernabe-Ortiz, Antonio; Cotrina, Armando; Chiappe, Marina; Kochel, Tadeusz J.; Carcamo, Cesar P.; García, Patricia J.; Zunt, Joseph R.; Buffardi, Anne L.; Montano, Silvia M.

    2012-01-01

    Infections with HTLV-1 and -2 were detected in 12 (1.9%) and 6 (0.9%) indigenous individuals living in 27 Amazonian villages in Peru. All infections occurred in Shipibo-Konibo people. HTLV was more common among participants living in villages distant from larger port cities and women with non-monogamous sexual partners. PMID:22964719

  3. Inhibition of cell-to-cell transmission of human T-cell lymphotropic virus type 1 in vitro by carbohydrate-binding agents.

    PubMed

    Balestrieri, Emanuela; Ascolani, Arianna; Igarashi, Yasuhiro; Oki, Toshikazu; Mastino, Antonio; Balzarini, Jan; Macchi, Beatrice

    2008-08-01

    Peripheral blood mononuclear cells (PBMCs) from healthy individuals can be infected by human T-lymphotropic virus type 1 (HTLV-1) upon cocultivation of the PBMCs with irradiated HTLV-1-transformed human MT-2 cells. This model system closely mimics HTLV-1 transmission through cell-to-cell contact. Carbohydrate-binding agents (CBAs) such as the alpha(1,3)/alpha(1,6)mannose-specific Hippeastrum hybrid agglutinin and the GlcNAc-specific Urtica dioica agglutinin, and also the small, nonpeptidic alpha(1,2)-mannose-specific antibiotic pradimicin A, were able to efficiently prevent cell-to-cell HTLV-1 transmission at nontoxic concentrations, as evidenced by the lack of appearance of virus-specific mRNA and of the viral protein Tax in the acceptor cells. Consistently, antivirally active doses of CBAs fully prevented HTLV-1-induced stimulation of PBMC growth. The inhibitory effects of CBAs on HTLV-1 transmission were also evident when HTLV-1-infected C5MJ cells were used in place of MT-2 cells as a virus donor cell line. The anti-HTLV-1 properties of the CBAs highlight the importance of the envelope glycans in events underlying HTLV-1 passage from cell to cell and indicate that CBAs should be further investigated for their potential to prevent HTLV-1 infection, including mother-to-child virus transmission by cell-to-cell contact through breast milk feeding. PMID:18505856

  4. [Evaluation of commercial equipment used in blood banks in Córdoba for the detection of anti-HTLV-I/II antibodies].

    PubMed

    Llop, N; Gastaldello, R; Valle, M; Macedo, R; Maturano, E; Blanco, S; Medeot, S; Gallego, S

    2000-01-01

    In order to assess the efficiency of currently used screening tests, Abbott HTLV-I/HTLV-II EIA, Vironostika HTLV-I/II Organon Teknika, Particle Agglutination (PA) assay Serodia Fujirebio Inc. (Tokyo, Japan) for HTLV-I/II antibody detection in blood donors samples, a panel of 100 sera from different blood banks of Córdoba city were studied. An "in house" indirect immunofluorescence assay (IFA) was used as reference test. The correlation rates were: 66% for Abbott HTLV-I/HTLV-II EIA, 97% for Vironostika HTLV-I/II Organon Teknika EIA and 99% for PA Serodia. Vironostika HTLV-I/II Organon Teknika EIA and PA Serodia assay proved to be more reliable for HTlV-I/II antibody screening in blood donors from Córdoba, yielding a very low rate of false positive results as compared with Abbot HTLV-I/HTLV-II EIA.

  5. Short Communication: Current Prevalence and Risk Factors Associated with Human T Lymphotropic Virus Type 1 and Human T Lymphotropic Virus Type 2 Infections Among HIV/AIDS Patients in São Paulo, Brazil

    PubMed Central

    Sacchi, Cláudio Tavares; Gonçalves, Maria Gisele; Campos, Karoline Rodrigues; Magri, Mariana Cavalheiro; Alencar, Wong Kuen

    2015-01-01

    Abstract During the 1990s, high prevalences of HIV/human T lymphotropic virus type 1 (HTLV-1) and HIV/human T lymphotropic virus type 2 (HTLV-2) coinfections were detected in São Paulo, Brazil in association with intravenous drug use (IDU). The current prevalences and risk factors for HIV/HTLV-1/-2 were evaluated in 1,608 patients attending the AIDS/STD Reference and Training Center in São Paulo. Blood samples were analyzed for HTLV-1/2-specific antibodies using enzyme immunoassays (EIA Murex HTLV-I+II, Diasorin, and Gold ELISA HTLV-I+II, REM) and immunoblotting (HTLV Blot 2.4, MP Biomedicals and INNO-LIA HTLV-I/II, Innogenetics) and for the pol proviral DNA segments of HTLV-1 and HTLV-2 by “in-house” real-time PCR. These analyses revealed that 50 (3.11%) of the samples were HTLV positive, including 25 (1.55%) that were HTLV-1 positive, 21 (1.31%) that were HTLV-2 positive, and 4 (0.25%) that were HTLV positive (untypeable). The median age of the HIV/HTLV-coinfected individuals was 50 years versus 44 years in the overall population (p=0.000). The risk factors associated with HIV/HTLV-1/-2 coinfections were female gender (OR 3.26, 1.78–5.95), black/pardo color (OR 2.21, 1.21–4.03), infection with hepatitis B virus (HBV) (OR 4.27, 2.32–7.87) or hepatitis C virus (HCV) (OR 24.40, 12.51–48.11), and intravenous drug use (IDU) (OR 30.01, 15.21–59.29). The current low prevalence of HTLV-1/2 in HIV-infected patients in São Paulo could be explained in part by programs providing IDUs with sterile needles and syringes and changes in the drug usage patterns of individuals from injecting cocaine to smoking crack cocaine. PMID:25464979

  6. Short Communication: Current Prevalence and Risk Factors Associated with Human T Lymphotropic Virus Type 1 and Human T Lymphotropic Virus Type 2 Infections Among HIV/AIDS Patients in São Paulo, Brazil.

    PubMed

    Caterino-de-Araujo, Adele; Sacchi, Cláudio Tavares; Gonçalves, Maria Gisele; Campos, Karoline Rodrigues; Magri, Mariana Cavalheiro; Alencar, Wong Kuen

    2015-05-01

    During the 1990s, high prevalences of HIV/human T lymphotropic virus type 1 (HTLV-1) and HIV/human T lymphotropic virus type 2 (HTLV-2) coinfections were detected in São Paulo, Brazil in association with intravenous drug use (IDU). The current prevalences and risk factors for HIV/HTLV-1/-2 were evaluated in 1,608 patients attending the AIDS/STD Reference and Training Center in São Paulo. Blood samples were analyzed for HTLV-1/2-specific antibodies using enzyme immunoassays (EIA Murex HTLV-I+II, Diasorin, and Gold ELISA HTLV-I+II, REM) and immunoblotting (HTLV Blot 2.4, MP Biomedicals and INNO-LIA HTLV-I/II, Innogenetics) and for the pol proviral DNA segments of HTLV-1 and HTLV-2 by "in-house" real-time PCR. These analyses revealed that 50 (3.11%) of the samples were HTLV positive, including 25 (1.55%) that were HTLV-1 positive, 21 (1.31%) that were HTLV-2 positive, and 4 (0.25%) that were HTLV positive (untypeable). The median age of the HIV/HTLV-coinfected individuals was 50 years versus 44 years in the overall population (p=0.000). The risk factors associated with HIV/HTLV-1/-2 coinfections were female gender (OR 3.26, 1.78-5.95), black/pardo color (OR 2.21, 1.21-4.03), infection with hepatitis B virus (HBV) (OR 4.27, 2.32-7.87) or hepatitis C virus (HCV) (OR 24.40, 12.51-48.11), and intravenous drug use (IDU) (OR 30.01, 15.21-59.29). The current low prevalence of HTLV-1/2 in HIV-infected patients in São Paulo could be explained in part by programs providing IDUs with sterile needles and syringes and changes in the drug usage patterns of individuals from injecting cocaine to smoking crack cocaine. PMID:25464979

  7. Short Communication: Current Prevalence and Risk Factors Associated with Human T Lymphotropic Virus Type 1 and Human T Lymphotropic Virus Type 2 Infections Among HIV/AIDS Patients in São Paulo, Brazil.

    PubMed

    Caterino-de-Araujo, Adele; Sacchi, Cláudio Tavares; Gonçalves, Maria Gisele; Campos, Karoline Rodrigues; Magri, Mariana Cavalheiro; Alencar, Wong Kuen

    2015-05-01

    During the 1990s, high prevalences of HIV/human T lymphotropic virus type 1 (HTLV-1) and HIV/human T lymphotropic virus type 2 (HTLV-2) coinfections were detected in São Paulo, Brazil in association with intravenous drug use (IDU). The current prevalences and risk factors for HIV/HTLV-1/-2 were evaluated in 1,608 patients attending the AIDS/STD Reference and Training Center in São Paulo. Blood samples were analyzed for HTLV-1/2-specific antibodies using enzyme immunoassays (EIA Murex HTLV-I+II, Diasorin, and Gold ELISA HTLV-I+II, REM) and immunoblotting (HTLV Blot 2.4, MP Biomedicals and INNO-LIA HTLV-I/II, Innogenetics) and for the pol proviral DNA segments of HTLV-1 and HTLV-2 by "in-house" real-time PCR. These analyses revealed that 50 (3.11%) of the samples were HTLV positive, including 25 (1.55%) that were HTLV-1 positive, 21 (1.31%) that were HTLV-2 positive, and 4 (0.25%) that were HTLV positive (untypeable). The median age of the HIV/HTLV-coinfected individuals was 50 years versus 44 years in the overall population (p=0.000). The risk factors associated with HIV/HTLV-1/-2 coinfections were female gender (OR 3.26, 1.78-5.95), black/pardo color (OR 2.21, 1.21-4.03), infection with hepatitis B virus (HBV) (OR 4.27, 2.32-7.87) or hepatitis C virus (HCV) (OR 24.40, 12.51-48.11), and intravenous drug use (IDU) (OR 30.01, 15.21-59.29). The current low prevalence of HTLV-1/2 in HIV-infected patients in São Paulo could be explained in part by programs providing IDUs with sterile needles and syringes and changes in the drug usage patterns of individuals from injecting cocaine to smoking crack cocaine.

  8. Increased expression of OX40 is associated with progressive disease in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis

    PubMed Central

    2013-01-01

    Background OX40 is a member of the tumor necrosis factor receptor family that is expressed primarily on activated CD4+ T cells and promotes the development of effector and memory T cells. Although OX40 has been reported to be a target gene of human T-cell leukemia virus type-1 (HTLV-1) viral transactivator Tax and is overexpressed in vivo in adult T-cell leukemia (ATL) cells, an association between OX40 and HTLV-1-associated inflammatory disorders, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), has not yet been established. Moreover, because abrogation of OX40 signals ameliorates chronic inflammation in animal models of autoimmune disease, novel monoclonal antibodies against OX40 may offer a potential treatment for HTLV-1-associated diseases such as ATL and HAM/TSP. Results In this study, we showed that OX40 was specifically expressed in CD4+ T cells naturally infected with HTLV-1 that have the potential to produce pro-inflammatory cytokines along with Tax expression. We also showed that OX40 was overexpressed in spinal cord infiltrating mononuclear cells in a clinically progressive HAM/TSP patient with a short duration of illness. The levels of the soluble form of OX40 (sOX40) in the cerebrospinal fluid (CSF) from chronic progressive HAM/TSP patients or from patients with other inflammatory neurological diseases (OINDs) were not different. In contrast, sOX40 levels in the CSF of rapidly progressing HAM/TSP patients were higher than those in the CSF from patients with OINDs, and these patients showed higher sOX40 levels in the CSF than in the plasma. When our newly produced monoclonal antibody against OX40 was added to peripheral blood mononuclear cells in culture, HTLV-1-infected T cells were specifically removed by a mechanism that depends on antibody-dependent cellular cytotoxicity. Conclusions Our study identified OX40 as a key molecule and biomarker for rapid progression of HAM/TSP. Furthermore, blocking OX40 may have potential in

  9. IL28B gene polymorphisms and Th1/Th2 cytokine levels might be associated with HTLV-associated arthropathy.

    PubMed

    de Sá, Keyla Santos Guedes; Santana, Bárbara Brasil; de Souza Ferreira, Tuane Carolina; Sousa, Rita Catarina Medeiros; Caldas, Cezar Augusto Muniz; Azevedo, Vânia Nakauth; Feitosa, Rosimar Neris Martins; Machado, Luiz Fernando Almeida; de Oliveira Guimarães Ishak, Marluísa; Ishak, Ricardo; Vallinoto, Antonio Carlos Rosário

    2016-01-01

    The present study is the first investigation of the association between single nucleotide polymorphisms (SNPs - rs8099917, rs12979860 and rs8103142) of the IL28B gene and the development of human T-lymphotropic virus (HTLV)-associated arthropathy (HAA). Individuals with HAA exhibited low interleukin (IL) 6 (p<0.05) and high IL-10 (p<0.05) levels compared with asymptomatic patients. TNF-α/CD4(+) T cell count, TNF-α/CD8(+) T cell count and IFN-γ/proviral load positively correlated in asymptomatic patients. The allelic and genotypic frequencies did not differ between patients with HAA and asymptomatic patients. Seven haplotypes were detected in the investigated population, with haplotype CCT (p<0.05) being the most frequent among the HTLV-infected individuals, while haplotype TTG (p<0.05) was detected in the group with HAA only. Compared with asymptomatic patients, individuals with HAA and genotype TT (rs8099917) exhibited larger numbers of CD8(+) T cells (p<0.05) and higher proviral load levels (p<0.05). Those patients with HAA and genotypes CC (rs12979860) and TT (rs8103142) exhibited high TNF-β (p<0.05) and IFN-γ (p<0.05) levels. Those patients with HAA and genotype CT/TT (rs12979860) exhibited high IL-10 levels (p<0.05). These results suggest that haplotypes CCT and TTG might be associated with susceptibility to HTLV infection and progression to HAA, respectively. Genotype TT (rs8099917) might be a risk factor for elevation of the proviral load and CD8(+) T cell count. In addition, genotypes CC (rs12979860) and TT (rs8103142) seem to be associated with increased TNF-β and IFN-γ levels. PMID:26546777

  10. Determination of antibodies against LAV/HTLV III: comparative evaluation of four different commercial test kits.

    PubMed

    Abb, J

    1986-01-01

    Four different, commercially available ELISA tests for the detection of antibodies against LAV/HTLV III were evaluated for specificity and sensitivity. The relative specificity of the kits was determined by investigating a test panel of 76 sera collected from asymptomatic or symptomatic homosexual men. Completely concordant results were obtained for sera from asymptomatic male homosexuals (11% positive for Anti-LAV/HTLV III) or from patients with the AIDS-related complex (91% positive for Anti-LAV/HTLV III). Differences between the ELISA test kits, however, were observed with sera obtained from patients with AIDS. While Anti-LAV/HTLV III was detected by the Abbott, Electro-Nucleonics, and Organon test in all 17 sera from AIDS patients, the Pasteur test failed to detect Anti-LAV/HTLV III in 7 consecutive sera from an individual patient with late-stage AIDS. The relative sensitivity of the ELISA tests was determined by endpoint titration of confirmed Anti-LAV/HTLV III positive sera from donors of different risk groups for AIDS. The titration experiments demonstrated that the Abbott test clearly was the most sensitive of the ELISA tests studied, followed by the Electro-Nucleonics, Pasteur, and Organon test. The results further indicate that most of the differences of specificity and sensitivity observed between the Anti-LAV/HTLV III tests could be abolished by a modified definition of minimum positive absorbance values.

  11. Association of Sicca Syndrome with Proviral Load and Proinflammatory Cytokines in HTLV-1 Infection

    PubMed Central

    Lima, Clara Mônica; Santos, Silvane; Dourado, Adriana; Carvalho, Natália B.; Bittencourt, Valéria; Lessa, Marcus Miranda; Siqueira, Isadora; Carvalho, Edgar M.

    2016-01-01

    The Sjögren syndrome has been diagnosed in patients with HTLV-1 associated myelopathy and dry mouth and dry eyes are documented in HTLV-1 carriers. However the diagnosis of Sjögren syndrome in these subjects has been contested. In this cross-sectional study, we evaluated the role of immunological factors and proviral load, in sicca syndrome associated with HTLV-1 in patients without myelopathy. Subjects were recruited in the HTLV-1 Clinic, from 2009 to 2011. The proviral load and cytokine levels (IFN-γ, TNF-α, IL-5, and IL-10) were obtained from a database containing the values presented by the subjects at admission in the clinic. Of the 272 participants, 59 (21.7%) had sicca syndrome and in all of them anti-Sjögren syndrome related antigen A (SSA) and antigen B (SSB) were negatives. The production of TNF-α and IFN-γ was higher in the group with sicca syndrome (P < 0.05) than in HTLV-1 infected subjects without sicca syndrome. Our data indicates that patients with sicca syndrome associated with HTLV-1 do not have Sjögren syndrome. However the increased production of TNF-α and IFN-γ in this group of patients may contribute to the pathogenesis of sicca syndrome associated with HTLV-1. PMID:26904697

  12. Prevalence of HTLV-1 Antibody among Major Thalassemic Patients in Gorgan (South East of Caspian Sea)

    NASA Astrophysics Data System (ADS)

    Moradi, A.; Mansurian, A. R.; Ahmadi, A. R.; Ghaemi, E.; Kalavi, K. H.; Marjani, A.; Sanei Moghaddam, E.

    In this study, the prevalence of HTLV-1 infection among the thalassemic patients was investigated. 181 thalassemic patients whom referred to Talghani hospital during, Oct. 2004-Sep. 2005 were participated in this study. HTLV antibody was determined using ELISA technique. In this procedure (Diapron laboratory kit) HTLV, positive samples tested by HTLV-1 western blot (kit, 2.4) to confirm, ELISA positive samples and also to detect the HTLV types. From 181 thalassemic patients, 93 (51.4%) were males. The age rate of these ranged 1-25 years, (mean of 14.11±6.5). Of these subjects 169 patients (93.4%) were received packet cell at least one unite per month. 28(14.9%) of subjects were HTLV positive, while only 4.4% of them were confirmed by western blot and also for contamination with type-1 virus infection. Contamination with this virus increased, as the patients were getting older. The findings derived from this study indicated that among the thalassemic patients in Gorgan there were cases with HTLV-1, infection that was correlated with the other part of the country. It is therefore concluded; that further comprehensive studies are required to identify infected blood donations by blood donors in Gorgan.

  13. A Transgenic Drosophila melanogaster Model To Study Human T-Lymphotropic Virus Oncoprotein Tax-1-Driven Transformation In Vivo.

    PubMed

    Shirinian, Margret; Kambris, Zakaria; Hamadeh, Lama; Grabbe, Caroline; Journo, Chloé; Mahieux, Renaud; Bazarbachi, Ali

    2015-08-01

    Human T-cell lymphotropic virus type 1 (HTLV-1)-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. HTLV-2 is genetically related to HTLV-1 but does not cause any malignant disease. HTLV-1 Tax transactivator (Tax-1) contributes to leukemogenesis via NF-κB. We describe transgenic Drosophila models expressing Tax in the compound eye and plasmatocytes. We demonstrate that Tax-1 but not Tax-2 induces ommatidial perturbation and increased plasmatocyte proliferation and that the eye phenotype is dependent on Kenny (IKKγ/NEMO), thus validating this new in vivo model.

  14. A case of peripheral T-cell lymphoma, not otherwise specified in a HCV and HTLV-II-positive patient, diagnosed by abdominal fluid cytology

    PubMed Central

    Parekh, Trisha M.; Qian, You-Wen; Elghetany, M. Tarek; Schnadig, Vicki; Nawgiri, Ranjina

    2016-01-01

    Background Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a rare neoplasm that typically presents as generalized lymphadenopathy. PTCL, NOS presenting as malignant ascites is rare. Methods A 61-year-old African-American man with past medical history of HCV, cryoglobulinemia, and cryptococcal pneumonia was admitted for dyspnea on exertion over a period of 1 month and new onset of abdominal distension. Results Ascites, splenomegaly, hepatomegaly and extensive lymphadenopathy were found by imaging. Paracentesis obtained 1.3 liter of abdominal fluid, the cytologic evaluation showed a monomorphic population of intermediate-sized lymphoid cells with irregular to convoluted nuclear contours. Fluid sent for flow cytometry showed an abnormal T-lymphocyte population expressing CD4, weak surface CD3 and absence of CD7. PCR studies of ascitic fluid detected a clonal T-lymphocyte population with T-cell receptor gamma gene rearrangement. Serologic testing for human T lymphotropic virus (HTLV) was positive for HTLV-II. Subsequent bone marrow biopsy revealed lymphomatous involvement. CD30 and ALK-1 immunostaining were negative. This case was classified as PTCL, NOS. Conclusions PTCL, NOS can have unusual clinical presentation such as ascites and pleural effusion, and may also occur as a complication of immunodeficiency state. Further studies are needed to determine if HCV or HTLV-II viral infection is associated with PTCL. PMID:27034820

  15. Physalin F, a seco-steroid from Physalis angulata L., has immunosuppressive activity in peripheral blood mononuclear cells from patients with HTLV1-associated myelopathy.

    PubMed

    Pinto, Lorena A; Meira, Cássio S; Villarreal, Cristiane F; Vannier-Santos, Marcos A; de Souza, Claudia V C; Ribeiro, Ivone M; Tomassini, Therezinha C B; Galvão-Castro, Bernardo; Soares, Milena B P; Grassi, Maria F R

    2016-04-01

    Human T-lymphotropic virus type 1 (HTLV-1) induces a strong activation of the immune system, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Physalin F is a secosteroid with potent anti-inflammatory and immunomodulatory activities. The present study aimed to investigate the effects of physalin F on peripheral blood mononuclear cells (PBMC) of HAM/TSP subjects. A concentration-dependent inhibition of spontaneous proliferation of PBMC from HAM/TSP subjects was observed in the presence of physalin F, as evaluated by (3)H-thymidine uptake. The IC50 for physalin F was 0.97 ± 0.11 μM. Flow cytometry analysis using Cytometric Bead Array (CBA) showed that physalin F (10 μM) significantly reduced the levels of IL-2, IL-6, IL-10, TNF-α and IFN-γ, but not IL-17A, in supernatants of PBMC cultures. Next, apoptosis induction was addressed by using flow cytometry to evaluate annexin V expression. Treatment with physalin F (10 μM) increased the apoptotic population of PBMC in HAM/TSP subjects. Transmission electron microscopy analysis of PBMC showed that physalin F induced ultrastructural changes, such as pyknotic nuclei, damaged mitochondria, enhanced autophagic vacuole formation, and the presence of myelin-like figures. In conclusion, physalin F induces apoptosis of PBMC, decreasing the spontaneous proliferation and cytokine production caused by HTLV-1 infection.

  16. Barefoot Plantar Pressure Indicates Progressive Neurological Damage in Patients with Human T-Cell Lymphotropic Virus Type 1 Infection

    PubMed Central

    Vasconcelos, Beatriz Helena B.; Souza, Givago S.; Barroso, Tatiana G. C. P.; Silveira, Luiz Carlos L.; Sousa, Rita Catarina M.; Callegari, Bianca; Xavier, Marília B.

    2016-01-01

    Background The human T-Cell Lymphotropic Virus Type 1 (HTLV-1) is a retrovirus associated with neurological alterations; individuals with HTLV-1 infection may develop HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP). Frequent neurological complaints include foot numbness and leg weakness. In this study, we compared the distribution of the body weight on different areas of the foot in HTLV-1 patients with HAM/TSP, asymptomatic HTLV-1 patients, and healthy individuals. Methodology We studied 36 HTLV-1 infected patients, who were divided in two groups of 18 patients each based on whether or not they had been diagnosed with HAM/TSP, and 17 control subjects. The evaluation included an interview on the patient’s clinical history and examinations of the patient’s reflexes, foot skin tactile sensitivity, and risk of falling. The pressure distribution on different areas of the foot was measured with baropodometry, using a pressure platform, while the patients had their eyes open or closed. Main Findings The prevalence of neurological disturbances—altered reflexes and skin tactile sensitivity and increased risk of falling—was higher in HTLV-1 HAM/TSP patients than in HTLV-1 asymptomatic patients. The medium and maximum pressure values were higher in the forefoot than in the midfoot and hindfoot in both HTLV-1 groups. In addition, the pressure on the hindfoot was lower in HAM/TSP patients compared to control subjects. Conclusions The neurological disturbances associated with HTLV-1 infection gradually worsened from HTLV-1 asymptomatic patients to HAM/TSP patients. Baropodometry is a valuable tool to establish the extent of neurological damage in patients suffering from HTLV-1 infection. PMID:26998608

  17. Phylogenetic relationship and geographic distribution of multiple human T-cell lymphotropic virus type II subtypes.

    PubMed Central

    Switzer, W M; Pieniazek, D; Swanson, P; Samdal, H H; Soriano, V; Khabbaz, R F; Kaplan, J E; Lal, R B; Heneine, W

    1995-01-01

    The current env-based subtyping of human T-cell lymphotropic virus type II (HTLV-II) identifies only two heterogenetic groups, HTLV-IIa and HTLV-IIb. To better understand the genetic diversity and phylogeny of HTLV-II, we examined the most divergent genomic region of HTLV-II, the long terminal repeat, by using restriction fragment length polymorphism (RFLP) and sequence analysis. Long terminal repeat sequences were amplified from peripheral blood mononuclear cells by PCR and digested with seven restriction endonucleases that differentiated HTLV-II into five HTLV-IIa (IIa0 to IIa4) and six HTLV-IIb (IIb0 to IIb5) restriction types, with HTLV-IIa0 and HTLV-IIb0 being prototypes for the MoT and NRA isolates, respectively. We examined 169 HTLV-II-infected samples, including 123 from blood donors and intravenous drug users (IDU) from the Americas, 16 from IDU from Europe, and 30 from Amerindians. Of the 169 samples, 109 (64.5%) were categorized as HTLV-IIa and 60 (35.5%) were categorized as HTLV-IIb. The predominant restriction types seen among the U.S. blood donors and U.S. IDU were IIa0 (68.7%) and IIb4 (10.4%). Four Spanish and seven Italian samples were IIb4, while five Norwegian samples were IIa2. Twelve Guaymi and all ten Seminole samples were single restriction types (IIb1 and IIb5, respectively), whereas the two Navajo and six Pueblo samples had a mixture of restriction types IIa0, IIa4, and IIb5. Of the HTLV-IIb restriction types observed in the U.S. non-Indians, 42.8% appear to have originated from the North Amerindian (IIb5), while 57.2% were similar to the European IIb4 restriction type. Sequences of 15 selected HTLV-II samples were determined and phylogenetically compared with 7 previously published HTLV-II LTR sequences. The derived topologies revealed three HTLV-IIa phylogroups (A-I to A-III) and four HTLV-IIb phylogroups (B-I to B-IV). Furthermore, the HTLV-IIa phylogroups appear to have evolved from the HTLV-IIb phylogroups. In the HTLV-IIa cluster, a

  18. Immunological signature of the different clinical stages of the HTLV-1 infection: establishing serum biomarkers for HTLV-1-associated disease morbidity.

    PubMed

    Starling, Ana Lúcia Borges; Coelho-Dos-Reis, Jordana Grazziela Alves; Peruhype-Magalhães, Vanessa; Pascoal-Xavier, Marcelo Antônio; Gonçalves, Denise Utsch; Béla, Samantha Ribeiro; Lambertucci, José Roberto; Labanca, Ludimila; Souza Pereira, Silvio Roberto; Teixeira-Carvalho, Andréa; Ribas, João Gabriel; Trindade, Bruno Caetano; Faccioli, Lucia Helena; Carneiro-Proietti, Anna Bárbara Freitas; Martins-Filho, Olindo Assis

    2015-01-01

    This study aimed at establishing the immunological signature and an algorithm for clinical management of the different clinical stages of the HTLV-1-infection based on serum biomarkers. A panel of serum biomarkers was evaluated by four sets of innovative/non-conventional data analysis approaches in samples from 87 HTLV-1 patients: asymptomatic carriers (AC), putative HTLV-1 associated myelopathy/tropical spastic paraparesis (pHAM/TSP) and HAM/TSP. The analysis of cumulative curves and molecular signatures pointed out that HAM/TSP presented a pro-inflammatory profile mediated by CXCL10/LTB-4/IL-6/TNF-α/IFN-γ, counterbalanced by IL-4/IL-10. The analysis of biomarker networks showed that AC presented a strongly intertwined pro-inflammatory/regulatory net with IL-4/IL-10 playing a central role, while HAM/TSP exhibited overall immune response toward a predominant pro-inflammatory profile. At last, the classification and regression trees proposed for clinical practice allowed for the construction of an algorithm to discriminate AC, pHAM and HAM/TSP patients with the elected biomarkers: IFN-γ, TNF-α, IL-10, IL-6, IL-4 and CysLT. These findings reveal a complex interaction among chemokine/leukotriene/cytokine in HTLV-1 infection and suggest the use of the selected but combined biomarkers for the follow-up/diagnosis of disease morbidity of HTLV-1-infected individuals.

  19. Prevalence of antibodies to HTLV in antenatal clinic attenders in south east London.

    PubMed

    Hale, A; Leung, T; Sivasubramaniam, S; Kenny, J; Sutherland, S

    1997-07-01

    The prevalence of antibodies to HTLV in women attending a south east London antenatal clinic between October 1990 and July 1992 was determined using sera referred for routine rubella antibody testing. Samples were screened for HTLV antibody using a modified Fujirebio gel particle agglutination test and reactive sera confirmed by ELISA (Abbott Laboratories, North Chicago, IL) and two commercial Western blots (Cambridge Biotech Inc., Rockville, MD, and Diagnostic Biotechnology, Genelab Diagnostics, Louvaine, Belgium). This strategy confirmed the presence of HTLV-1 antibodies in 12 out of 6,289 sera (0.19%, 95% confidence limits 0.083% to 0.30%) and HTLV-2 antibodies in 2 (0.03%) sera. Specimens from 8 of 821 (0.97%, 95% confidence limits 0.42% to 1.9%) Afro-Caribbean women, three of 1,136 (0.26%, 95% confidence limits 0.055% to 0.78%) African women, and one of 3,049 (0.033%, 95% confidence limits 0.006% to 0.18%) Caucasian women were positive for HTLV-1 antibodies. Sera from Afro-Caribbean women born in the Caribbean were 7.6 times more likely to be HTLV-1 antibody positive than sera from Afro-Caribbean women born in the UK (P = 0.012). Selective testing of Afro-Caribbean and African antenatal clinic attenders, in this setting, would have identified 11 of the 12 HTLV-1 infections at an estimated cost of prevention of HTLV-1 associated disease of 100,000 pounds per case which is considerably less than the 1.3 million pounds which has been estimated to prevent a case by universal screening of UK blood donors.

  20. Gastrointestinal parasitic infection in healthy Jamaican carriers of HTLV-I.

    PubMed

    Robinson, R D; Murphy, E L; Wilks, R J; Neva, F A; Terry, S I; Hanchard, B; Figueroa, J P; Blattner, W A

    1991-12-01

    A subsample (1.6%; n = 13,260) of a healthy Jamaican population of food-handlers, studied by Murphy et al. (1991), who were serologically positive (n = 99) or negative (n = 113) for HTLV-I was investigated for intestinal parasitic infection using coprological methods. Helminth infection included Ascaris lumbricoides (2.8%), Trichuris trichiura (7.1%) and hookworms (6.1%). Entamoeba coli was found in 21.8% of samples, while E. hartmanni, Giardia lamblia, Endolimax nana, Iodamoeba bütschlii and Chilomastix mesnili each occurred in less than 10% of responders. T. trichiura displayed a higher prevalence (10.6 vs 3%) (chi 2 = 4.623; P = 0.03) in the HTLV-I negative group. G. lamblia was detected more frequently among HTLV-I carriers compared to controls (9.1 and 3.5%, respectively), but the association was not statistically significant (chi 2 = 2.825; P = 0.09). Infection with intestinal parasites is likely to occur independent of HTLV-I status: however, possible HTLV-I-induced immunosuppression may lead to higher intensity infections of certain organisms thus facilitating easier detection using parasitological methods. The immunomodulatory potential of HTLV-I infection in the aetiology of non-malignant diseases requires further investigation. PMID:1758014

  1. Endemic versus epidemic viral spreads display distinct patterns of HTLV-2b replication

    SciTech Connect

    Gabet, Anne-Sophie; Moules, Vincent; Sibon, David; Nass, Catharie C.; Mortreux, Franck; Mauclere, Philippe; Gessain, Antoine; Murphy, Edward L.; Wattel, Eric . E-mail: wattel@lyon.fnclcc.fr

    2006-02-05

    As the replication pattern of leukemogenic PTLVs possesses a strong pathogenic impact, we investigated HTLV-2 replication in vivo in asymptomatic carriers belonging into 2 distinct populations infected by the same HTLV-2b subtype. They include epidemically infected American blood donors, in whom HTLV-2b has been present for only 30 years, and endemically infected Bakola Pygmies from Cameroon, characterized by a long viral endemicity (at least few generations). In blood donors, both the circulating proviral loads and the degree of infected cell proliferation were largely lower than those characterizing asymptomatic carriers infected with leukemogenic PTLVs (HTLV-1, STLV-1). This might contribute to explain the lack of known link between HTLV-2b infection and the development of malignancies in this population. In contrast, endemically infected individuals displayed high proviral loads resulting from the extensive proliferation of infected cells. The route and/or the duration of infection, viral genetic drift, host immune response, genetic background, co-infections or a combination thereof might have contributed to these differences between endemically and epidemically infected subjects. As the clonality pattern observed in endemically infected individuals is very reminiscent of that of leukemogenic PTLVs at the pre-leukemic stage, our results highlight the possible oncogenic effect of HTLV-2b infection in such population.

  2. Modes of Human T Cell Leukemia Virus Type 1 Transmission, Replication and Persistence

    PubMed Central

    Carpentier, Alexandre; Barez, Pierre-Yves; Hamaidia, Malik; Gazon, Hélène; de Brogniez, Alix; Perike, Srikanth; Gillet, Nicolas; Willems, Luc

    2015-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes cancer (Adult T cell Leukemia, ATL) and a spectrum of inflammatory diseases (mainly HTLV-associated myelopathy—tropical spastic paraparesis, HAM/TSP). Since virions are particularly unstable, HTLV-1 transmission primarily occurs by transfer of a cell carrying an integrated provirus. After transcription, the viral genomic RNA undergoes reverse transcription and integration into the chromosomal DNA of a cell from the newly infected host. The virus then replicates by either one of two modes: (i) an infectious cycle by virus budding and infection of new targets and (ii) mitotic division of cells harboring an integrated provirus. HTLV-1 replication initiates a series of mechanisms in the host including antiviral immunity and checkpoint control of cell proliferation. HTLV-1 has elaborated strategies to counteract these defense mechanisms allowing continuous persistence in humans. PMID:26198240

  3. Ubiquitination and sumoylation of the HTLV-2 Tax-2B protein regulate its NF-κB activity: a comparative study with the HTLV-1 Tax-1 protein

    PubMed Central

    2012-01-01

    Background Retroviruses HTLV-1 and HTLV-2 have homologous genomic structures but differ significantly in pathogenicity. HTLV-1 is associated with Adult T cell Leukemia (ATL), whereas infection by HTLV-2 has no association with neoplasia. Transformation of T lymphocytes by HTLV-1 is linked to the capacity of its oncoprotein Tax-1 to alter cell survival and cell cycle control mechanisms. Among these functions, Tax-1-mediated activation of cellular gene expression via the NF-κB pathway depends on Tax-1 post-translational modifications by ubiquitination and sumoylation. The Tax-2 protein of HTLV-2B (Tax-2B) is also modified by ubiquitination and sumoylation and activates the NF-κB pathway to a level similar to that of Tax-1. The present study aims to understand whether ubiquitination and sumoylation modifications are involved in Tax-2B-mediated activation of the NF-κB pathway. Results The comparison of Tax-1 and Tax-2B lysine to arginine substitution mutants revealed conserved patterns and levels of ubiquitination with notable difference in the lysine usage for sumoylation. Neither Tax-1 nor Tax-2B ubiquitination and sumoylation deficient mutants could activate the NF-κB pathway and fusion of ubiquitin or SUMO-1 to the C-terminus of the ubiquitination and sumoylation deficient Tax-2B mutant strikingly restored transcriptional activity. In addition, ubiquitinated forms of Tax-2B colocalized with RelA and IKKγ in prominent cytoplasmic structures associated with the Golgi apparatus, whereas colocalization of Tax-2B with the RelA subunit of NF-κB and the transcriptional coactivator p300 in punctate nuclear structures was dependent on Tax-2B sumoylation, as previously observed for Tax-1. Conclusions Both Tax-1 and Tax-2 activate the NF-κB pathway via similar mechanisms involving ubiquitination and sumoylation. Therefore, the different transforming potential of HTLV-1 and HTLV-2 is unlikely to be related to different modes of activation of the canonical NF-κB pathway

  4. HTLV-2B Tax oncoprotein is modified by ubiquitination and sumoylation and displays intracellular localization similar to its homologue HTLV-1 Tax

    SciTech Connect

    Turci, Marco; Lodewick, Julie; Righi, Paola; Polania, Angela; Romanelli, Maria Grazia; Bex, Francoise; Bertazzoni, Umberto

    2009-03-30

    HTLV-1 is more pathogenic than HTLV-2B. The difference is generally attributed to the properties of their individual transactivating Tax proteins. By using internal Flag-6His tagged Tax-1 and Tax-2B, which display transcriptional activities comparable to the untagged proteins and can be recognized by a single anti-Flag antibody, we demonstrate that Tax-2B is modified by ubiquitination and sumoylation. In addition, Tax2B is distributed in punctuate nuclear structures that include the RelA subunit of NF-{kappa}B, as has been previously demonstrated for Tax-1.

  5. Elimination of human T cell leukemia virus type-1-infected cells by neutralizing and antibody-dependent cellular cytotoxicity-inducing antibodies against human t cell leukemia virus type-1 envelope gp46.

    PubMed

    Tanaka, Yuetsu; Takahashi, Yoshiaki; Tanaka, Reiko; Kodama, Akira; Fujii, Hideki; Hasegawa, Atsuhiko; Kannagi, Mari; Ansari, Aftab A; Saito, Mineki

    2014-06-01

    Human T cell leukemia virus type-1 (HTLV-1) is prevalent worldwide with foci of high prevalence. However, to date no effective vaccine or drug against HTLV-1 infection has been developed. In efforts to define the role of antibodies in the control of HTLV-1 infection, we capitalized on the use of our previously defined anti-gp46 neutralizing monoclonal antibody (mAb) (clone LAT-27) and high titers of human anti-HTLV-1 IgG purified from HAM/TSP patients (HAM-IgG). LAT-27 and HAM-IgG completely blocked syncytium formation and T cell immortalization mediated by HTLV-1 in vitro. The addition of these antibodies to cultures of CD8(+) T cell-depleted peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients at the initiation of culture not only decreased the numbers of Tax-expressing cells and the production of HTLV-1 p24 but also inhibited the spontaneous immortalization of T cells. Coculture of in vitro-HTLV-1-immortalized T cell lines with autologous PBMCs in the presence of LAT-27 or HAM-IgG, but not an F(ab')2 fragment of LAT-27 or nonneutralizing anti-gp46 mAbs, resulted in depletion of HTLV-1-infected cells. A 24-h (51)Cr release assay showed the presence of significant antibody-dependent cellular cytotoxicity (ADCC) activity in LAT-27 and HAM-IgG, but not F(ab')2 of LAT-27, resulting in the depletion of HTLV-1-infected T cells by autologous PBMCs. The depletion of natural killer (NK) cells from the effector PBMCs reduced this ADCC activity. Altogether, the present data demonstrate that the neutralizing and ADCC-inducing activities of anti-HTLV-1 antibodies are capable of reducing infection and eliminating HTLV-1-infected cells in the presence of autologous PBMCs. PMID:24524420

  6. Use of anti-tumor necrosis factor biologics in the treatment of rheumatoid arthritis does not change human T-lymphotropic virus type 1 markers: a case series.

    PubMed

    Umekita, Kunihiko; Umeki, Kazumi; Miyauchi, Shunichi; Ueno, Shiro; Kubo, Kazuyoshi; Kusumoto, Norio; Takajo, Ichiro; Nagatomo, Yasuhiro; Okayama, Akihiko

    2015-09-01

    Anti-tumor necrosis factor (anti-TNF) biologics are effective in the treatment of rheumatoid arthritis (RA); however, it is still not clear whether this treatment promotes the development of malignancies such as lymphoma. Human T-lymphotropic virus type 1 (HTLV-1), which is a causative agent of adult T-cell lymphoma (ATL), is prevalent in Japan. Many HTLV-1-positive patients with RA are assumed to exist; however, there have thus far been no reports on the effect of anti-TNF biologics on HTLV-1-positive patients. We analyzed the response to treatment with anti-TNF biologics and change of HTLV-1 markers in two cases of RA. The two cases showed no response based on the European League Against of Rheumatism response criteria 60-96 weeks after administration of anti-TNF biologics (infliximab and etanercept). No signs of ATL were observed and HTLV-1 markers, such as proviral load and clonality of HTLV-1-infected cells, showed no significant change in either of two cases. Therefore, treatment with anti-TNF biologics did not induce activation of HTLV-1, although the effect on RA was not as effective as in HTLV-1-negative patients in this limited study. Further long-term study with a greater number of patients is necessary to clarify the safety and efficacy of anti-TNF biologics in HTLV-1-positive patients with RA.

  7. HTLV-1 in rural Guinea-Bissau: prevalence, incidence and a continued association with HIV between 1990 and 2007

    PubMed Central

    2010-01-01

    Background HTLV-1 is endemic in Guinea-Bissau, and the highest prevalence in the adult population (5.2%) was observed in a rural area, Caió, in 1990. HIV-1 and HIV-2 are both prevalent in this area as well. Cross-sectional associations have been reported for HTLV-1 with HIV infection, but the trends in prevalence of HTLV-1 and HIV associations are largely unknown, especially in Sub Saharan Africa. In the current study, data from three cross-sectional community surveys performed in 1990, 1997 and 2007, were used to assess changes in HTLV-1 prevalence, incidence and its associations with HIV-1 and HIV-2 and potential risk factors. Results HTLV-1 prevalence was 5.2% in 1990, 5.9% in 1997 and 4.6% in 2007. Prevalence was higher among women than men in all 3 surveys and increased with age. The Odds Ratio (OR) of being infected with HTLV-1 was significantly higher for HIV positive subjects in all surveys after adjustment for potential confounding factors. The risk of HTLV-1 infection was higher in subjects with an HTLV-1 positive mother versus an uninfected mother (OR 4.6, CI 2.6-8.0). The HTLV-1 incidence was stable between 1990-1997 (Incidence Rate (IR) 1.8/1,000 pyo) and 1997-2007 (IR 1.6/1,000 pyo) (Incidence Rate Ratio (IRR) 0.9, CI 0.4-1.7). The incidence of HTLV-1 among HIV-positive individuals was higher compared to HIV negative individuals (IRR 2.5, CI 1.0-6.2), while the HIV incidence did not differ by HTLV-1 status (IRR 1.2, CI 0.5-2.7). Conclusions To our knowledge, this is the largest community based study that has reported on HTLV-1 prevalence and associations with HIV. HTLV-1 is endemic in this rural community in West Africa with a stable incidence and a high prevalence. The prevalence increases with age and is higher in women than men. HTLV-1 infection is associated with HIV infection, and longitudinal data indicate HIV infection may be a risk factor for acquiring HTLV-1, but not vice versa. Mother to child transmission is likely to contribute to the

  8. Activation of WIP1 Phosphatase by HTLV-1 Tax Mitigates the Cellular Response to DNA Damage

    PubMed Central

    Dayaram, Tajhal; Lemoine, Francene J.; Donehower, Lawrence A.; Marriott, Susan J.

    2013-01-01

    Genomic instability stemming from dysregulation of cell cycle checkpoints and DNA damage response (DDR) is a common feature of many cancers. The cancer adult T cell leukemia (ATL) can occur in individuals infected with human T cell leukemia virus type 1 (HTLV-1), and ATL cells contain extensive chromosomal abnormalities, suggesting that they have defects in the recognition or repair of DNA damage. Since Tax is the transforming protein encoded by HTLV-1, we asked whether Tax can affect cell cycle checkpoints and the DDR. Using a combination of flow cytometry and DNA repair assays we showed that Tax-expressing cells exit G1 phase and initiate DNA replication prematurely following damage. Reduced phosphorylation of H2AX (γH2AX) and RPA2, phosphoproteins that are essential to properly initiate the DDR, was also observed in Tax-expressing cells. To determine the cause of decreased DDR protein phosphorylation in Tax-expressing cells, we examined the cellular phosphatase, WIP1, which is known to dephosphorylate γH2AX. We found that Tax can interact with Wip1 in vivo and in vitro, and that Tax-expressing cells display elevated levels of Wip1 mRNA. In vitro phosphatase assays showed that Tax can enhance Wip1 activity on a γH2AX peptide target by 2-fold. Thus, loss of γH2AX in vivo could be due, in part, to increased expression and activity of WIP1 in the presence of Tax. siRNA knockdown of WIP1 in Tax-expressing cells rescued γH2AX in response to damage, confirming the role of WIP1 in the DDR. These studies demonstrate that Tax can disengage the G1/S checkpoint by enhancing WIP1 activity, resulting in reduced DDR. Premature G1 exit of Tax-expressing cells in the presence of DNA lesions creates an environment that tolerates incorporation of random mutations into the host genome. PMID:23405243

  9. A gorilla reservoir for human T-lymphotropic virus type 4

    PubMed Central

    LeBreton, Matthew; Switzer, William M; Djoko, Cyrille F; Gillis, Amethyst; Jia, Hongwei; Sturgeon, Michele M; Shankar, Anupama; Zheng, Haoqiang; Nkeunen, Gerard; Tamoufe, Ubald; Nana, Ahmadou; Le Doux Diffo, Joseph; Tafon, Babila; Kiyang, John; Schneider, Bradley S; Burke, Donald S; Wolfe, Nathan D

    2014-01-01

    Of the seven known species of human retroviruses only one, human T-cell lymphotropic virus type 4 (HTLV-4), lacks a known animal reservoir. We report the largest screening for simian T-cell lymphotropic virus (STLV-4) to date in a wide range of captive and wild non-human primate (NHP) species from Cameroon. Among the 681 wild and 426 captive NHPs examined, we detected STLV-4 infection only among gorillas by using HTLV-4-specific quantitative polymerase chain reaction. The large number of samples analyzed, the diversity of NHP species examined, the geographic distribution of infected animals relative to the known HTLV-4 case, as well as detailed phylogenetic analyses on partial and full genomes, indicate that STLV-4 is endemic to gorillas, and that rather than being an ancient virus among humans, HTLV-4 emerged from a gorilla reservoir, likely through the hunting and butchering of wild gorillas. Our findings shed further light on the importance of gorillas as keystone reservoirs for the evolution and emergence of human infectious diseases and provide a clear course for preventing HTLV-4 emergence through management of human contact with wild gorillas, the development of improved assays for HTLV-4/STLV-4 detection and the ongoing monitoring of STLV-4 among gorillas and for HTLV-4 zoonosis among individuals exposed to gorilla populations. PMID:26038495

  10. Zoonotic Transmission of Two New Strains of Human T-lymphotropic Virus Type 4 in Hunters Bitten by a Gorilla in Central Africa.

    PubMed

    Richard, Léa; Mouinga-Ondémé, Augustin; Betsem, Edouard; Filippone, Claudia; Nerrienet, Eric; Kazanji, Mirdad; Gessain, Antoine

    2016-09-15

    Molecular screening of 300 at-risk people from Central Africa identified 2 human T-lymphotropic virus (HTLV)-4-infected individuals. A zoonotic origin of infection was suggested, as both individuals reported being severely bitten by a gorilla during hunting activities. One strain was highly divergent and was designated as the HTLV-4 subtype-b prototype. PMID:27325689

  11. Zoonotic Transmission of Two New Strains of Human T-lymphotropic Virus Type 4 in Hunters Bitten by a Gorilla in Central Africa.

    PubMed

    Richard, Léa; Mouinga-Ondémé, Augustin; Betsem, Edouard; Filippone, Claudia; Nerrienet, Eric; Kazanji, Mirdad; Gessain, Antoine

    2016-09-15

    Molecular screening of 300 at-risk people from Central Africa identified 2 human T-lymphotropic virus (HTLV)-4-infected individuals. A zoonotic origin of infection was suggested, as both individuals reported being severely bitten by a gorilla during hunting activities. One strain was highly divergent and was designated as the HTLV-4 subtype-b prototype.

  12. NLRP3 polymorphism is associated with protection against human T-lymphotropic virus 1 infection

    PubMed Central

    Kamada, Anselmo Jiro; Pontillo, Alessandra; Guimarães, Rafael Lima; Loureiro, Paula; Crovella, Sergio; Brandão, Lucas André Cavalcanti

    2014-01-01

    Inter-individual heterogeneity in the response to human T-lymphotropic virus 1 (HTLV-1) infection has been partially attributed to host genetic background. The antiviral activity of the inflammasome cytoplasmic complex recognises viral molecular patterns and regulates immune responses via the activation of interleukin (IL)-1 family (IL-1, IL-18 and IL-33) members. The association between polymorphisms in the inflammasome receptors NLRP1 and NLRP3 and HTLV-1 infection was evaluated in a northeastern Brazilian population (84 HTLV-1 carriers and 155 healthy controls). NLRP3 rs10754558 G/G was associated with protection against HTLV-1 infection (p = 0.012; odds ratio = 0.37). rs10754558 affects NLRP3 mRNA stability; therefore, our results suggest that higher NLRP3 expression may augment first-line defences, leading to the effective protection against HTLV-1 infection.

  13. NLRP3 polymorphism is associated with protection against human T-lymphotropic virus 1 infection.

    PubMed

    Kamada, Anselmo Jiro; Pontillo, Alessandra; Guimarães, Rafael Lima; Loureiro, Paula; Crovella, Sergio; Brandão, Lucas André Cavalcanti

    2014-11-01

    Inter-individual heterogeneity in the response to human T-lymphotropic virus 1 (HTLV-1) infection has been partially attributed to host genetic background. The antiviral activity of the inflammasome cytoplasmic complex recognises viral molecular patterns and regulates immune responses via the activation of interleukin (IL)-1 family (IL-1, IL-18 and IL-33) members. The association between polymorphisms in the inflammasome receptors NLRP1 and NLRP3 and HTLV-1 infection was evaluated in a northeastern Brazilian population (84 HTLV-1 carriers and 155 healthy controls). NLRP3 rs10754558 G/G was associated with protection against HTLV-1 infection (p = 0.012; odds ratio = 0.37). rs10754558 affects NLRP3 mRNA stability; therefore, our results suggest that higher NLRP3 expression may augment first-line defences, leading to the effective protection against HTLV-1 infection.

  14. Construction and characterization of a human T-cell lymphotropic virus type 3 infectious molecular clone.

    PubMed

    Chevalier, Sébastien Alain; Ko, Nga Ling; Calattini, Sara; Mallet, Adeline; Prévost, Marie-Christine; Kehn, Kylene; Brady, John N; Kashanchi, Fatah; Gessain, Antoine; Mahieux, Renaud

    2008-07-01

    We and others have uncovered the existence of human T-cell lymphotropic virus type 3 (HTLV-3). We have now generated an HTLV-3 proviral clone. We established that gag, env, pol, pro, and tax/rex as well as minus-strand mRNAs are present in cells transfected with the HTLV-3 clone. HTLV-3 p24(gag) protein is detected in the cell culture supernatant. Transfection of 293T-long terminal repeat (LTR)-green fluorescent protein (GFP) cells with the HTLV-3 clone promotes formation of syncytia, a hallmark of Env expression, together with the appearance of fluorescent cells, demonstrating that Tax is expressed. Viral particles are visible by electron microscopy. These particles are infectious, as demonstrated by infection experiments with purified virions.

  15. Transcription of the human T-cell lymphotropic virus type I promoter by an alpha-amanitin-resistant polymerase.

    PubMed Central

    Piras, G; Kashanchi, F; Radonovich, M F; Duvall, J F; Brady, J N

    1994-01-01

    The human T-lymphotropic virus type I (HTLV-I) promoter contains the structural features of a typical RNA polymerase II (pol II) template. The promoter contains a TATA box 30 bp upstream of the transcription initiation site and binding sites for several pol II transcription factors, and long poly(A)+ RNA is synthesized from the integrated HTLV-I proviral DNA in vivo. Consistent with these characteristics, HTLV-I transcription activity was reconstituted in vitro by using TATA-binding protein, TFIIA, recombinant TFIIB, TFIIE, and TFIIF, TFIIH, and pol II. Transcription of the HTLV-I promoter in the reconstituted system requires RNA pol II. In HeLa whole cell extracts, however, the HTLV-I long terminal repeat also contains an overlapping transcription unit (OTU). HTLV-I OTU transcription is initiated at the same nucleotide site as the RNA isolated from the HTLV-I-infected cell line MT-2 but was not inhibited by the presence of alpha-amanitin at concentrations which inhibited the adenovirus major late pol II promoter (6 micrograms/ml). HTLV-I transcription was inhibited when higher concentrations of alpha-amanitin (60 micrograms/ml) were used, in the range of a typical pol III promoter (VA-I). Neutralization and depletion experiments with three distinct pol II antibodies demonstrate that RNA pol II is not required for HTLV-I OTU transcription. Antibodies to basal transcription factors TATA-binding protein and TFIIB, but not TFIIIC, inhibited HTLV-I OTU transcription. These observations suggest that the HTLV-I long terminal repeat contains overlapping promoters, a typical pol II promoter and a unique pol III promoter which requires a distinct set of transcription factors. Images PMID:7521915

  16. David D. Derse, 1949-2009

    PubMed Central

    2009-01-01

    David D. Derse, Ph.D., Head of the Retrovirus Gene Expression Section in the HIV Drug Resistance Program at the National Cancer Institute-Frederick (NCI-Frederick), passed away on October 9, 2009, a scant six weeks after being diagnosed with liver cancer. It was with great sadness that family, friends, and colleagues gathered together for his memorial service on Saturday, October 17, 2009, at the Middletown United Methodist Church in Maryland. As a NCI scientist since 1986, Dave studied the molecular mechanisms of infection and replication of a number of different types of retroviruses. Dave became an internationally known expert on human T cell lymphotrophic viruses type 1 and 2 (HTLV-1 and HTLV-2) and served on the editorial boards of Virology and Retrovirology. His most recent studies focused on the mechanisms of HTLV-1 virion morphogenesis, transmission, and replication. PMID:19951436

  17. Human T-Cell Lymphotropic Virus Types 1 and 2 Seropositivity among Blood Donors at Mbarara Regional Blood Bank, South Western Uganda

    PubMed Central

    Uchenna Tweteise, Patience; Natukunda, Bernard; Bazira, Joel

    2016-01-01

    Background. The human T-cell lymphotropic virus types 1 and 2 (HTLV 1/2) are retroviruses associated with different pathologies. HTLV-1 causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP); HTLV-2 is not clearly associated with a known clinical disease. Both viruses may be transmitted by whole blood transfusion, from mother to child predominantly through breastfeeding, and by sexual contact. Presently, none of the regional blood banks in Uganda perform routine pretransfusion screening for HTLV. The aim of this study was to determine the prevalence of anti-human T-cell lymphotropic virus types 1/2 (HTLV-1/2) antibodies among blood donors at Mbarara Regional Blood Bank in South Western Uganda. A cross-sectional study was conducted between June 2014 and September 2014. Methodology. Consecutive blood samples of 368 blood donors were screened for anti-HTLV-1/2 antibodies using an enzyme linked immunosorbent assay (ELISA). Samples reactive on a first HTLV-1/2 ELISA were further retested in duplicate using the same ELISA. Of the three hundred and sixty-eight blood donors (229 (62.2%) males and 139 (37.8%) females), only two male donors aged 20 and 21 years were HTLV-1/2 seropositive, representing a prevalence of 0.54%. Conclusion. HTLV-1/2 prevalence is low among blood donors at Mbarara Regional Blood Bank. Studies among other categories of people at risk for HTLV 1/2 infection should be carried out. PMID:27034840

  18. Human T-Cell Lymphotropic Virus Types 1 and 2 Seropositivity among Blood Donors at Mbarara Regional Blood Bank, South Western Uganda.

    PubMed

    Uchenna Tweteise, Patience; Natukunda, Bernard; Bazira, Joel

    2016-01-01

    Background. The human T-cell lymphotropic virus types 1 and 2 (HTLV 1/2) are retroviruses associated with different pathologies. HTLV-1 causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP); HTLV-2 is not clearly associated with a known clinical disease. Both viruses may be transmitted by whole blood transfusion, from mother to child predominantly through breastfeeding, and by sexual contact. Presently, none of the regional blood banks in Uganda perform routine pretransfusion screening for HTLV. The aim of this study was to determine the prevalence of anti-human T-cell lymphotropic virus types 1/2 (HTLV-1/2) antibodies among blood donors at Mbarara Regional Blood Bank in South Western Uganda. A cross-sectional study was conducted between June 2014 and September 2014. Methodology. Consecutive blood samples of 368 blood donors were screened for anti-HTLV-1/2 antibodies using an enzyme linked immunosorbent assay (ELISA). Samples reactive on a first HTLV-1/2 ELISA were further retested in duplicate using the same ELISA. Of the three hundred and sixty-eight blood donors (229 (62.2%) males and 139 (37.8%) females), only two male donors aged 20 and 21 years were HTLV-1/2 seropositive, representing a prevalence of 0.54%. Conclusion. HTLV-1/2 prevalence is low among blood donors at Mbarara Regional Blood Bank. Studies among other categories of people at risk for HTLV 1/2 infection should be carried out.

  19. IL28B Gene Polymorphism SNP rs8099917 Genotype GG Is Associated with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in HTLV-1 Carriers

    PubMed Central

    Luiz, Olinda do Carmo; Malta, Fernanda; Pinho, João Renato Rebello; Gonçalves, Fernanda de Toledo; Duarte, Alberto Jose da Silva; de Oliveira, Augusto Cesar Penalva

    2014-01-01

    Background The polymorphisms of IL28B have been described as important in the pathogenesis of infections caused by some viruses. The aim of this research was to evaluate whether IL28B gene polymorphisms (SNP rs8099917 and SNP rs12979860) are associated with HAM/TSP. Methods The study included 229 subjects, classified according to their neurological status in two groups: Group I (136 asymptomatic HTLV-1 carriers) and Group II (93 HAM/TSP patients). The proviral loads were quantified, and the rs8099917 and rs12979860 SNPs in the region of IL28B-gene were analyzed by StepOnePlus Real-time PCR System. Results A multivariate model analysis, including gender, age, and HTLV-1 DNA proviral load, showed that IL28B polymorphisms were independently associated with HAM/TSP outcome in rs12979860 genotype CT (OR = 2.03; IC95% = 0.96–4.27) and in rs8099917 genotype GG (OR = 7.61; IC95% = 1.82–31.72). Conclusion Subjects with SNP rs8099917 genotype GG and rs12979618 genotype CT may present a distinct immune response against HTLV-1 infection. So, it seems reasonable to suggest that a search for IL28B polymorphisms should be performed for all HTLV-1-infected subjects in order to monitor their risk for disease development; however, since this is the first description of such finding in the literature, we should first replicate this study with more HTLV-1-infected persons to strengthen the evidence already provided by our results. PMID:25233462

  20. In vivo immunogenicity of Tax(11-19) epitope in HLA-A2/DTR transgenic mice: implication for dendritic cell-based anti-HTLV-1 vaccine.

    PubMed

    Sagar, Divya; Masih, Shet; Schell, Todd; Jacobson, Steven; Comber, Joseph D; Philip, Ramila; Wigdahl, Brian; Jain, Pooja; Khan, Zafar K

    2014-05-30

    Viral oncoprotein Tax plays key roles in transformation of human T-cell leukemia virus (HTLV-1)-infected T cells leading to adult T-cell leukemia (ATL), and is the key antigen recognized during HTLV-associated myelopathy (HAM). In HLA-A2+ asymptomatic carriers as well as ATL and HAM patients, Tax(11-19) epitope exhibits immunodominance. Here, we evaluate CD8 T-cell immune response against this epitope in the presence and absence of dendritic cells (DCs) given the recent encouraging observations made with Phase 1 DC-based vaccine trial for ATL. To facilitate these studies, we first generated an HLA-A2/DTR hybrid mouse strain carrying the HLA-A2.1 and CD11c-DTR genes. We then studied CD8 T-cell immune response against Tax(11-19) epitope delivered in the absence or presence of Freund's adjuvant and/or DCs. Overall results demonstrate that naturally presented Tax epitope could initiate an antigen-specific CD8T cell response in vivo but failed to do so upon DC depletion. Presence of adjuvant potentiated Tax(11-19)-specific response. Elevated serum IL-6 levels coincided with depletion of DCs whereas decreased TGF-β was associated with adjuvant use. Thus, Tax(11-19) epitope is a potential candidate for the DC-based anti-HTLV-1 vaccine and the newly hybrid mouse strain could be used for investigating DC involvement in human class-I-restricted immune responses.

  1. Human T lymphotropic virus type 1 uveitis after Graves' disease.

    PubMed Central

    Yamaguchi, K; Mochizuki, M; Watanabe, T; Yoshimura, K; Shirao, M; Araki, S; Miyata, N; Mori, S; Kiyokawa, T; Takatsuki, K

    1994-01-01

    A distinct clinical entity of uveitis associated with human T lymphotropic virus type 1 (HTLV-I) has been reported previously. During the period between January 1989 and April 1992, 93 patients were observed with HTLV-I uveitis and a significant correlation was found between Graves' disease and HTLV-I uveitis. Sixteen of the 93 patients with HTLV-I uveitis (17.2%) had a previous history of Graves' disease. Fifteen patients were female (15/60, 25.0%) and one was male (1/33, 3.0%). Interestingly, uveitis occurred after the onset of Graves' disease in all cases. On the other hand, none of 222 patients with idiopathic uveitis who were seronegative to HTLV-I had a history of Graves' disease. Although the mechanisms by which HTLV-I causes the correlation between uveitis and Graves' disease are unknown, the present data suggest that immune mediated or autoimmune mechanisms are involved in HTLV-I uveitis. Images PMID:8148330

  2. Molecular characterization and phylogenetic analysis of a human T cell leukemia virus type 2 strain from French Guiana.

    PubMed

    Kazanji, M; Benoit, B; Meddeb, M; Meertens, L; Marty, C; Gessain, A; Talarmin, A

    2001-04-10

    Extensive studies have been carried out on native Amerindian populations living in French Guiana in an attempt to detect human T cell leukemia virus type 2 (HTLV-2). However, the first strain of this virus identified in this region was not detected in these populations, but in a Brazilian woman of Amerindian origin. Comparative analyses of the nucleotide sequences of 589 bp of the gp21 env gene and of 625 bp of the long terminal repeat (LTR) showed that this new HTLV-2 strain (HTLV-2 GUY) was of subtype A. Sequence comparison and phylogenetic analyses demonstrated that HTLV-2 GUY was closely related to a group of distinct variants of HTLV-2 subtype A strains originating mostly from Brazilian inhabitants and formerly called HTLV-2 subtype C. As there is a high level of immigration from Brazil in French Guiana, we carried out a seroepidemiological study of 175 Brazilians, mostly women (obtained from a serum databank) and 72 female Brazilian prostitutes living in French Guiana to determine whether HTLV-2 is likely to become an emerging infection in this area. No HTLV-2 infection was detected, indicating that this virus is unlikely to become prevalent in the near future.

  3. Psychiatric Disorders in HTLV-1-Infected Individuals with Bladder Symptoms

    PubMed Central

    Orge, Glória O.; Dellavechia, Thais R.; Carneiro-Neto, José Abraão; Araújo-de-Freitas, Lucas; Daltro, Carla H. C.; Santos, Carlos T.; Quarantini, Lucas C.

    2015-01-01

    Background Previous studies have reported high rates of depression and anxiety in HTLV-1 infected individuals with the neurological disease and in the asymptomatic phase. No study has investigated the rates in individuals that already show bladder symptoms without severe neurological changes; that is, during the oligosymptomatic phase. The present study investigated patients in this intermediate form on the spectrum of the infection. Methodology/Principal Findings Participants answered a sociodemographic questionnaire, the Mini International Neuropsychiatric Interview Brazilian Version 5.0.0 (MINI PLUS) and the Hospital Anxiety and Depression Scale (HADS). Data analysis was performed in STATA statistical software (version 12.0). Depressive disorder was the most frequent comorbidity. Current depressive disorder was higher in the group of overactive bladder subjects (11.9%), and lifelong depression was more frequent in the HAM/TSP group (35%). The three groups had similar frequencies of anxiety disorders. Increased frequency and severity of anxiety and depression symptoms were observed in the overactive bladder group. Conclusion/Significance The results suggest that individuals with overactive bladders need a more thorough assessment from the mental health perspective. These patients remain an understudied group regarding psychiatric comorbidities. PMID:26018525

  4. Phylogenetic and similarity analysis of HTLV-1 isolates from HIV-coinfected patients from the south and southeast regions of Brazil.

    PubMed

    Magri, Mariana Cavalheiro; Brigido, Luis Fernando de Macedo; Rodrigues, Rosangela; Morimoto, Helena Kaminami; Ferreira, João Leandro de Paula; Caterino-de-Araujo, Adele

    2012-01-01

    HTLV-1 is endemic in Brazil and HIV/HTLV-1 coinfection has been detected, mostly in the northeast region. Cosmopolitan HTLV-1a is the main subtype that circulates in Brazil. This study characterized 17 HTLV-1 isolates from HIV coinfected patients of southern (n=7) and southeastern (n=10) Brazil. HTLV-1 provirus DNA was amplified by nested PCR (env and LTR) and sequenced. Env sequences (705 bp) from 15 isolates and LTR sequences (731 bp) from 17 isolates showed 99.5% and 98.8% similarity among sequences, respectively. Comparing these sequences with ATK (HTLV-1a) and Mel5 (HTLV-1c) prototypes, similarities of 99% and 97.4%, respectively, for env and LTR with ATK, and 91.6% and 90.3% with Mel5, were detected. Phylogenetic analysis showed that all sequences belonged to the transcontinental subgroup A of the Cosmopolitan subtype, clustering in two Latin American clusters.

  5. No proof of HTLV-I/II in intravenous drug abusers with a high rate of HIV-1 infection in central Thailand.

    PubMed

    Saguanwongse, S; Muangpom, A; Ruchusatsawat, N; Wongcheree, S; Warachit, P; Miyamura, K; Yamazaki, S; Honda, M

    1996-01-01

    Serum specimens of 1,074 intravenous drug abusers (IVDA) were examined for infection with HIV-1, HTLV-I and HTLV-II in central Thailand. Three hundred and sixty-two of the specimens were seropositive for HIV-1 (33.7%). The HIV-1 seropositive IVDAs exhibited increased seropositivity with age through group 40-44 and significantly decreased seropositivity over the age of 45. In contrast, no seropositivity to either HTLV-I or -II was detected in the samples tested by a particle-agglutination assay for HTLV followed by type-specific Western blotting for HTLV. Reference to previous reports suggested that the rate of HIV infection in IVDAs has decreased with no HTLV-I or HTLV-II in Thailand when compared with that of the HIV infection in 1992.

  6. Regulation of HTLV-1 tax stability, cellular trafficking and NF-κB activation by the ubiquitin-proteasome pathway.

    PubMed

    Lavorgna, Alfonso; Harhaj, Edward William

    2014-10-23

    Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%-5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T-cell proliferation and cell survival. The Tax oncoprotein promotes T-cell transformation, in part via constitutive activation of the NF-κB transcription factor; however, the underlying mechanisms remain unknown. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Emerging studies indicate that Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-κB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine 63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. In addition to NF-κB signaling, mono- and polyubiquitination of Tax also regulate its subcellular trafficking and stability. Here, we review recent advances in the diverse roles of ubiquitin in Tax function and how Tax usurps the ubiquitin-proteasome pathway to promote oncogenesis.

  7. HIV-2 and HTLV-1 infections in Spain, a non-endemic region.

    PubMed

    de Mendoza, Carmen; Caballero, Estrella; Aguilera, Antonio; Pirón, María; Ortiz de Lejarazu, Raúl; Rodríguez, Carmen; Cabezas, Teresa; González, Rocío; Treviño, Ana; Soriano, Vicente

    2014-01-01

    The annual workshop of the Spanish HIV‑2/HTLV Study Group was held at the Instituto de Salud Carlos III in Madrid on December 11, 2013. Nearly 100 experts and researchers in retroviruses other than HIV‑1, the classical AIDS agent, convened for a one‑day meeting devoted to updating knowledge on the epidemiology of HIV‑2 and HTLV-1 infections and discussing new diagnostic and therapeutic strategies, with special attention to non‑endemic regions such as Spain. The Group was funded 25 years ago and since then has been responsible for the national registry of cases, recording all relevant information for each subject and inviting them to enroll in a prospective cohort and biobank. Up to the end of 2013, a total of 297 individuals with HIV‑2 infection were reported in Spain. All but 10 carry HIV‑2 subtype A, with the rest being infected with subtype B. Overall, 71% came from sub‑Saharan Africa. During the last decade, the incidence of new HIV‑2 infections in Spain has remained fairly stable with around 20 cases per year. At the time of diagnosis, plasma HIV‑2 RNA was undetectable in 61% of individuals and values in viremic subjects tended to be low (2.8 logs on average). To date, only 26% of HIV‑2 individuals have been treated with antiretrovirals. The CD4 counts, however, only increased above 200 cells/mm³ in 42% of them. On the other hand, 74% of non‑treated HIV‑2 individuals have > 500 CD4+ T‑cells/mm³. As in HIV‑1 infection, X4 tropism in HIV‑2 is associated with lower CD4 counts. A total of 253 individuals with HTLV-1 infection were reported in Spain by the end of 2013. Overall, 58% came from Latin America. HTLV-1‑associated myelopathy was diagnosed in 29 patients and adult T‑cell leukemia/lymphoma in 18. The highest incidence occurred in 2013, with 34 new HTLV-1 diagnoses, largely as result of expanding HTLV screening in blood banks. Attempts to reduce HTLV-1 proviral load in symptomatic or asymptomatic patients with elevated

  8. Identification of clonally rearranged T-cell receptor beta chain genes in HTLV-I carriers as a potential instrument for early detection of neoplasia.

    PubMed

    Sales, M M; Bezerra, C N A; Hiraki, Y; Melo, N B; Rebouças, N A

    2005-05-01

    We analyzed the genetic recombination pattern of the T-cell receptor beta-chain gene (TCR-beta) in order to identify clonal expansion of T-lymphocytes in 17 human T-lymphotropic virus type I (HTLV-I)-positive healthy carriers, 7 of them with abnormal features in the peripheral blood lymphocytes. Monoclonal or oligoclonal expansion of T-cells was detected in 5 of 7 HTLV-I-positive patients with abnormal lymphocytes and unconfirmed diagnosis by using PCR amplification of segments of TCR-beta gene, in a set of reactions that target 102 different variable (V) segments, covering all members of the 24 V families available in the gene bank, including the more recently identified segments of the Vbeta-5 and Vbeta-8 family and the two diversity beta segments. Southern blots, the gold standard method to detect T-lymphocyte clonality, were negative for all of these 7 patients, what highlights the low sensitivity of this method that requires a large amount of very high quality DNA. To evaluate the performance of PCR in the detection of clonality we also analyzed 18 leukemia patients, all of whom tested positive. Clonal expansion was not detected in any of the negative controls or healthy carriers without abnormal lymphocytes. In conclusion, PCR amplification of segments of rearranged TCR-beta is reliable and highly suitable for the detection of small populations of clonal T-cells in asymptomatic HTLV-I carriers who present abnormal peripheral blood lymphocytes providing an additional instrument for following up these patients with potentially higher risk of leukemia. PMID:15917950

  9. Pentosan polysulfate treatment ameliorates motor function with increased serum soluble vascular cell adhesion molecule-1 in HTLV-1-associated neurologic disease.

    PubMed

    Nakamura, Tatsufumi; Satoh, Katsuya; Fukuda, Taku; Kinoshita, Ikuo; Nishiura, Yoshihiro; Nagasato, Kunihiko; Yamauchi, Atsushi; Kataoka, Yasufumi; Nakamura, Tadahiro; Sasaki, Hitoshi; Kumagai, Kenji; Niwa, Masami; Noguchi, Mitsuru; Nakamura, Hideki; Nishida, Noriyuki; Kawakami, Atsushi

    2014-06-01

    The main therapeutic strategy against human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) characterized by lower extremity motor dysfunction is immunomodulatory treatment, with drugs such as corticosteroid hormone and interferon-α, at present. However, there are many issues in long-term treatment with these drugs, such as insufficient effects and various side effects. We now urgently need to develop other therapeutic strategies. The heparinoid, pentosan polysulfate sodium (PPS), has been safely used in Europe for the past 50 years as a thrombosis prophylaxis and for the treatment of phlebitis. We conducted a clinical trial to test the effect of subcutaneous administration of PPS in 12 patients with HAM/TSP in an open-labeled design. There was a marked improvement in lower extremity motor function, based on reduced spasticity, such as a reduced time required for walking 10 m and descending a flight of stairs. There were no significant changes in HTLV-I proviral copy numbers in peripheral blood contrary to the inhibitory effect of PPS in vitro for intercellular spread of HTLV-I. However, serum soluble vascular cell adhesion molecule (sVCAM)-1 was significantly increased without significant changes of serum level of chemokines (CXCL10 and CCL2). There was a positive correlation between increased sVCAM-1and reduced time required for walking 10 m. PPS might induce neurological improvement by inhibition of chronic inflammation in the spinal cord, through blocking the adhesion cascade by increasing serum sVCAM-1, in addition to rheological improvement of the microcirculation. PPS has the potential to be a new therapeutic tool for HAM/TSP.

  10. Immunization of mice with a peptide derived from the HTLV-1 TAX1BP1 protein induces cross-reactive antibodies against aquaporin 4.

    PubMed

    Kampylafka, Eleni I; Alexopoulos, Harry; El Hamidieh, Avraam; Dalakas, Marinos C; Andreakos, Evangelos; Tzioufas, Athanasios G

    2015-01-01

    Antibodies against aquaporin-4 (AQP4) are specific and pathogenetic for Neuromyelitis Optica (NMO). In a previous study, three linear intracellular AQP4 B-cell epitopes were uncovered in NMO patients. A particular epitope showed high-sequence similarity with a segment of the human TAX1BP1 protein, which is necessary for the replication of HTLV-1 virus. The aim of the present study was to investigate whether immunization of mice with the TAX1BP1 peptide could produce specific antibodies against AQP4 epitopes or induce symptoms. Eight C57Bl/6 mice were immunized with TAX1BP1pep in Complete Freund's Adjuvant and eight with adjuvant only. Animals received three subcutaneous injections and sera were obtained before each immunization and at sacrifice. All sera were evaluated by ELISA for antibodies against the TAX1BP1peptide, the homologous AQP4 peptide and all linear AQP4 epitopes. Homologous and cross-inhibition assays were performed to ensure binding specificity, and reactivity against conformational AQP4 epitopes was evaluated by a cell-based assay. Sera from immunized animals showed high reactivity against the immunization peptide, and the homologous AQP4 epitope. Inhibition assays confirmed binding specificity. No antibodies were produced against any other epitopes, either linear or conformational. No clinical or brain inflammatory signs were observed in the animals. The induction of antibodies to an AQP4 epitope in mice immunized with the TAX1BP1-derived peptide suggests that a latent HTLV-1 infection could lead to TAX1BP1 antigen presentation and the production of anti-AQP4 antibodies, probably through T cell-mediated mechanisms. Further studies are needed for exploring triggering factors for NMO especially in HTLV-1-endemic regions.

  11. High Prevalence of Human T-Lymphotropic Virus Infection in Indigenous Women from the Peruvian Amazon

    PubMed Central

    García, Patricia J.; Cárcamo, Cesar; Montano, Silvia M.; Mori, Nicanor; Muñante, Ricardo; Zunt, Joseph R.

    2013-01-01

    Background In an earlier study, we detected an association between human T-cell lymphotropic virus (HTLV) infection and cervical human papillomavirus (HPV) in indigenous Amazonian Peruvian women of the Shipibo-Konibo ethnic group. As both HTLV and HPV can be transmitted sexually, we now report a population-based study examining the prevalence and risk factors for HTLV-1 and HTLV-2 infection in this population. Methods Between July and December 2010, we conducted a comprehensive screening for HTLV among Shipibo-Konibo women 15 to 39 years of age living in two communities located in Lima and in 17 communities located within four hours by car or boat from the Amazonian city of Pucallpa in Peru. Results We screened 1,253 Shipibo-Konibo women for HTLV infection 74 (5.9%) tested positive for HTLV-1, 47 (3.8%) for HTLV-2 infection, and 4 (0.3%) had indeterminate results. In the multivariate analysis, factors associated with HTLV-1 infection included: older age (Prevalence Ratio (PR): 1.04, 95% CI 1.00–1.08), primary education or less (PR: 2.01, 95% CI: 1.25–3.24), younger or same age most recent sex partner (PR: 1.66, 95% CI: 1.00–2.74), and having a most recent sex partner who worked at a logging camp (PR: 1.73, 95% CI: 1.09–2.75). The only factor associated with HTLV-2 infection was older age (PR: 1.08, 95% CI: 1.03–1.12). Conclusion HTLV infection is endemic among Shipibo-Konibo women. Two characteristics of the sexual partner (younger age and labor history) were associated with infection in women. These results suggest the need for implementation of both HTLV screening during the antenatal healthcare visits of Shipibo-Konibo women, and counseling about the risk of HTLV transmission through prolonged breastfeeding in infected women. We also recommend the implementation of prevention programs to reduce sexual transmission of these viruses. PMID:24040133

  12. Control of the Inflammatory Response Mechanisms Mediated by Natural and Induced Regulatory T-Cells in HCV-, HTLV-1-, and EBV-Associated Cancers

    PubMed Central

    Moralès, Olivier; Delhem, Nadira

    2014-01-01

    Virus infections are involved in chronic inflammation and, in some cases, cancer development. Although a viral infection activates the immune system's response that eradicates the pathogen mainly through inflammatory mechanisms, it is now recognized that this inflammatory condition is also favorable to the development of tumors. Indeed, it is well described that viruses, such as hepatitis C virus (HCV), Epstein Barr virus (EBV), human papillomavirus (HPV) or human T-cell lymphotropic virus type-1 (HTLV-1), are important risk factors for tumor malignancies. The inflammatory response is a fundamental immune mechanism which involves several molecular and cellular components consisting of cytokines and chemokines that are released by various proinflammatory cells. In parallel to this process, some endogenous recruited components release anti-inflammatory mediators to restore homeostasis. The development of tools and strategies using viruses to hijack the immune response is mostly linked to the presence of regulatory T-cells (Treg) that can inhibit inflammation and antiviral responses of other effector cells. In this review, we will focus on current understanding of the role of natural and induced Treg in the control and the resolution of inflammatory response in HCV-, HTLV-1-, and EBV-associated cancers. PMID:25525301

  13. Adult T-cell leukemia-lymphoma in a pregnant woman diagnosed as a human T-cell lymphotropic virus type 1 carrier.

    PubMed

    Fuchi, Naoki; Miura, Kiyonori; Imaizumi, Yoshitaka; Hasegawa, Hiroo; Yanagihara, Katsunori; Miyazaki, Yasushi; Masuzaki, Hideaki

    2016-03-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia-lymphoma (ATL), which is difficult to cure. In Japan, a nationwide HTLV-1 screening test in pregnant women has been recommended since 2011. A 30-year-old woman was diagnosed as being an HTLV-1 carrier in her previous pregnancy. During the current pregnancy, she had persistent fever and cough. Although she had treatment with antibiotics, peripheral white blood cell count remained high, with an abnormal lymphocyte count. Given that she was an HTLV-1 carrier, she was diagnosed with unfavorable chronic ATL (aggressive ATL) at 12 weeks gestation. After pregnancy termination, her ATL status became favorable chronic ATL (indolent ATL). Therefore, watchful waiting was performed until disease progression. This is the first case report of chronic ATL in early pregnancy, in a woman already diagnosed as an HTLV-1 carrier on screening test. PMID:26663442

  14. Absence of cytotoxic antibody to human immunodeficiency virus-infected cells in humans and its induction in animals after infection or immunization with purified envelope glycoprotein gp120

    SciTech Connect

    Nara, P.L.; Robey, W.G.; Gonda, M.A.; Carter, S.G.; Fischinger, P.J.

    1987-06-01

    The presence of antibody-dependent complement-mediated cytotoxicity (ACC) was assessed in humans and chimpanzees, which are capable of infection with human immunodeficiency virus isolate HTLV-IIIb, and examined in the goat after immunization with the major viral glycoprotein (gp120) of HTLV-IIIb. In infected humans no antibody mediating ACC was observed regardless of the status of disease. Even healthy individuals with high-titer, broadly reactive, neutralizing antibodies has no ACC. In contrast, chimpanzees infected with HTLV-IIIb, from whom virus could be isolated, not only had neutralizing antibody but also antibodies broadly reactive in ACC, even against distantly related human immunodeficiency virus isolates, as well as against their own reisolated virus. In the goat, the gp120 of HTLV-IIIb induced a highly type-specific response as measured by both ACC and flow cytofluorometry of live infected H9 cells. Normal human cells were not subject to ACC by animal anti-HTLV-III gp120-specific sera. Induction of ACC and neutralizing antibody were closely correlated in the animal experimental models but not in humans. The presence of ACC in gp120-inoculated goats and HTLV-III-infected chimpanzees represent a qualitative difference that may be important in the quest for the elicitation of a protective immunity in humans.

  15. Concomitant augmentation of CD4+ CD29+ helper inducer and diminution of CD4+ CD45RA+ suppressor inducer subset in patients infected with human T cell lymphotropic virus types I or II.

    PubMed Central

    Lal, R B; Rudolph, D L; Schmid, D S; Lairmore, M D

    1992-01-01

    To examine the immunomodulatory effects of HTLV infection, lymphocyte subset analysis was performed on patients infected with human T cell lymphotropic virus type-I (HTLV-I, n = 6) or -II (HTLV-II, n = 12) and on normal blood donors (n = 16). The percentages of total B lymphocytes (CD19), natural killer (NK) cells (CD16), T lymphocytes and their subsets (CD2, CD3, CD4, CD5, CD7, CD8), and IL-2R (CD25) were found to be within the range found in normal donors. However, the expression of CD8+ HLA-DR+ increased significantly in patients with HTLV-I or HTLV-II infection (14.1 +/- 3.9% and 9.7 +/- 2.4% respectively; P less than 0.01) when compared with controls (3.2 +/- 1.1%). In addition, there was a significantly greater proportion of CD4+CD29+ T lymphocytes (29.3 +/- 6.1% and 31.1 +/- 9.0%; P less than 0.05) with concomitant diminution of CD4+CD45RA+ T lymphocytes (8.3 +/- 3.3% and 11.4 +/- 1.5%; P less than 0.01) in patients infected with HTLV-I or HTLV-II respectively, when compared with controls. The increased percentage of CD4+CD29+ subpopulations showed a direct correlation (rs = 0.86; P less than 0.001) with HTLV-specific antibody production. No difference in the CD8 population coexpressing CD29 and S6F1 (an epitope of LFA-1) were observed in the HTLV-infected group when compared with normal donors and functional analysis exhibited minimal cytotoxicity against lectin labelled heterologous target cells. Thus, the shift in the suppressor/cytotoxic to helper/inducer 'memory' CD4+ may be associated with immunoregulatory abnormalities often found in persons infected with HTLV-I or HTLV-II. PMID:1370929

  16. One-step, multiplex, real-time PCR assay with molecular beacon probes for simultaneous detection, differentiation, and quantification of human T-cell leukemia virus types 1, 2, and 3.

    PubMed

    Besson, Guillaume; Kazanji, Mirdad

    2009-04-01

    A single-tube, multiplex, real-time PCR assay with molecular beacons was established in which various probes were used for the simultaneous detection, differentiation, and quantification of human T-cell leukemia virus types 1, 2, and 3 (HTLV-1, HTLV-2, and HTLV-3, respectively) and of simian T-cell leukemia virus types 1 and 3 (STLV-1 and STLV-3, respectively). The quantitative amplification of the standards with MT4 (HTLV-1) and C19 (HTLV-2) cell lines and a molecular clone of HTLV-3 was linear, with the simplex and multiplex methods having similar efficiencies. A maximum difference of 0.9 (mean, 0.4; range, 0.0 to 0.9) was found between threshold cycle values in single and multiplex reactions. The efficiency with each probe in the multiplex reaction was close to 100%, indicating strong linear amplification. The albumin gene was used to standardize the copy number. Comparable results for the detection and quantification of HTLV-1 were obtained with our new methods and with other real-time PCR methods described previously. With our new multiplex assay, however, we were able to detect and quantify HTLV-2 and -3 and STLV-1 and -3 in clinical specimens, with an excellent dynamic range of 10(6) to 10(0) copies per assay, which the other assays could not do. Thus, it will be possible to determine a wide range of HTLV types in both standard and clinical samples, with a detection of 1 to 10 HTLV copies in samples containing at least 100 cells. Furthermore, our system can provide evidence for multiple infections with the three HTLV types, with separate proviral load results. Our new method also could be used for epidemiological studies in Africa and in countries where HTLVs and STLVs are endemic.

  17. Nivolumab in Treating Patients With HTLV-Associated T-Cell Leukemia/Lymphoma

    ClinicalTrials.gov

    2016-10-17

    Acute Adult T-Cell Leukemia/Lymphoma; Adult T-Cell Leukemia/Lymphoma; Chronic Adult T-Cell Leukemia/Lymphoma; HTLV-1 Infection; Lymphomatous Adult T-Cell Leukemia/Lymphoma; Recurrent Adult T-Cell Leukemia/Lymphoma; Smoldering Adult T-Cell Leukemia/Lymphoma

  18. Immunization against HTLV-I with chitosan and tri-methylchitosan nanoparticles loaded with recombinant env23 and env13 antigens of envelope protein gp46.

    PubMed

    Amirnasr, Maryam; Fallah Tafti, Tannan; Sankian, Mojtaba; Rezaei, Abdorrahim; Tafaghodi, Mohsen

    2016-08-01

    To prevent the spread of HTLV-I (Human T-lymphotropic virus type 1), a safe and effective vaccine is required. To increase immune responses against the peptide antigens can be potentiated with polymer-based nanoparticles, like chitosan (CHT) and trimethylchitosan (TMC), as delivery system/adjuvant. CHT and TMC nanoparticles loaded with recombinant proteins (env23 & env13) of gp46 were prepared by direct coating of antigens with positively charged polymers. The size of CHT and TMC nanoparticles (NPs) loaded with each antigen was about 400 nm. The physical stability of NPs was followed for 4 weeks. Both formulations showed to be stable for about 15 days. The immunogenicity of NPs loaded with antigens was studied after nasal and subcutaneous immunization in mice. Three immunizations (7.5 μg antigen) were performed with 2 weeks intervals. Two weeks after the last booster dose, sera IgG subtypes were measured. After subcutaneous administration, for both nanoparticulate antigens, serum IgG1 and IgGtotal levels were higher than antigen solution (P < 0.001). After nasal administration, for env23, IgG2a levels and IgG2a/IgG1 ratio was significantly higher than groups with subcutaneous administration (P < 0.001). Both nanoparticles showed good immunoadjuvant potential. Env23 antigen was a better candidate for vaccination against HTLV-I, as it induced higher cellular immune responses, compared with env13. PMID:27235335

  19. High seroprevalence of human T-cell lymphotropic virus type 1 in blood donors in Guyana and molecular and phylogenetic analysis of new strains in the Guyana shelf (Guyana, Suriname, and French Guiana).

    PubMed

    Pouliquen, Jean-François; Hardy, Lynette; Lavergne, Anne; Kafiludine, Eric; Kazanji, Mirdad

    2004-05-01

    The prevalence of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2 in blood donors in Guyana has never been estimated. We evaluated the prevalence of these viruses in blood donors by enzyme-linked immunosorbent assay and Western blotting and showed a prevalence of HTLV-1 of 1.3%; no HTLV-2 was detected. Female donors had a much higher HTLV-1 seroprevalence (3.6%) than male donors (0.7%). HTLV-1-seropositive donors tended to be slightly older than the average age for the total pool of donors. We also investigated the phylogenetic and molecular characteristics of HTLV-1 strains in Guyana and compared them with those identified in Suriname and French Guiana. Analysis of portions of the env and long terminal repeat nucleotide sequences showed that all the strains in Guyana and Suriname, like those in French Guiana, belonged to the transcontinental group of cosmopolitan subtype A. The similarities were greater between strains from Suriname and Guyana than between strains from Suriname and Guyana and those from French Guiana. Nevertheless, our results confirm that the HTLV-1 strains in all three countries have a common African origin.

  20. Decrease of human T-cell lymphotropic virus type I prevalence and low incidence among pregnant women from a high endemic ethnic group in French Guiana.

    PubMed

    Tortevoye, P; Tuppin, P; Peneau, C; Carles, G; Gessain, A

    2000-08-15

    To assess the prevalence and incidence of human T-cell lymphotropic virus type I (HTLV-I), 4,234 pregnant women of different ethnic origins were tested before each delivery between 1991 and 1997 in a high HTLV-I endemic area of French Guiana. HTLV-I was significantly more prevalent among ethnic groups of African descent as the Noir-Marrons (4.8%, 95% confidence interval [CI]: 4.0-5.6) and Haitians (5%, 95% CI 1.6-8.4). An age dependence of HTLV-I seroprevalence was observed. The mean age of Noir-Marron HTLV-I seronegative women was lower than for HTLV-I seropositive women (24. 7 vs. 28.6, p < 0.001). A decline in HTLV-I seroprevalence was observed, particularly in the Noir-Marron younger than 21 years old (p = 0.04). For five HTLV-I seroconversions observed, the incidence per 100 women-years in the Noir-Marron group was 0.19 (95% CI 0.02-0. 35) for all women, 0.32 in those 25 years old or younger (95% CI 0-0. 64), and 0.07 in those older than 25 years (95% CI 0-0.2). This observation was inconsistent with HTLV-I seroprevalence observed for those 25 years old or younger (2.8%) and those older than 25 (8.3%). These data demonstrate, for the first time outside Japan, a birth cohort effect for HTLV-I in a highly endemic ethnic group.

  1. Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans

    PubMed Central

    de Castro-Amarante, Maria Fernanda; McKinnon, Katherine; Washington Parks, Robyn; Galli, Veronica; Omsland, Maria; Andresen, Vibeke; Massoud, Raya; Brunetto, Giovanna; Caruso, Breanna; Venzon, David; Jacobson, Steven

    2015-01-01

    ABSTRACT Because the viral DNA burden correlates with disease development, we investigated the contribution of monocyte subsets (classical, intermediate, and nonclassical monocytes) to the total viral burden in 22 human T cell leukemia virus type 1 (HTLV-1)-infected individuals by assessing their infectivity status, frequency, as well as chemotactic and phagocytic functions. All three monocyte subsets sorted from HTLV-1-infected individuals were positive for viral DNA, and the frequency of classical monocytes was lower in the blood of HTLV-1-infected individuals than in that of uninfected individuals, while the expression levels of the chemokine receptors CCR5, CXCR3, and CX3CR1 in classical monocytes were higher in HTLV-1-infected individuals than uninfected individuals; the percentage of intermediate monocytes and their levels of chemokine receptor expression did not differ between HTLV-1-infected and uninfected individuals. However, the capacity of intermediate monocytes to migrate to CCL5, the ligand for CCR5, was higher, and a higher proportion of nonclassical monocytes expressed CCR1, CXCR3, and CX3CR1. The level of viral DNA in the monocyte subsets correlated with the capacity to migrate to CCL2, CCL5, and CX3CL1 for classical monocytes, with lower levels of phagocytosis for intermediate monocytes, and with the level of viral DNA in CD8+ and CD4+ T cells for nonclassical monocytes. These data suggest a model whereby HTLV-1 infection augments the number of classical monocytes that migrate to tissues and become infected and the number of infected nonclassical monocytes that transmit virus to CD4+ and CD8+ T cells. These results, together with prior findings in a macaque model of HTLV-1 infection, support the notion that infection of monocytes by HTLV-1 is likely a requisite for viral persistence in humans. IMPORTANCE Monocytes have been implicated in immune regulation and disease progression in patients with HTLV-1-associated inflammatory diseases. We detected

  2. Molecular epidemiology and clinical features of human T cell lymphotropic virus type 1 infection in Spain.

    PubMed

    Treviño, Ana; Alcantara, Luiz Carlos; Benito, Rafael; Caballero, Estrella; Aguilera, Antonio; Ramos, José Manuel; de Mendoza, Carmen; Rodríguez, Carmen; García, Juan; Rodríguez-Iglesias, Manuel; Ortiz de Lejarazu, Raúl; Roc, Lourdes; Parra, Patricia; Eiros, José; del Romero, Jorge; Soriano, Vincent

    2014-09-01

    Human T cell lymphotropic virus type 1 (HTLV-1) infection in Spain is rare and mainly affects immigrants from endemic regions and native Spaniards with a prior history of sexual intercourse with persons from endemic countries. Herein, we report the main clinical and virological features of cases reported in Spain. All individuals with HTLV-1 infection recorded at the national registry since 1989 were examined. Phylogenetic analysis was performed based on the long terminal repeat (LTR) region. A total of 229 HTLV-1 cases had been reported up to December 2012. The mean age was 41 years old and 61% were female. Their country of origin was Latin America in 59%, Africa in 15%, and Spain in 20%. Transmission had occurred following sexual contact in 41%, parenteral exposure in 12%, and vertically in 9%. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was diagnosed in 27 cases and adult T cell leukemia/lymphoma (ATLL) in 17 subjects. HTLV-1 subtype could be obtained for 45 patients; all but one belonged to the Cosmopolitan subtype a. One Nigerian pregnant woman harbored HTLV-1 subtype b. Within the Cosmopolitan subtype a, two individuals (from Bolivia and Peru, respectively) belonged to the Japanese subgroup B, another two (from Senegal and Mauritania) to the North African subgroup D, and 39 to the Transcontinental subgroup A. Of note, one divergent HTLV-1 strain from an Ethiopian branched off from all five known Cosmopolitan subtype 1a subgroups. Divergent HTLV-1 strains have been introduced and currently circulate in Spain. The relatively large proportion of symptomatic cases (19%) suggests that HTLV-1 infection is underdiagnosed in Spain.

  3. Molecular Epidemiology and Clinical Features of Human T Cell Lymphotropic Virus Type 1 Infection in Spain

    PubMed Central

    Alcantara, Luiz Carlos; Benito, Rafael; Caballero, Estrella; Aguilera, Antonio; Ramos, José Manuel; de Mendoza, Carmen; Rodríguez, Carmen; García, Juan; Rodríguez-Iglesias, Manuel; Ortiz de Lejarazu, Raúl; Roc, Lourdes; Parra, Patricia; Eiros, José; del Romero, Jorge; Soriano, Vincent

    2014-01-01

    Abstract Human T cell lymphotropic virus type 1 (HTLV-1) infection in Spain is rare and mainly affects immigrants from endemic regions and native Spaniards with a prior history of sexual intercourse with persons from endemic countries. Herein, we report the main clinical and virological features of cases reported in Spain. All individuals with HTLV-1 infection recorded at the national registry since 1989 were examined. Phylogenetic analysis was performed based on the long terminal repeat (LTR) region. A total of 229 HTLV-1 cases had been reported up to December 2012. The mean age was 41 years old and 61% were female. Their country of origin was Latin America in 59%, Africa in 15%, and Spain in 20%. Transmission had occurred following sexual contact in 41%, parenteral exposure in 12%, and vertically in 9%. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was diagnosed in 27 cases and adult T cell leukemia/lymphoma (ATLL) in 17 subjects. HTLV-1 subtype could be obtained for 45 patients; all but one belonged to the Cosmopolitan subtype a. One Nigerian pregnant woman harbored HTLV-1 subtype b. Within the Cosmopolitan subtype a, two individuals (from Bolivia and Peru, respectively) belonged to the Japanese subgroup B, another two (from Senegal and Mauritania) to the North African subgroup D, and 39 to the Transcontinental subgroup A. Of note, one divergent HTLV-1 strain from an Ethiopian branched off from all five known Cosmopolitan subtype 1a subgroups. Divergent HTLV-1 strains have been introduced and currently circulate in Spain. The relatively large proportion of symptomatic cases (19%) suggests that HTLV-1 infection is underdiagnosed in Spain. PMID:24924996

  4. Comparison of four commercial screening assays for the diagnosis of human T-cell lymphotropic virus types 1 and 2.

    PubMed

    Berini, Carolina A; Susana Pascuccio, M; Bautista, Christian T; Gendler, Silvina A; Eirin, Maria E; Rodriguez, Claudia; Pando, Maria A; Biglione, Mirna M

    2008-02-01

    Serological assays for human T-cell lymphotropic virus types 1 and 2 (HTLV-1/2) are widely used in routine screening of blood donors. The aim of this study was to compare the performance of four commercial screening assays for HTLV-1/2 infection frequently used in South America. A total of 142 HTLV-1 and HTLV-2 seropositive and 336 seronegative samples were analyzed by using four commercial tests (BioKit, Vironostika, Murex and Fujirebio). These tests are commonly used for HTLV-1/2 detection in blood banks in Argentina. A nested-PCR was used as the reference standard. The most sensitive tests for HTLV-1/2 were Fujirebio and Biokit (98.6%) followed by Murex (97.2%) and Vironostika (96.5%). The most specific test was Murex (99.7%), followed by Biokit (97.0%), Fujirebio (95.8%), and Vironostika (92.9%). The kappa index of agreement was higher for Murex (kappa=0.97), followed by BioKit (kappa=0.94), Fujirebio (kappa=0.92), and Vironostika (kappa=0.86). The highest index of agreement was shown by Murex test while Vironostika had the lowest performance. Of the four tests evaluated, only the Vironostika assay is approved by the Food and Drug Administration. These results should be considered for choosing the most accurate serological screening assays in order to obtain an optimal efficiency of the current algorithm for HTLV-1/2 diagnosis.

  5. Analysis of human T-cell lymphotropic virus in CD25+ anaplastic large cell lymphoma in children.

    PubMed

    Gualco, Gabriela; Chioato, Lucimara; Weiss, Lawrence M; Harrington, William J; Bacchi, Carlos E

    2009-07-01

    Anaplastic large cell lymphoma (ALCL) is recognized as 2 distinct diseases: anaplastic lymphoma kinase (ALK)+ ALCL and ALK- ALCL. ALK+ ALCL occurs in younger patients and has a better prognosis. Human T-cell lymphotropic virus (HTLV-1) is linked to the development of adult T-cell leukemia/lymphoma (ATLL), which frequently expresses CD25. CD25 is significantly expressed in childhood ALCL. In Brazil, HTLV-1 infection is endemic, and vertical transmission is responsible for spread to children. Of HTLV-1 carriers, 90% or more remain asymptomatic. Some cases of adult HTLV-1-related lymphomas have characteristics of ALCL but are considered CD30+ ATLL subtypes. No similar cases have been described in children. We analyzed 33 cases of pediatric ALCL, CD25+ and CD25-, for proviral HTLV-1 DNA. All cases corresponded to the common histologic ALCL type and were CD30+ in virtually all neoplastic cells. ALK expression was observed in 31 (94%) of 33 cases; CD25 was positive in 27 (82%), including 1 ALK- ALCL case. There was a strong positive correlation between ALK and CD25 expression. None of the cases showed proviral HTLV-1 DNA. ALCL in children has no relationship with HTLV-1; the frequent CD25 expression must be explained by a mechanism different from that in ATLL.

  6. Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis

    PubMed Central

    Panfil, Amanda R.; Dissinger, Nathan J.; Howard, Cory M.; Murphy, Brandon M.; Landes, Kristina; Fernandez, Soledad A.

    2016-01-01

    ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that transform T cells in vitro but have distinct pathological outcomes in vivo. HTLV-1 encodes a protein from the antisense strand of its proviral genome, the HTLV-1 basic leucine zipper factor (HBZ), which inhibits Tax-1-mediated viral transcription and promotes cell proliferation, a high proviral load, and persistence in vivo. In adult T-cell leukemia/lymphoma (ATL) cell lines and patient T cells, hbz is often the only viral gene expressed. The antisense strand of the HTLV-2 proviral genome also encodes a protein termed APH-2. Like HBZ, APH-2 is able to inhibit Tax-2-mediated viral transcription and is detectable in most primary lymphocytes from HTLV-2-infected patients. However, unlike HBZ, the loss of APH-2 in vivo results in increased viral replication and proviral loads, suggesting that HBZ and APH-2 modulate the virus and cellular pathways differently. Herein, we examined the effect of APH-2 on several known HBZ-modulated pathways: NF-κB (p65) transactivation, transforming growth factor β (TGF-β) signaling, and interferon regulatory factor 1 (IRF-1) transactivation. Like HBZ, APH-2 has the ability to inhibit p65 transactivation. Conversely, HBZ and APH-2 have divergent effects on TGF-β signaling and IRF-1 transactivation. Quantitative PCR and protein half-life experiments revealed a substantial disparity between HBZ and APH-2 transcript levels and protein stability, respectively. Taken together, our data further elucidate the functional differences between HBZ and APH-2 and how these differences can have profound effects on the survival of infected cells and, ultimately, pathogenesis. IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that have distinct pathological outcomes in infected hosts. Functional comparisons of HTLV-1 and HTLV-2 proteins provide a better understanding about how HTLV-1

  7. Detection of a major gene predisposing to human T lymphotropic virus type I infection in children among an endemic population of African origin.

    PubMed

    Plancoulaine, S; Gessain, A; Joubert, M; Tortevoye, P; Jeanne, I; Talarmin, A; de Thé, G; Abel, L

    2000-08-01

    Human T lymphotropic virus type I (HTLV-I) is a human oncoretrovirus that causes an adult T cell leukemia/lymphoma and a chronic neuromyelopathy. To investigate whether familial aggregation of HTLV-I infection (as determined by specific seropositive status) could be explained in part by genetic factors, we conducted a large genetic epidemiological survey in an HTLV-I-endemic population of African origin from French Guiana. All of the families in 2 villages were included, representing 83 pedigrees with 1638 subjects, of whom 165 (10.1%) were HTLV-I seropositive. The results of segregation analysis are consistent with the presence of a dominant major gene predisposing to HTLV-I infection, in addition to the expected familial correlations (mother-offspring, spouse-spouse) due to the virus transmission routes. Under this genetic model, approximately 1. 5% of the population is predicted to be highly predisposed to HTLV-I infection, and almost all seropositive children <10 years of age are genetic cases, whereas most HTLV-I seropositive adults are sporadic cases.

  8. Preexisting infection with human T-cell lymphotropic virus type 2 neither exacerbates nor attenuates simian immunodeficiency virus SIVmac251 infection in macaques.

    PubMed

    Gordon, Shari N; Weissman, Anna R; Cecchinato, Valentina; Fenizia, Claudio; Ma, Zhong-Min; Lee, Tzong-Hae; Zaffiri, Lorenzo; Andresen, Vibeke; Parks, Robyn Washington; Jones, Kathryn S; Heraud, Jean Michel; Ferrari, Maria Grazia; Chung, Hye Kyung; Venzon, David; Mahieux, Renaud; Murphy, Edward L; Jacobson, Steven; Miller, Christopher J; Ruscetti, Francis W; Franchini, Genoveffa

    2010-03-01

    Coinfection with human T-cell lymphotropic virus type 2 (HTLV-2) and human immunodeficiency virus type 1 (HIV-1) has been reported to have either a slowed disease course or to have no effect on progression to AIDS. In this study, we generated a coinfection animal model and investigated whether HTLV-2 could persistently infect macaques, induce a T-cell response, and impact simian immunodeficiency virus SIV(mac251)-induced disease. We found that inoculation of irradiated HTLV-2-infected T cells into Indian rhesus macaques elicited humoral and T-cell responses to HTLV-2 antigens at both systemic and mucosal sites. Low levels of HTLV-2 provirus DNA were detected in the blood, lymphoid tissues, and gastrointestinal tracts of infected animals. Exposure of HTLV-2-infected or naïve macaques to SIV(mac251) demonstrated comparable levels of SIV(mac251) viral replication, similar rates of mucosal and peripheral CD4(+) T-cell loss, and increased T-cell proliferation. Additionally, neither the magnitude nor the functional capacity of the SIV-specific T-cell-mediated immune response was different in HTLV-2/SIV(mac251) coinfected animals versus SIV(mac251) singly infected controls. Thus, HTLV-2 targets mucosal sites, persists, and importantly does not exacerbate SIV(mac251) infection. These data provide the impetus for the development of an attenuated HTLV-2-based vectored vaccine for HIV-1; this approach could elicit persistent mucosal immunity that may prevent HIV-1/SIV(mac251) infection.

  9. Hepatitis C virus/human T lymphotropic virus 1/2 co-infection: Regional burden and virological outcomes in people who inject drugs

    PubMed Central

    Castro, Erika; Roger, Elena

    2016-01-01

    This review analyses current data concerning co-infection with hepatitis C virus (HCV) and human T lymphotropic virus (HTLV)-1/2 in people who inject drugs (PWID), with a particular focus on disease burden and global implications for virological outcome. In addition, the available treatment options for HTLV-1/2 are summarized and the ongoing and likely future research challenges are discussed. The data in this review was obtained from 34 articles on HCV/HTLV-1/2 co-infection in PWID retrieved from the PubMed literature database and published between 1997 and 2015. Despite unavailable estimates of the burden of HCV/HTLV-1/2 co-infection in general, the epidemiologic constellation of HTLV-1/2 shows high incidence in PWID with history of migration, incarceration, and other blood-borne infectious diseases such as HCV or human immunodeficiency virus. The most recent research data strongly suggest that HTLV-1 co-infection can influence HCV viral load, HCV sustained virological response to α-interferon treatment, and HCV-related liver disease progression. In short, outcome of HCV infection is worse in the context of HTLV-1 co-infection, yet more studies are needed to gain accurate estimations of the burden of HCV/HTLV-1/2 co-infections. Moreover, in the current era of new direct-acting antiviral treatments for HCV and proven HTLV-1/2 treatment options, prospective clinical and treatment studies should be carried out, with particular focus on the PWID patient population, with the aim of improving virological outcomes. PMID:27175351

  10. Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 rex mutants.

    PubMed

    Heger, P; Rosorius, O; Hauber, J; Stauber, R H

    1999-07-15

    The HTLV-1 Rex protein is an essential shuttle protein required for nuclear export of unspliced and incompletely-spliced viral RNAs. Several trans-dominant (TD) mutant Rex proteins have been reported, however, the mechanism of trans-dominance is not known. We compared TD Rex mutants and found that a natural occurring Rex mutant, Rexp21, lacking the RNA binding domain, was highly TD and inhibited also HIV-1 Rev function. Using fusions to the green fluorescent protein (GFP) we observed that Rexp21-GFP displayed a cytoplasmic localization but was actively shuttling between the nucleus and the cytoplasm in live human cells. The presence of Rexp21-GFP inhibited the nuclear export of Rex and HIV-1 Rev as assayed by cotransfection and microinjection experiments. However, Rex-GFP or Rexp21-GFP did not form heteromultimers with nuclear Rex mutants in vivo. In contrast, shuttling was essential for trans-dominance. Thus, we propose that TD Rex mutants do not function by retaining WT Rex in the nucleus by protein-protein interactions, as demonstrated for Rev, but to titrate factors essential for Rex/Rev export. Our findings demonstrate differences between the regulatory proteins Rex and Rev and implicate a novel strategy to generate highly TD Rex mutants also applicable to other proteins.

  11. HTLV-1 Tax protein recruitment into IKKε and TBK1 kinase complexes enhances IFN-I expression.

    PubMed

    Diani, Erica; Avesani, Francesca; Bergamo, Elisa; Cremonese, Giorgia; Bertazzoni, Umberto; Romanelli, Maria Grazia

    2015-02-01

    The Tax protein expressed by human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in the deregulation of cellular pathways involved in the immune response, inflammation, cell survival, and cancer. Many of these effects derive from Tax multiple interactions with host factors, including the subunits of the IKK-complex that are required for NF-κB activation. IKKɛ and TBK1 are two IKK-related kinases that allow the phosphorylation of interferon regulatory factors that trigger IFN type I gene expression. We observed that IKKɛ and TBK1 recruit Tax into cellular immunocomplexes. We also found that TRAF3, which regulates cell receptor signaling effectors, forms complexes with Tax. Transactivation analyses revealed that expression of Tax, in presence of IKKɛ and TBK1, enhances IFN-β promoter activity, whereas the activation of NF-κB promoter is not modified. We propose that Tax may be recruited into the TBK1/IKKɛ complexes as a scaffolding-adaptor protein that enhances IFN-I gene expression.

  12. The cutaneous T cell lymphoma, mycosis fungoides, is a human T cell lymphotropic virus-associated disease. A study of 50 patients.

    PubMed Central

    Pancake, B A; Zucker-Franklin, D; Coutavas, E E

    1995-01-01

    For nearly two decades it has been suspected that the cutaneous T cell lymphoma, mycosis fungoides (MF), and its leukemic variant, the Sézary syndrome, are caused by the human T lymphotropic virus (HTLV-I/II). Arguments against this concept included the finding that only a small number of MF patients have antibodies to HTLV-I/II and that attempts to detect proviral sequences by mere Southern hybridization of extracted DNA usually met with failure. However, we have reported repeatedly that HTLV-like particles emerge in blood mononuclear cell (PBMC) cultures of practically all patients with this disease. In several instances, the particles were identified as HTLV by immunoelectron microscopy as well as biomolecular analysis. With the assumptions that the virus in MF patients may have become detection by Southern hybridization alone, the extracts of freshly isolated PBMC of 50 consecutive patients were subjected to combined PCR/Southern analysis. Here we report the presence of HTLV pol and/or tax proviral sequences in 46 out of 50 (92%) of the patients tested. In addition, five of the patients, who lacked antibodies to HTLV-I/II structural proteins, were found to be seropositive for tax. It thus seems reasonable to conclude that MF/Sézary syndrome is an HTLV-associated disease and that lack of an immune response does not preclude infection with this type of virus. Images PMID:7860737

  13. Two Cases of Human T-Lymphotropic Virus Type I-Associated Myelopathy/Tropical Spastic Paraparesis Caused by Living-Donor Renal Transplantation

    PubMed Central

    Matsumura, Mariko; Yaguchi, Hiroaki; Mito, Yasunori

    2016-01-01

    In rare instances, recipients of organ transplants from human T-lymphotropic virus type I- (HTLV-I-) positive donors reportedly developed neurologic symptoms due to HTLV-I-associated myelopathy (HAM). We present herein two cases of HAM associated with renal transplantation from HTLV-I seropositive living-donors. The first patient was a 42-year-old woman with chronic renal failure for twelve years and seronegative for HTLV-I. She underwent renal transplantation with her HTLV-I seropositive mother as the donor, and she developed HAM three years after the transplantation. The second patient was a 65-year-old man who had been suffering from diabetic nephropathy. He was seronegative for HTLV-I and underwent renal transplantation one year previously, with his HTLV-I seropositive wife as the donor. He developed HAM eight months after renal transplantation. Both cases showed neurological improvements after the immunomodulating therapies. We tried to shed some light on the understanding of immunological mechanisms of transplantation-associated HAM, focusing on therapeutic strategies based on the immunopathogenesis of the condition. PMID:27777805

  14. Target epitope in the Tax protein of human T-cell leukemia virus type I recognized by class I major histocompatibility complex-restricted cytotoxic T cells.

    PubMed

    Kannagi, M; Shida, H; Igarashi, H; Kuruma, K; Murai, H; Aono, Y; Maruyama, I; Osame, M; Hattori, T; Inoko, H

    1992-05-01

    A trans-acting regulatory gene product p40tax (Tax) of human T-cell leukemia virus type I (HTLV-I) is one of the main target antigens recognized by cytotoxic T lymphocytes (CTL) specific for HTLV-I. A CTL epitope within the Tax protein was identified in this report. HTLV-I-specific CD8+ CTL lines established from two HTLV-I carriers with HTLV-I-associated myelopathy or Sjögren syndrome were previously demonstrated to kill predominantly the target cells expressing HTLV-I Tax. The CTL from two patients showed significant levels of cytotoxicity to autologous target cells pulsed with a synthetic peptide of 24 amino acids corresponding to the amino-terminal sequences of the Tax protein. Allogeneic target cells were also sensitized for CTL by this peptide when the target cells have HLA-A2. Tax-specific cytotoxicity, detected as cytolysis of the target cells infected with vaccinia virus-HTLV-I recombinant expressing Tax protein, was almost completely inhibited by competitor cells pulsed with the synthetic peptide. This indicates that a major CTL epitope is present in this peptide. Further analysis using shorter peptides revealed that the core sequence of the CTL epitope was LLFGYPVYV at positions 11 through 19. This sequence can be aligned with the HLA-A2-specific motifs reported recently. PMID:1373197

  15. A Case of Pneumonia Caused by Pneumocystis Jirovecii and Cryptococcus Neoformans in a Patient with HTLV-1 Associated Adult T- Cell Leukemia/Lymphoma: Occam's Razor Blunted.

    PubMed

    Desai, Anish; Fe, Alexander; Desai, Amishi; Ilowite, Jonathan; Cunha, Burke A; Mathew, Joseph P

    2016-02-01

    Adult T-cell leukemia/lymphoma (ATLL) is usually preceded by infection with human T-cell lymphotropic virus I (HTLV-I). Patients with ATLL frequently get opportunistic infections of the lungs, intestines, and central nervous system. Pneumocystis pneumonia is commonly known as an AIDS defining illness. Grocott's methenamine silver stain of bronchoalveolar lavage (BAL) samples obtained via bronchoscopy remain the gold standard for diagnosis. Pulmonary cryptococcosis is seen in patients with T-cell deficiencies and a diagnosis is made by culture of sputum, BAL, or occasionally of pleural fluid. We present the second case of coinfection with these two organisms in a patient with ATLL who was successfully treated with trimethoprim-sulfamethoxazole, corticosteroids, and fluconazole. We illustrate the need for high clinical vigilance for seeking out an additional diagnosis, especially in immunocompromised patients if they are not improving despite receiving appropriate treatment. PMID:27024978

  16. No evidence of HTLV-I proviral integration in lymphoproliferative disorders associated with cutaneous T-cell lymphoma.

    PubMed Central

    Wood, G. S.; Schaffer, J. M.; Boni, R.; Dummer, R.; Burg, G.; Takeshita, M.; Kikuchi, M.

    1997-01-01

    Several recent studies have reported detection of HTLV-I genetic sequences in patients with cutaneous T-cell lymphoma (CTCL) including mycosis fungoides and Sezary syndrome. The purpose of this study was to determine whether HTLV-I was detectable in lesional tissues of patients suffering from diseases known to be associated with CTCL. Thirty-five cases were obtained from diverse geographical locations including Ohio, California, Switzerland, and Japan. Six of them had concurrent CTCL. Cases were analyzed using a combination of genomic polymerase chain reaction (PCR)/ Southern blot, dot blot, and Southern blot analyses. All assays were specific for HTLV-I provirus. Sensitivity ranged from approximately 10(-6) for PCR-based studies to 10(-2) for unamplified genomic blotting. Lesional DNA from patients with lymphomatoid papulosis (fourteen cases), Hodgkin's disease (twelve cases), and CD30+ large-cell lymphoma (nine cases) was tested for the HTLV-I proviral pX region using a genomic PCR assay followed by confirmatory Southern blot analysis with a nested oligonucleotide pX probe. All cases were uniformly negative. All of the Hodgkin's disease cases, eight of the large-cell lymphoma cases, and six of the lymphomatoid papulosis cases were then subjected to dot blot analysis of genomic DNA using a full-length HTLV-I proviral DNA probe that spans all regions of the HTLV-I genome. Again, all cases were negative. Finally, eleven of the Hodgkin's disease cases were also subjected to Southern blot analysis of EcoRI-digested genomic DNA using the same full-length HTLV-I probe. Once again, all cases were negative. These findings indicated that, despite utilization of a variety of sensitive and specific molecular biological methods, HTLV-I genetic sequences were not detectable in patients with CTCL-associated lymphoproliferative disorders. These results strongly suggest that the HTLV-I retrovirus is not involved in the pathogenesis of these diseases. Images Figure 1 Figure 2

  17. HTLV-1 in pregnant women from the Southern Bahia, Brazil: a neglected condition despite the high prevalence

    PubMed Central

    2014-01-01

    Background As the most frequent pathway of vertical transmission of HTLV-1 is breast-feeding, and considering the higher prevalence in women, it is very important to perform screening examinations for anti-HTLV-1 antibodies as part of routine prenatal care. So far, no studies of HTLV-1 seroprevalence in pregnant women in the Southern region of Bahia, Brazil, have been described. Methods Pregnant women were selected at the two regional reference centers for health care from Southern Bahia. A total of 2766 pregnant women attending the antenatal unit between November 2008 and May 2010 have been analyzed. An extra blood sample was drawn during their routine antenatal testing. A standardized questionnaire was applied and all positive plasma samples were tested by ELISA and were confirmed by Western Blot and PCR. Besides that, positive women were contacted and visited. The family members that were present during the visit were asked to be serologically screened to the virus. A prospective study was also carried out and newborns were followed up to two years for evaluation of vertical transmission. Results HTLV prevalence was 1.05% (CI 95%: 0.70-1.50). There was no association of HTLV-1 infection with age, education, income and ethnic differences. The association with marital status was borderline (OR = 7.99; 95% CI 1.07-59.3; p = 0.042). In addition, 43 family members of the HTLV-1 seropositive women have been analyzed and specific reactivity was observed in 32.56%, including two children from previous pregnancy. Conclusion: It is very important to emphasize that the lack of HTLV-1 screening in pregnant women can promote HTLV transmission especially in endemic areas. HTLV screening in this vulnerable population and the promotion of bottle-feeding for children of seropositive mothers could be important cost-effective methods to limit the vertical transmission. Besides that, our data reinforce the need to establish strategies of active surveillance in household and

  18. [HTLV-I/II seroprevalence and risk factors associated with infection in a blood donor population in Córdoba, Argentina].

    PubMed

    Gallego, S; Maturano, E; Recalde, A; Gastaldello, R; Sileoni, S; Bepre, H; Medeot, S

    2001-01-01

    In this study we have determined the seroprevalence of infections by HTLV-I/II in the blood donor population from the city of Córdoba. A total of 5476 blood donor sera were screened for HTLV-I/II antibodies by particle agglutination assay (PA) (SERODIA HTLV-I, Fujirebio INC, Tokyo, Japan). The reactive sera samples were confirmed by an "in house" indirect immunofluorescence assay (IFA). 14 out of 5476 blood donors studied were PA reactive and were confirmed positive by IFA, showing a prevalence of 0.26% (95% confidence interval: 0.126%-0.394%). All the positive samples, except one, met the criteria for HTLV-I. Although one HTLV-I infected donor was an intravenous drug abuser and two donors were born in highly endemic areas for HTLV-I, no specific risk factors were identified among the others. The demonstration that HTLV-I circulates in blood donor population of Córdoba, points out that the systematic screening of blood for HTLV-I/II antibodies must be implemented in the blood banks, in an attempt to prevent the spread of infections with this oncogenic virus in Argentina.

  19. HTLV-1 Tax Stimulates Ubiquitin E3 Ligase, Ring Finger Protein 8, to Assemble Lysine 63-Linked Polyubiquitin Chains for TAK1 and IKK Activation.

    PubMed

    Ho, Yik-Khuan; Zhi, Huijun; Bowlin, Tara; Dorjbal, Batsukh; Philip, Subha; Zahoor, Muhammad Atif; Shih, Hsiu-Ming; Semmes, Oliver John; Schaefer, Brian; Glover, J N Mark; Giam, Chou-Zen

    2015-08-01

    Human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, impacts a multitude of cellular processes, including I-κB kinase (IKK)/NF-κB signaling, DNA damage repair, and mitosis. These activities of Tax have been implicated in the development of adult T-cell leukemia (ATL) in HTLV-1-infected individuals, but the underlying mechanisms remain obscure. IKK and its upstream kinase, TGFβ-activated kinase 1 (TAK1), contain ubiquitin-binding subunits, NEMO and TAB2/3 respectively, which interact with K63-linked polyubiquitin (K63-pUb) chains. Recruitment to K63-pUb allows cross auto-phosphorylation and activation of TAK1 to occur, followed by TAK1-catalyzed IKK phosphorylation and activation. Using cytosolic extracts of HeLa and Jurkat T cells supplemented with purified proteins we have identified ubiquitin E3 ligase, ring finger protein 8 (RNF8), and E2 conjugating enzymes, Ubc13:Uev1A and Ubc13:Uev2, to be the cellular factors utilized by Tax for TAK1 and IKK activation. In vitro, the combination of Tax and RNF8 greatly stimulated TAK1, IKK, IκBα and JNK phosphorylation. In vivo, RNF8 over-expression augmented while RNF8 ablation drastically reduced canonical NF-κB activation by Tax. Activation of the non-canonical NF-κB pathway by Tax, however, is unaffected by the loss of RNF8. Using purified components, we further demonstrated biochemically that Tax greatly stimulated RNF8 and Ubc13:Uev1A/Uev2 to assemble long K63-pUb chains. Finally, co-transfection of Tax with increasing amounts of RNF8 greatly induced K63-pUb assembly in a dose-dependent manner. Thus, Tax targets RNF8 and Ubc13:Uev1A/Uev2 to promote the assembly of K63-pUb chains, which signal the activation of TAK1 and multiple downstream kinases including IKK and JNK. Because of the roles RNF8 and K63-pUb chains play in DNA damage repair and cytokinesis, this mechanism may also explain the genomic instability of HTLV-1-transformed T cells and ATL cells.

  20. Development of a cytotoxic T-cell assay in rabbits to evaluate early immune response to human T-lymphotropic virus type 1 infection.

    PubMed

    Haynes, Rashade A H; Phipps, Andrew J; Yamamoto, Brenda; Green, Patrick; Lairmore, Michael D

    2009-12-01

    Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell lymphoma/leukemia (ATL) following a prolonged clinical incubation period, despite a robust adaptive immune response against the virus. Early immune responses that allow establishment of the infection are difficult to study without effective animal models. We have developed a cytotoxic T-lymphocyte (CTL) assay to monitor the early events of HTLV-1 infection in rabbits. Rabbit skin fibroblast cell lines were established by transformation with a plasmid expressing simian virus 40 (SV40) large T antigen and used as autochthonous targets (derived from same individual animal) to measure CTL activity against HTLV-1 infection in rabbits. Recombinant vaccinia virus (rVV) constructs expressing either HTLV-1 envelope surface unit (SU) glycoprotein 46 or Tax proteins were used to infect fibroblast targets in a (51)Cr-release CTL assay. Rabbits inoculated with Jurkat T cells or ACH.2 cells (expressing ACH HTLV-1 molecule clone) were monitored at 0, 2, 4, 6, 8, 13, 21, and 34 wk post-infection. ACH.2-inoculated rabbits were monitored serologically and for viral infected cells following ex vivo culture. Proviral load analysis indicated that rabbits with higher proviral loads had significant CTL activity against HTLV-1 SU as early as 2 wk post-infection, while both low- and high-proviral-load groups had minimal Tax-specific CTL activity throughout the study. This first development of a stringent assay to measure HTLV-1 SU and Tax-specific CTL assay in the rabbit model will enhance immunopathogenesis studies of HTLV-1 infection. Our data suggest that during the early weeks following infection, HTLV-1-specific CTL responses are primarily targeted against Env-SU. PMID:19951176

  1. INTERFERON BETA-1A TREATMENT IN HTLV-1-ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS: A CASE REPORT

    PubMed Central

    Viana, Graça Maria de Castro; da Silva, Marcos Antonio Custódio Neto; Souza, Victor Lima; Lopes, Natália Barbosa da Silva; da Silva, Diego Luz Felipe; Nascimento, Maria do Desterro Soares Brandão

    2014-01-01

    Here a young patient (< 21 years of age) with a history of infective dermatitis is described. The patient was diagnosed with myelopathy associated with HTLV-1/tropical spastic paraparesis and treated with interferon beta-1a. The disease was clinically established as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and laboratory tests confirmed the presence of antibodies to HTLV-1 in the cerebrospinal fluid (CSF). Mumps, cytomegalovirus, Epstein-Barr virus, schistosomiasis, herpes virus 1 and 2, rubella, measles, varicella-zoster toxoplasmosis, hepatitis, HIV, and syphilis were excluded by serology. The patient was diagnosed with neurogenic bladder and presented with nocturia, urinary urgency, paresthesia of the lower left limb, a marked reduction of muscle strength in the lower limbs, and a slight reduction in upper limb strength. During the fourth week of treatment with interferon beta-1a, urinary urgency and paresthesia disappeared and clinical motor skills improved. PMID:25229227

  2. Interferon beta-1a treatment in HTLV-1-associated myelopathy/tropical spastic paraparesis: a case report.

    PubMed

    Viana, Graça Maria de Castro; Silva, Marcos Antonio Custódio Neto da; Souza, Victor Lima; Lopes, Natália Barbosa da Silva; Silva, Diego Luz Felipe da; Nascimento, Maria do Desterro Soares Brandão

    2014-01-01

    Here a young patient (< 21 years of age) with a history of infective dermatitis is described. The patient was diagnosed with myelopathy associated with HTLV-1/tropical spastic paraparesis and treated with interferon beta-1a. The disease was clinically established as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and laboratory tests confirmed the presence of antibodies to HTLV-1 in the cerebrospinal fluid (CSF). Mumps, cytomegalovirus, Epstein-Barr virus, schistosomiasis, herpes virus 1 and 2, rubella, measles, varicella-zoster toxoplasmosis, hepatitis, HIV, and syphilis were excluded by serology. The patient was diagnosed with neurogenic bladder and presented with nocturia, urinary urgency, paresthesia of the lower left limb, a marked reduction of muscle strength in the lower limbs, and a slight reduction in upper limb strength. During the fourth week of treatment with interferon beta-1a, urinary urgency and paresthesia disappeared and clinical motor skills improved. PMID:25229227

  3. Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome

    SciTech Connect

    DeFreitas, E.; Hilliard, B.; Cheney, P.R.; Bell, D.S.; Kiggundu, E.; Sankey, D.; Wroblewska, Z.; Palladino, M.; Woodward, J.P.; Koprowski, H. )

    1991-04-01

    Chronic fatigue immune dysfunction syndrome (CFIDS) is a recently recognized illness characterized by debilitating fatigue as well as immunological and neurological abnormalities. Once thought to be caused by Epstein-Barr virus, it is now thought to have a different but unknown etiology. The authors evaluted 30 adult and pediatric CFIDS patients from six eastern states for the presence of human T-lymphotropic virus (HTLV) types I and II by Western immunoblotting, polymerase chain reaction, and in situ hybridization of blood samples. The majority of patients were positive for HTLV antibodies by Western blotting and for HTLV-II gag sequences by polymerase chain reaction and in situ hybridization. Twenty nonexposure healthy controls were negative in all assays. These data support an association between an HTLV-II-like virus and CFIDS.

  4. HIV-1, HIV-2, HTLV-I/II and STD among female prostitutes in Buenos Aires, Argentina.

    PubMed

    Zapiola, I; Salomone, S; Alvarez, A; Scolastico, M C; Koessel, R A; Lemus, J; Wainstein, C; Muchinik, G

    1996-02-01

    To determine the prevalence of HIV-1 and HTLV-I/II among female prostitutes from different areas of the city of Buenos Aires, we studied serum samples from 237 individuals (mean age: 25; range 17 to 39). Prostitutes were recruited from 16 different Buenos Aires locations with different economical status. Information on sexual behaviour, health and socioeconomic conditions was collected through a questionnaire. HIV-1 and HTLV-I/II antibodies (ab) were tested by ELISA (Abbott) and Particle agglutination (Fujirebio, Tokyo) respectively. Positive results were confirmed by immunofluorescence assay. Samples that were positive for HIV-1 antibodies were also tested for p24 antigen (Abbott). VDRL for syphilis was performed in all samples. Fifteen (6.3%) out of the 237 individuals were positive for HIV-1 antibodies. Moreover, 2 (0.8%) HIV-1 seropositive prostitutes were also positive for HTLV-I/II antibodies and for HIV p24-Ag. Even though PCR for HTLV-I/II was not performed, titration by IFA in these two samples suggests HTLV-I. Our serologic results indicate a relatively high HIV-1 infection among prostitutes working in Buenos Aires. As we previously mentioned for other risk groups, we found an association between HTLV-I/II and HIV-1 infection in this particular group. Although we did not find any significant difference between HIV-1 seropositivity and the variables analyzed through the questionnaire, the prevalence of HIV-1 infection was higher in prostitutes working in mask brothels ('sauna or massage houses') as compared with hotel or street prostitutes.

  5. Suppression of human T-cell leukemia virus I gene expression by pokeweed antiviral protein.

    PubMed

    Mansouri, Sheila; Choudhary, Gunjan; Sarzala, Paulina M; Ratner, Lee; Hudak, Katalin A

    2009-11-01

    Human T-cell leukemia virus I (HTLV-I) is a deltaretrovirus that is the causative agent of adult T-cell leukemia and the neurological disorder HTLV-I-associated myelopathy/tropical spastic paraparesis. Currently, no effective antiretroviral treatment options are available to restrict the development of diseases associated with the virus. In this work, we investigated the activity of pokeweed antiviral protein (PAP) on HTLV-I, when expressed from a proviral clone in 293T cells or in an HTLV-I immortalized cell line. PAP is a plant-derived N-glycosidase that exhibits antiviral activity against a number of viruses; however, its mode of action has not been clearly defined. Here, we describe the mechanism by which PAP inhibited production of HTLV-I. We show that PAP depurinated nucleotides within the gag open reading frame and suppressed the synthesis of viral proteins in part by decreasing the translational efficiency of HTLV-I gag/pol mRNA. Observed reduction in levels of viral mRNAs were not due to enhanced degradation; rather, decreased amounts of viral transactivator protein, Tax, led to feed-back inhibition of transcription from the viral promoter. Therefore, PAP efficiently suppressed HTLV-I gene expression at both translational and transcriptional levels, resulting in substantially diminished virus production. Significantly, no changes in viability or rates of cellular transcription or translation were observed in cells expressing PAP, indicating that this protein was not toxic. Antiviral activity, together with the absence of cytotoxicity, supports further investigation of this enzyme as a novel therapeutic agent against the progression of HTLV-I infection.

  6. Differential transforming activity of the retroviral Tax oncoproteins in human T lymphocytes.

    PubMed

    Ren, Tong; Cheng, Hua

    2013-01-01

    Human T cell leukemia virus type 1 and type 2 (HTLV-1 and -2) are two closely related retroviruses. HTLV-1 causes adult T cell leukemia and lymphoma, whereas HTLV-2 infection is not etiologically linked to human disease. The viral genomes of HTLV-1 and -2 encode highly homologous transforming proteins, Tax-1 and Tax-2, respectively. Tax-1 is thought to play a central role in transforming CD4+ T lymphocytes. Expression of Tax-1 is crucial for promoting survival and proliferation of virally infected human T lymphocytes and is necessary for initiating HTLV-1-mediated oncogenesis. In transgenic mice and humanized mouse model, Tax-1 has proven to be leukemogenic. Although Tax-1 is able to efficiently transform rodent fibroblasts and to induce lymphoma in mouse model, it rarely transforms primary human CD4+ T lymphocytes. In contrast, Tax-2 efficiently immortalizes human CD4+ T cells though it exhibits a lower transforming activity in rodent cells as compared to Tax-1. We here discuss our recent observation and views on the differential transforming activity of Tax-1 and Tax-2 in human T cells.

  7. Clinical Associations of Human T-Lymphotropic Virus Type 1 Infection in an Indigenous Australian Population

    PubMed Central

    Einsiedel, Lloyd; Spelman, Tim; Goeman, Emma; Cassar, Olivier; Arundell, Mick; Gessain, Antoine

    2014-01-01

    Introduction In resource-poor areas, infectious diseases may be important causes of morbidity among individuals infected with the Human T-Lymphotropic Virus type 1 (HTLV-1). We report the clinical associations of HTLV-1 infection among socially disadvantaged Indigenous adults in central Australia. Methodology and Principal Findings HTLV-1 serological results for Indigenous adults admitted 1st January 2000 to 31st December 2010 were obtained from the Alice Springs Hospital pathology database. Infections, comorbid conditions and HTLV-1 related diseases were identified using ICD-10 AM discharge morbidity codes. Relevant pathology and imaging results were reviewed. Disease associations, admission rates and risk factors for death were compared according to HTLV-1 serostatus. HTLV-1 western blots were positive for 531 (33.3%) of 1595 Indigenous adults tested. Clinical associations of HTLV-1 infection included bronchiectasis (adjusted Risk Ratio, 1.35; 95% CI, 1.14–1.60), blood stream infections (BSI) with enteric organisms (aRR, 1.36; 95% CI, 1.05–1.77) and admission with strongyloidiasis (aRR 1.38; 95% CI, 1.16–1.64). After adjusting for covariates, HTLV-1 infection remained associated with increased numbers of BSI episodes (adjusted negative binomial regression, coefficient, 0.21; 95% CI, 0.02–0.41) and increased admission numbers with strongyloidiasis (coefficient, 0.563; 95% CI, 0.17–0.95) and respiratory conditions including asthma (coefficient, 0.99; 95% CI, 0.27–1.7), lower respiratory tract infections (coefficient, 0.19; 95% CI, 0.04–0.34) and bronchiectasis (coefficient, 0.60; 95% CI, 0.02–1.18). Two patients were admitted with adult T-cell Leukemia/Lymphoma, four with probable HTLV-1 associated myelopathy and another with infective dermatitis. Independent predictors of mortality included BSI with enteric organisms (aRR 1.78; 95% CI, 1.15–2.74) and bronchiectasis (aRR 2.07; 95% CI, 1.45–2.98). Conclusion HTLV-1 infection contributes to

  8. Distinct Morphology of Human T-Cell Leukemia Virus Type 1-Like Particles.

    PubMed

    Maldonado, José O; Cao, Sheng; Zhang, Wei; Mansky, Louis M

    2016-01-01

    The Gag polyprotein is the main retroviral structural protein and is essential for the assembly and release of virus particles. In this study, we have analyzed the morphology and Gag stoichiometry of human T-cell leukemia virus type 1 (HTLV-1)-like particles and authentic, mature HTLV-1 particles by using cryogenic transmission electron microscopy (cryo-TEM) and scanning transmission electron microscopy (STEM). HTLV-1-like particles mimicked the morphology of immature authentic HTLV-1 virions. Importantly, we have observed for the first time that the morphology of these virus-like particles (VLPs) has the unique local feature of a flat Gag lattice that does not follow the curvature of the viral membrane, resulting in an enlarged distance between the Gag lattice and the viral membrane. Other morphological features that have been previously observed with other retroviruses include: (1) a Gag lattice with multiple discontinuities; (2) membrane regions associated with the Gag lattice that exhibited a string of bead-like densities at the inner leaflet; and (3) an arrangement of the Gag lattice resembling a railroad track. Measurement of the average size and mass of VLPs and authentic HTLV-1 particles suggested a consistent range of size and Gag copy numbers in these two groups of particles. The unique local flat Gag lattice morphological feature observed suggests that HTLV-1 Gag could be arranged in a lattice structure that is distinct from that of other retroviruses characterized to date. PMID:27187442

  9. Sexual transmission of human T-cell lymphotropic virus type 1.

    PubMed

    Paiva, Arthur; Casseb, Jorge

    2014-01-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is endemic in many parts of the world and is primarily transmitted through sexual intercourse or from mother to child. Sexual transmission occurs more efficiently from men to women than women to men and might be enhanced by sexually transmitted diseases that cause ulcers and result in mucosal ruptures, such as syphilis, herpes simplex type 2 (HSV-2), and chancroid. Other sexually transmitted diseases might result in the recruitment of inflammatory cells and could increase the risk of HTLV-1 acquisition and transmission. Additionally, factors that are associated with higher transmission risks include the presence of antibodies against the viral oncoprotein Tax (anti-Tax), a higher proviral load in peripheral blood lymphocytes, and increased cervicovaginal or seminal secretions. Seminal fluid has been reported to increase HTLV replication and transmission, whereas male circumcision and neutralizing antibodies might have a protective effect. Recently, free virions were discovered in plasma, which reveals a possible new mode of HTLV replication. It is unclear how this discovery might affect the routes of HTLV transmission, particularly sexual transmission, because HTLV transmission rates are significantly higher from men to women than women to men. PMID:25075475

  10. Distinct Morphology of Human T-Cell Leukemia Virus Type 1-Like Particles

    PubMed Central

    Maldonado, José O.; Cao, Sheng; Zhang, Wei; Mansky, Louis M.

    2016-01-01

    The Gag polyprotein is the main retroviral structural protein and is essential for the assembly and release of virus particles. In this study, we have analyzed the morphology and Gag stoichiometry of human T-cell leukemia virus type 1 (HTLV-1)-like particles and authentic, mature HTLV-1 particles by using cryogenic transmission electron microscopy (cryo-TEM) and scanning transmission electron microscopy (STEM). HTLV-1-like particles mimicked the morphology of immature authentic HTLV-1 virions. Importantly, we have observed for the first time that the morphology of these virus-like particles (VLPs) has the unique local feature of a flat Gag lattice that does not follow the curvature of the viral membrane, resulting in an enlarged distance between the Gag lattice and the viral membrane. Other morphological features that have been previously observed with other retroviruses include: (1) a Gag lattice with multiple discontinuities; (2) membrane regions associated with the Gag lattice that exhibited a string of bead-like densities at the inner leaflet; and (3) an arrangement of the Gag lattice resembling a railroad track. Measurement of the average size and mass of VLPs and authentic HTLV-1 particles suggested a consistent range of size and Gag copy numbers in these two groups of particles. The unique local flat Gag lattice morphological feature observed suggests that HTLV-1 Gag could be arranged in a lattice structure that is distinct from that of other retroviruses characterized to date. PMID:27187442

  11. Alternate receptor usage of neuropilin-1 and glucose transporter protein 1 by the human T cell leukemia virus type 1

    SciTech Connect

    Jin Qingwen; Alkhatib, Bashar; Cornetta, Kenneth; Alkhatib, Ghalib

    2010-01-20

    Recent studies have demonstrated that neuropilin 1 (NP-1) is involved in HTLV-1 entry; however, the role NP-1 plays in this process is not understood. We demonstrated that ectopic expression of human NP-1 but not NP-2 cDNA increased susceptibility to HTLV-1. SiRNA-mediated inhibition of NP-1 expression correlated with significant reduction of HTLV-1 Env-mediated fusion. The vascular endothelial growth factor (VEGF{sub 165}) caused downmodulation of surface NP-1 and inhibited HTLV-1 infection of U87 cells. In contrast, VEGF{sub 165} partially inhibited infection of primary astrocytes and had no significant effect on infection of HeLa cells. VEGF{sub 165} and antibodies to the glucose transporter protein 1 (anti-GLUT-1) were both needed to block infection of primary astrocytes, however, only anti-GLUT-1 antibodies were sufficient to block infection of HeLa cells. HTLV-1 Env forms complexes with both NP-1 and GLUT-1 in primary human astrocytes. The alternate usage of these two cellular receptors may have important implications regarding HTLV-1 neuro-tropism.

  12. Seroprevalence of HIV, HTLV-I/II and other perinatally-transmitted pathogens in Salvador, Bahia.

    PubMed

    dos Santos, J I; Lopes, M A; Deliège-Vasconcelos, E; Couto-Fernandez, J C; Patel, B N; Barreto, M L; Ferreira Júnior, O C; Galvão-Castro, B

    1995-01-01

    Generation of epidemiological data on perinatally-transmitted infections is a fundamental tool for the formulation of health policies. In Brazil, this information is scarce, particularly in Northeast, the poorest region of the country. In order to gain some insights of the problem we studied the seroprevalence of some perinatally-transmitted infections in 1,024 low income pregnant women in Salvador, Bahia. The prevalences were as follow: HIV-1 (0.10%), HTLV-I/II (0.88%), T.cruzi (2.34%). T.pallidum (3.91%), rubella virus (77.44%). T.gondii IgM (2.87%) and IgG (69.34%), HBs Ag (0.6%) and anti-HBs (7.62%). Rubella virus and T.gondii IgG antibodies were present in more than two thirds of pregnant women but antibodies against other pathogens were present at much lower rates. We found that the prevalence of HTLV-I/II was nine times higher than that found for HIV-1. In some cases such as T.cruzi and hepatitis B infection there was a decrease in the prevalence over the years. On the other hand, there was an increase in the seroprevalence of T.gondii infection. Our data strongly recommend mandatory screening tests for HTLV-I/II, T.gondii (IgM), T.pallidum and rubella virus in prenatal routine for pregnant women in Salvador. Screening test for T.cruzi, hepatitis and HIV-1 is recommended whenever risk factors associated with these infections are suspected. However in areas with high prevalence for these infections, the mandatory screening test in prenatal care should be considered. PMID:8599064

  13. Phylogenetic and Similarity Analysis of HTLV-1 Isolates from HIV-Coinfected Patients from the South and Southeast Regions of Brazil

    PubMed Central

    Magri, Mariana Cavalheiro; de Macedo Brigido, Luis Fernando; Rodrigues, Rosangela; Morimoto, Helena Kaminami; de Paula Ferreira, João Leandro

    2012-01-01

    Abstract HTLV-1 is endemic in Brazil and HIV/HTLV-1 coinfection has been detected, mostly in the northeast region. Cosmopolitan HTLV-1a is the main subtype that circulates in Brazil. This study characterized 17 HTLV-1 isolates from HIV coinfected patients of southern (n=7) and southeastern (n=10) Brazil. HTLV-1 provirus DNA was amplified by nested PCR (env and LTR) and sequenced. Env sequences (705 bp) from 15 isolates and LTR sequences (731 bp) from 17 isolates showed 99.5% and 98.8% similarity among sequences, respectively. Comparing these sequences with ATK (HTLV-1a) and Mel5 (HTLV-1c) prototypes, similarities of 99% and 97.4%, respectively, for env and LTR with ATK, and 91.6% and 90.3% with Mel5, were detected. Phylogenetic analysis showed that all sequences belonged to the transcontinental subgroup A of the Cosmopolitan subtype, clustering in two Latin American clusters. PMID:21591992

  14. Small Noncoding RNAs in Cells Transformed by Human T-Cell Leukemia Virus Type 1: a Role for a tRNA Fragment as a Primer for Reverse Transcriptase

    PubMed Central

    Ruggero, Katia; Guffanti, Alessandro; Corradin, Alberto; Sharma, Varun Kumar; De Bellis, Gianluca; Corti, Giorgio; Grassi, Angela; Zanovello, Paola; Bronte, Vincenzo; D'Agostino, Donna M.

    2014-01-01

    ABSTRACT The present study employed mass sequencing of small RNA libraries to identify the repertoire of small noncoding RNAs expressed in normal CD4+ T cells compared to cells transformed with human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma (ATLL). The results revealed distinct patterns of microRNA expression in HTLV-1-infected CD4+ T-cell lines with respect to their normal counterparts. In addition, a search for virus-encoded microRNAs yielded 2 sequences that originated from the plus strand of the HTLV-1 genome. Several sequences derived from tRNAs were expressed at substantial levels in both uninfected and infected cells. One of the most abundant tRNA fragments (tRF-3019) was derived from the 3′ end of tRNA-proline. tRF-3019 exhibited perfect sequence complementarity to the primer binding site of HTLV-1. The results of an in vitro reverse transcriptase assay verified that tRF-3019 was capable of priming HTLV-1 reverse transcriptase. Both tRNA-proline and tRF-3019 were detected in virus particles isolated from HTLV-1-infected cells. These findings suggest that tRF-3019 may play an important role in priming HTLV-1 reverse transcription and could thus represent a novel target to control HTLV-1 infection. IMPORTANCE Small noncoding RNAs, a growing family of regulatory RNAs that includes microRNAs and tRNA fragments, have recently emerged as key players in many biological processes, including viral infection and cancer. In the present study, we employed mass sequencing to identify the repertoire of small noncoding RNAs in normal T cells compared to T cells transformed with human T-cell leukemia virus type 1 (HTLV-1), a retrovirus that causes adult T-cell leukemia/lymphoma. The results revealed a distinct pattern of microRNA expression in HTLV-1-infected cells and a tRNA fragment (tRF-3019) that was packaged into virions and capable of priming HTLV-1 reverse transcription, a key event in the retroviral life cycle

  15. First seroepidemiological study and phylogenetic characterization of human T-cell lymphotropic virus type I and II infection among Amerindians in French Guiana.

    PubMed

    Talarmin, A; Vion, B; Ureta-Vidal, A; Du Fou, G; Marty, C; Kazanji, M

    1999-12-01

    We investigated the serological, epidemiological and molecular aspects of human T-cell lymphotropic virus type I and II (HTLV-I/II) infection in the Amerindian populations of French Guiana by testing 847 sera. No HTLV-II antibodies were detected, but five individuals (0.59%) were seropositive for HTLV-I. Analysis of the nucleotide sequences of 522 bp of the env gene and the compete LTR showed that all of the strains from French Guiana belonged to the cosmopolitan subtype A. The similarities were greater between Amerindian and Creole strains than between Amerindian and Noir-Marron strains or than between Creole and Noir-Marron strains. Phylogenetic analysis showed two clusters: one of strains from Amerindians and Creoles, which belong to the transcontinental subgroup, and the other of strains from Noirs-Marrons, belonging to the West African subgroup. Our results suggest that the Amerindian HTLV-I strains are of African origin.

  16. Human T cell lymphotropic virus type 1 viral load variability and long-term trends in asymptomatic carriers and in patients with human T cell lymphotropic virus type 1-related diseases.

    PubMed

    Demontis, Maria A; Hilburn, Silva; Taylor, Graham P

    2013-02-01

    Human T cell lymphotropic virus type 1 (HTLV-1) proviral load (PVL) in peripheral blood mononuclear cells (PBMCs) is high in patients with adult T cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and in some asymptomatic carriers, but fluctuates. Our objectives were to document ranges of HTLV PVL across a broader spectrum of diseases and tissues, to quantify the normal range of intrapatient PVL variability, and to identify which PVL values and changes deserve further investigation. PVL was measured in 191 patients with HTLV-1-associated diseases and in 211 asymptomatic carriers, using real-time quantitative PCR. The intraassay variability increases as viral load decreases: 8% at high load, 17% at medium load, and 33% at low load. The interassay variability is not different from the intraassay. Mean intrapatient CV is 65% (SD 21) in asymptomatic carriers and 59% (SD 22) in HAM/TSP. PVL values varied widely between individuals, but were relatively constant within individuals. High PVL in cerebrospinal fluid (CSF) and lymph nodes (LN) was associated with disease but 57% of asymptomatic carriers had a PVL greater than 1% in PBMCs. Our results suggest that (1) PVL changes falling outside a coefficient of variation of 100% require more detailed assessment, (2) asymptomatic carriers with PVL higher than 10% should undergo more frequent clinical and laboratory monitoring, and (3) HTLV-1 PVL in blood and tissue is helpful in the diagnosis and monitoring of HTLV-1 infection.

  17. HTLV-1 Tax protein sensitizes cells to apoptotic cell death induced by DNA damaging agents.

    PubMed

    Kao, S Y; Lemoine, F J; Mariott, S J

    2000-04-27

    Transient HTLV-1 Tax expression suppresses cellular nucleotide excision repair, and this effect correlates with Tax transactivation of the proliferating cell nuclear antigen promoter. The inability to repair DNA damage typically induces apoptotic cell death. Therefore, we investigated the effect of Tax-mediated suppression of DNA repair on apoptosis in stable Tax-expressing cells. Constitutive Tax expression reduced cellular nucleotide excision repair activity compared with parental and control cells. Tax-expressing cells were also more sensitive to apoptosis induced by DNA damaging agents than control cells. Even though Tax-expressing cells displayed reduced DNA repair, they showed increased DNA replication following UV damage. These results suggest that Tax suppresses the cell's ability to repair DNA damage and stimulates DNA replication even in the presence of damage. The inability to repair DNA damage is likely to stimulate apoptotic cell death in the majority of Tax-expressing cells while the ability to promote DNA replication may also allow the survival of a small population of cells. We propose that together these effects contribute to the monoclonal nature and low efficiency of HTLV-1 transformation.

  18. Synergistic activation of the HTLV1 LTR Ets-responsive region by transcription factors Ets1 and Sp1.

    PubMed Central

    Gégonne, A; Bosselut, R; Bailly, R A; Ghysdael, J

    1993-01-01

    Ets1 is the prototype of a family of transcriptional activators whose activity depends on the binding to specific DNA sequences characterized by an invariant GGA core sequence. We have previously demonstrated that transcriptional activation by Ets1 of the long terminal repeat (LTR) of human T cell lymphotropic virus type 1 is strictly dependent on the binding of Ets1 to two sites, ERE-A and ERE-B, localized in a 44 bp long Ets-responsive region (ERR1). We report here that the activity of ERR1 as an efficient Ets1 response element in HeLa cells also depends on the integrity of an Sp1 binding site localized immediately upstream of ERE-A. The response to Ets1 of an element restricted to the SP1/ERE-A binding sites is also strictly dependent on both the Ets1 and Sp1 binding sites. In vitro, Sp1 and Ets1 are shown to cooperate to form a ternary complex with the SP1/ERE-A element. Reconstitution experiments in Drosophila melanogaster Schneider cells show that Ets1 and Sp1 act synergistically to activate transcription from either the ERR1 or the SP1/ERE-A elements and that synergy requires the binding of both Sp1 and Ets1 to their cognate sites. SP1/ERE-A elements are found in the enhancer/promoter region of several cellular genes, suggesting that synergy between Ets1 and Sp1 is not restricted to the ERR1 region of the HTLV1 LTR. These results strengthen the notion that Ets1 as well as other members of the Ets family usually function as components of larger transcription complexes to regulate the activity of a variety of viral and cellular genes. Images PMID:8458329

  19. Interleukin-1 alpha produced by human T-cell leukaemia virus type I-infected T cells induces intercellular adhesion molecule-1 expression on lung epithelial cells.

    PubMed

    Nakayama, Yuko; Ishikawa, Chie; Tamaki, Kazumi; Senba, Masachika; Fujita, Jiro; Mori, Naoki

    2011-12-01

    The pathogenic mechanism of human T-cell leukaemia virus type I (HTLV-I)-related pulmonary disease, which involves overexpression of intercellular adhesion molecule-1 (ICAM-1) in lung epithelial cells, was investigated. The supernatant of HTLV-I-infected Tax(+) MT-2 and C5/MJ cells induced ICAM-1 expression on A549 cells, a human tumour cell line with the properties of alveolar epithelial cells. Neutralization of ICAM-1 partially inhibited HTLV-I-infected T-cell adhesion to A549 cells. Analysis of the ICAM-1 promoter showed that the nuclear factor-kappa B-binding site was important for supernatant-induced ICAM-1 expression. Induction of interleukin (IL)-1 alpha (IL-1α) expression in MT-2 and C5/MJ cells was observed compared with uninfected controls and HTLV-I-infected Tax-negative cell lines. The significance of IL-1α as a soluble messenger was supported by blocking the biological activities of MT-2 supernatant with an IL-1α-neutralizing mAb. Moreover, Tax and IL-1α expression was demonstrated in the bronchoalveolar lavage cells of patients with HTLV-I-related pulmonary disease. Immunohistochemistry confirmed ICAM-1 and IL-1α expression in lung epithelial cells and lymphocytes of patients with HTLV-I-related pulmonary diseases, and in a transgenic mouse model of Tax expression. These results suggest that IL-1α produced by HTLV-I-infected Tax(+) T cells is crucial for ICAM-1 expression in lung epithelial cells and subsequent adhesion of lymphocytes in HTLV-I-related pulmonary diseases.

  20. Human T-cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T-cells.

    PubMed

    Takachi, Takayuki; Takahashi, Masahiko; Takahashi-Yoshita, Manami; Higuchi, Masaya; Obata, Miki; Mishima, Yukio; Okuda, Shujiro; Tanaka, Yuetsu; Matsuoka, Masao; Saitoh, Akihiko; Green, Patrick L; Fujii, Masahiro

    2015-04-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-κB, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells.

  1. Lymphotoxin activation by human T-cell leukemia virus type I-infected cell lines: role for NF-kappa B.

    PubMed

    Paul, N L; Lenardo, M J; Novak, K D; Sarr, T; Tang, W L; Ruddle, N H

    1990-11-01

    Human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of biologically active lymphotoxin (LT; tumor necrosis factor-beta) protein and LT mRNA. To understand the regulation of LT transcription by HTLV-I, we analyzed the ability of a series of deletions of the LT promoter to drive the chloramphenicol acetyltransferase (CAT) reporter gene in HTLV-I-positive MT-2 cells. The smallest LT promoter fragment (-140 to +77) that was able to drive CAT activity contained a site that was similar to the immunoglobulin kappa-chain NF-kappa B-binding site. Since the HTLV-I tax gene activates the nuclear form of NF-kappa B, this finding suggested a possible means of HTLV-I activation of LT production. We found that the LT kappa B-like site specifically formed a complex with NF-kappa B-containing nuclear extract from MT-2, C81-66-45, and other activated T cells. Mutation of the LT kappa B site in the context of the LT promoter (-293 to +77) (mutant M1) reduced the ability of the promoter to drive the CAT gene in HTLV-I-infected and noninfected human T-cell lines. These data suggest a general role for NF-kappa B activation in the induction of LT gene transcription. Activation of LT in HTLV-I-infected cells may explain the pathology associated with HTLV-I infection, including the hypercalcemia that is prevalent in adult T-cell leukemia.

  2. A Human T-Cell Lymphotropic Virus Type 1 Enhancer of Myc Transforming Potential Stabilizes Myc-TIP60 Transcriptional Interactions

    PubMed Central

    Awasthi, Soumya; Sharma, Anima; Wong, Kasuen; Zhang, Junyu; Matlock, Elizabeth F.; Rogers, Lowery; Motloch, Pamela; Takemoto, Shigeki; Taguchi, Hirokuni; Cole, Michael D.; Lüscher, Bernhard; Dittrich, Oliver; Tagami, Hideaki; Nakatani, Yoshihiro; McGee, Monnie; Girard, Anne-Marie; Gaughan, Luke; Robson, Craig N.; Monnat, Raymond J.; Harrod, Robert

    2005-01-01

    The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4+ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30II/Myc-TIP60 chromatin-remodeling complexes. The p30II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30II interact with the TIP60 HAT, and p30II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis. PMID:15988028

  3. HTLV-1-associated cutaneous disease: a clinicopathological and molecular study of patients from the U.K.

    PubMed

    Whittaker, S J; Ng, Y L; Rustin, M; Levene, G; McGibbon, D H; Smith, N P

    1993-05-01

    The clinicopathological features of eight patients with cutaneous disease associated with HTLV-1 infection are reviewed. All were U.K. residents of West Indian extraction, and two are currently alive. Disease remained confined to the skin in two patients. Five patients with a cutaneous prodromal phase developed leukaemia after a median duration of 124 months (3 months-21 years), and in one of these combination chemotherapy produced a sustained clinical remission for 20 months. Two patients developed cutaneous disease after remission of their leukaemia. Cutaneous lesions were heterogeneous and included localized papules, a generalized papulonodular eruption, diffuse and localized erythematous plaques, pompholyx-like lesions on the palms and soles, and tumours. The histology of the skin lesions was also variable, and consisted of a heavy dermal infiltrate with lymphocytes, histiocytes, plasma cells, eosinophils and cytologically atypical mononuclear cells. Epidermotropism was present in biopsies from five patients. Tumour cells with large, densely staining, pleomorphic nuclei, arranged in rows between collagen bundles, were present in the majority of cases. In one patient the infiltrate also consisted of epithelioid cells and multinucleated giant cells. Six cases were classified histologically as pleomorphic T-cell lymphoma, and two as cerebriform or mycosis fungoides type. Molecular studies revealed a clonal T-cell population associated with monoclonal integration of HTLV-1 provirus in tissue DNA from six patients. In two patients HTLV-1 integration was established retrospectively using enzymatic in vitro amplification of a specific HTLV-1 po1 gene sequence in DNA extracted from paraffin-embedded sections. This study indicates that the clinical and pathological features of HTLV-1-associated cutaneous disease are diverse. Patients may have disease confined to the skin for prolonged periods, either at presentation or following clinical relapse--cutaneous adult T

  4. Requirement of the human T-cell leukemia virus p12 and p30 products for infectivity of human dendritic cells and macaques but not rabbits.

    PubMed

    Valeri, Valerio W; Hryniewicz, Anna; Andresen, Vibeke; Jones, Kathy; Fenizia, Claudio; Bialuk, Izabela; Chung, Hye Kyung; Fukumoto, Risaku; Parks, Robyn Washington; Ferrari, Maria Grazia; Nicot, Christophe; Cecchinato, Valentina; Ruscetti, Frank; Franchini, Genoveffa

    2010-11-11

    The identification of the genes necessary for human T-cell leukemia virus (HTLV-1) persistence in humans may provide targets for therapeutic approaches. We demonstrate that ablation of the HTLV-1 genes encoding p12, p30, or the HBZ protein, does not affect viral infectivity in rabbits and in this species, only the absence of HBZ is associated with a consistent reduction in virus levels. We observed reversion of the HTLV-1 mutants to the HTLV-1 wild-type genotype in none of the inoculated rabbits. In contrast, in macaques, the absence of HBZ was associated with reversion of the mutant virus to the wild-type genotype in 3 of the 4 animals within weeks from infection. Similarly, reversion to the wild type was observed in 2 of the 4 macaque inoculated with the p30 mutant. The 4 macaques exposed to the p12 knock remained seronegative, and only 2 animals were positive at a single time point for viral DNA in tissues. Interestingly, we found that the p12 and the p30 mutants were also severely impaired in their ability to replicate in human dendritic cells. These data suggest that infection of dendritic cells may be required for the establishment and maintenance of HTLV-1 infection in primate species.

  5. [Absence of HTLV-I/II virus circulation in blood donors from the provinces of Santa Fe and Santiago del Estero].

    PubMed

    Gastaldello, R; Fazzola, P; Caeiro, L; Maturano, E; Perez De Rosas, A; Fernandez, I; Racca, R; Rodriguez, M B; Molina, M; Alonso, S; Gallego, S

    2002-01-01

    In the present study, we evaluated the seroprevalence of HTLV-I/II infection among the blood donors in Santa Fe and Santiago del Estero provinces. A total of 1327 serum samples from blood donors from Rafaela blood bank of Santa Fe province and 3382 serum samples from blood donors from Dr Edgar Bouzon blood bank of Santiago del Estero province were studied. The antibody screening was done by particle agglutination assay (PA) (SERODIA, Fujirebio Inc., Tokyo, Japan) or by enzyme immuno assay (EIA) (Abbott HTLV-I/HTLV-II EIA, Abbott, Germany). The "in house" indirect immunofluorescence assay (IFA) and Western blot (Bioblot HTLV Biokit, Barcelona, Spain) were used as confirmatory assays. All the samples resulted negative for specific antibodies against HTLV-I/II. These results suggest that HTLV-I/II are not circulating in low risk populations in these provinces or that the prevalences of infection would be lower than that reported by blood banks in other provinces of Argentina.

  6. Relationship Among Strongyloides stercoralis Infection, Human T-Cell Lymphotropic Virus Type 1 Infection, and Cancer: A 24-Year Cohort Inpatient Study in Okinawa, Japan.

    PubMed

    Tanaka, Teruhisa; Hirata, Tetsuo; Parrott, Gretchen; Higashiarakawa, Miwa; Kinjo, Takeshi; Kinjo, Tetsu; Hokama, Akira; Fujita, Jiro

    2016-02-01

    This study evaluated the prevalence of Strongyloides stercoralis infection and human T-cell lymphotropic virus type 1 (HTLV-1) infection in the population. In addition, this study investigated the relationship between S. stercoralis infection or HTLV-1 infection and a patient's risk of developing related cancers. This is a retrospective cohort study of 5,209 patients. The prevalence of S. stercoralis infection was 5.2% among all patients. The prevalence among men (6.3%) was significantly higher than among women (3.6%, P < 0.001). The prevalence of HTLV-1 infection among this population was 13.6% and the prevalence among women (15.5%) was significantly higher than that of men (12.3%, P < 0.001). HTLV-1 seroprevalence was higher in patients with liver cancer (P = 0.003, odds ratio [OR]: 1.91, 95% confidence interval [CI]: 1.24, 2.95) and in those with lymphoma other than adult T-cell leukemia/lymphoma (ATLL) (P = 0.005, adjusted OR: 2.76, 95% CI: 1.36, 5.62) if compared with patients without any neoplasm. The prevalence of both S. stercoralis and HTLV-1 in the Okinawan population has been steadily decreasing over the past 24 years. HTLV-1 infection significantly increases the odds of developing liver cancer and lymphomas other than ATLL.

  7. Relationship among Strongyloides stercoralis Infection, Human T-Cell Lymphotropic Virus Type 1 Infection, and Cancer: A 24-Year Cohort Inpatient Study in Okinawa, Japan

    PubMed Central

    Tanaka, Teruhisa; Hirata, Tetsuo; Parrott, Gretchen; Higashiarakawa, Miwa; Kinjo, Takeshi; Kinjo, Tetsu; Hokama, Akira; Fujita, Jiro

    2016-01-01

    This study evaluated the prevalence of Strongyloides stercoralis infection and human T-cell lymphotropic virus type 1 (HTLV-1) infection in the population. In addition, this study investigated the relationship between S. stercoralis infection or HTLV-1 infection and a patient's risk of developing related cancers. This is a retrospective cohort study of 5,209 patients. The prevalence of S. stercoralis infection was 5.2% among all patients. The prevalence among men (6.3%) was significantly higher than among women (3.6%, P < 0.001). The prevalence of HTLV-1 infection among this population was 13.6% and the prevalence among women (15.5%) was significantly higher than that of men (12.3%, P < 0.001). HTLV-1 seroprevalence was higher in patients with liver cancer (P = 0.003, odds ratio [OR]: 1.91, 95% confidence interval [CI]: 1.24, 2.95) and in those with lymphoma other than adult T-cell leukemia/lymphoma (ATLL) (P = 0.005, adjusted OR: 2.76, 95% CI: 1.36, 5.62) if compared with patients without any neoplasm. The prevalence of both S. stercoralis and HTLV-1 in the Okinawan population has been steadily decreasing over the past 24 years. HTLV-1 infection significantly increases the odds of developing liver cancer and lymphomas other than ATLL. PMID:26621566

  8. Inferences about the global scenario of human T-cell lymphotropic virus type 1 infection using data mining of viral sequences

    PubMed Central

    Araujo, Thessika Hialla Almeida; Barreto, Fernanda Khouri; Luiz Carlos, Alcântara; Miranda, Aline Cristina Andrade Mota

    2014-01-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is mainly associated with two diseases: tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) and adult T-cell leukaemia/lymphoma. This retrovirus infects five-10 million individuals throughout the world. Previously, we developed a database that annotates sequence data from GenBank and the present study aimed to describe the clinical, molecular and epidemiological scenarios of HTLV-1 infection through the stored sequences in this database. A total of 2,545 registered complete and partial sequences of HTLV-1 were collected and 1,967 (77.3%) of those sequences represented unique isolates. Among these isolates, 93% contained geographic origin information and only 39% were related to any clinical status. A total of 1,091 sequences contained information about the geographic origin and viral subtype and 93% of these sequences were identified as subtype “a”. Ethnicity data are very scarce. Regarding clinical status data, 29% of the sequences were generated from TSP/HAM and 67.8% from healthy carrier individuals. Although the data mining enabled some inferences about specific aspects of HTLV-1 infection to be made, due to the relative scarcity of data of available sequences, it was not possible to delineate a global scenario of HTLV-1 infection. PMID:24863974

  9. [Epstein-Barr virus-specific immunity in asymptomatic carriers of human T-cell leukemia virus type 1].

    PubMed

    Kwon, K W

    1995-03-01

    Adult T-cell leukemia (ATL) patients are immunosuppressed as evidenced by anergy to recall antigens and the occurrence of opportunistic infections. The immunosuppression appears to be a critical factor or a predictive sign for the development of ATL in carriers of human T-cell leukemia virus type 1 (HTLV-1). This study was aimed at assessing the immune status of asymptomatic HTLV-1 carriers with the immunity specific to Epstein-Barr virus (EBV), a ubiquitous human herpesvirus with oncogenic potential. Forty-three asymptomatic HTLV-I carriers were examined for their EBV serology and EBV-specific cytotoxic T-cell (EBV-CTL) activity, in comparison with 10 HTLV-I-non-infected normal controls. Both carriers and controls were all positive for EBV capsid antigen (VCA) IgG. Significantly elevated titer of VCAIgG and lower titer of EBV-determined nuclear antigen (EBNA) antibodies were observed in asymptomatic HTLV-I carriers, suggesting reactivation of EBV. Among the HTLV-I carriers, 9 (20.9%) had reduced activity of EBV-CTL as revealed by lower incidence of regression of in vitro EBV-induced B-cell transformation. Accordingly, asymptomatic HTLV-I carriers were divided into three groups: the carriers with reduced EBV-specific cellular immunity (group I), the carriers showing normal cellular immunity but aberrant EBV-specific antibody titers (group II), and the carriers with normal EBV-specific cellular immunity and serology (group III). Higher positive rate of anti-HTLV-I Tax antibody was found in the former two groups (44.4% and 56.5%, respectively) compared with group III (18.2%). An immunosuppressive agent, 4-deoxyphorbol ester induced a remarkable decrease of EBV-CTL activity in the carriers of group II and III at the concentration that affected none of the normal controls. These findings indicate that asymptomatic HTLV-I carriers suffer stepwise impairment of EBV-specific immunities, which may be caused by HTLV-I infection.

  10. The 5′ Untranslated Region of the Human T-Cell Lymphotropic Virus Type 1 mRNA Enables Cap-Independent Translation Initiation

    PubMed Central

    Olivares, Eduardo; Landry, Dori M.; Cáceres, C. Joaquín; Pino, Karla; Rossi, Federico; Navarrete, Camilo; Huidobro-Toro, Juan Pablo; Thompson, Sunnie R.

    2014-01-01

    ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) is a complex human retrovirus that causes adult T cell leukemia and of HTLV-associated myelopathy/tropical spastic paraparesis. The mRNA of some complex retroviruses, including the human and simian immunodeficiency viruses (HIV and SIV), can initiate translation using a canonical cap-dependent mechanism or through an internal ribosome entry site (IRES). In this study, we present strong evidence showing that like HIV-1 and SIV, the 5′-untranslated region (5′UTR) of the HTLV-1 full-length mRNA harbors an IRES. Cap-independent translational activity was evaluated and demonstrated using dual luciferase bicistronic mRNAs in rabbit reticulocyte lysate, in mammalian cell culture, and in Xenopus laevis oocytes. Characterization of the HTLV-1 IRES shows that its activity is dependent on the ribosomal protein S25 (RPS25) and that its function is highly sensitive to the drug edeine. Together, these findings suggest that the 5′UTR of the HTLV-1 full-length mRNA enables internal recruitment of the eukaryotic translation initiation complex. However, the recognition of the initiation codon requires ribosome scanning. These results suggest that, after internal recruitment by the HTLV-1 IRES, a scanning step takes place for the 40S ribosomal subunit to be positioned at the translation initiation codon. IMPORTANCE The mechanism by which retroviral mRNAs recruit the 40S ribosomal subunit internally is not understood. This study provides new insights into the mechanism of translation initiation used by the human T-cell lymphotropic virus type 1 (HTLV-1). The results show that the HTLV-1 mRNA can initiate translation via a noncanonical mechanism mediated by an internal ribosome entry site (IRES). This study also provides evidence showing the involvement of cellular proteins in HTLV-1 IRES-mediated translation initiation. Together, the data presented in this report significantly contribute to the understanding of HTLV-1 gene

  11. Apoptosis induction by Epican Forte in HTLV-1 positive and negative malignant T-cells.

    PubMed

    Harakeh, S; Diab-Assaf, M; Niedzwiecki, A; Khalife, J; Abu-El-Ardat, K; Rath, M

    2006-07-01

    The effects of a novel nutrient formulation Epican Forte (EF) were evaluated on proliferation and induction of apoptosis using non-cytotoxic concentrations against HTLV-1 positive (HuT-102 & C91-PL) and negative (CEM & Jurkat) cells. EF showed anti-proliferative effect as determined by MTT assay and TGF mRNA protein expression using RT-PCR. EF resulted in the down-regulation of TGF-alpha and an up-regulation in TGF-beta2. EF caused a significant increase in apoptotic cells in the preG1 phase. These results were confirmed using Cell Death ELISA and Annexin V-FITC. Induction of apoptosis was caused by an up-regulation of p53, p21 and Bax protein levels and a down-regulation of Bcl-2alpha protein expression level. PMID:16427125

  12. Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein.

    PubMed

    Jaworski, Elizabeth; Narayanan, Aarthi; Van Duyne, Rachel; Shabbeer-Meyering, Shabana; Iordanskiy, Sergey; Saifuddin, Mohammed; Das, Ravi; Afonso, Philippe V; Sampey, Gavin C; Chung, Myung; Popratiloff, Anastas; Shrestha, Bindesh; Sehgal, Mohit; Jain, Pooja; Vertes, Akos; Mahieux, Renaud; Kashanchi, Fatah

    2014-08-01

    Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. The HTLV-1 transactivator protein Tax controls many critical cellular pathways, including host cell DNA damage response mechanisms, cell cycle progression, and apoptosis. Extracellular vesicles called exosomes play critical roles during pathogenic viral infections as delivery vehicles for host and viral components, including proteins, mRNA, and microRNA. We hypothesized that exosomes derived from HTLV-1-infected cells contain unique host and viral proteins that may contribute to HTLV-1-induced pathogenesis. We found exosomes derived from infected cells to contain Tax protein and proinflammatory mediators as well as viral mRNA transcripts, including Tax, HBZ, and Env. Furthermore, we observed that exosomes released from HTLV-1-infected Tax-expressing cells contributed to enhanced survival of exosome-recipient cells when treated with Fas antibody. This survival was cFLIP-dependent, with Tax showing induction of NF-κB in exosome-recipient cells. Finally, IL-2-dependent CTLL-2 cells that received Tax-containing exosomes were protected from apoptosis through activation of AKT. Similar experiments with primary cultures showed protection and survival of peripheral blood mononuclear cells even in the absence of phytohemagglutinin/IL-2. Surviving cells contained more phosphorylated Rb, consistent with the role of Tax in regulation of the cell cycle. Collectively, these results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells.

  13. Human T-lymphotropic Virus Type 1-infected Cells Secrete Exosomes That Contain Tax Protein*

    PubMed Central

    Jaworski, Elizabeth; Narayanan, Aarthi; Van Duyne, Rachel; Shabbeer-Meyering, Shabana; Iordanskiy, Sergey; Saifuddin, Mohammed; Das, Ravi; Afonso, Philippe V.; Sampey, Gavin C.; Chung, Myung; Popratiloff, Anastas; Shrestha, Bindesh; Sehgal, Mohit; Jain, Pooja; Vertes, Akos; Mahieux, Renaud; Kashanchi, Fatah

    2014-01-01

    Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. The HTLV-1 transactivator protein Tax controls many critical cellular pathways, including host cell DNA damage response mechanisms, cell cycle progression, and apoptosis. Extracellular vesicles called exosomes play critical roles during pathogenic viral infections as delivery vehicles for host and viral components, including proteins, mRNA, and microRNA. We hypothesized that exosomes derived from HTLV-1-infected cells contain unique host and viral proteins that may contribute to HTLV-1-induced pathogenesis. We found exosomes derived from infected cells to contain Tax protein and proinflammatory mediators as well as viral mRNA transcripts, including Tax, HBZ, and Env. Furthermore, we observed that exosomes released from HTLV-1-infected Tax-expressing cells contributed to enhanced survival of exosome-recipient cells when treated with Fas antibody. This survival was cFLIP-dependent, with Tax showing induction of NF-κB in exosome-recipient cells. Finally, IL-2-dependent CTLL-2 cells that received Tax-containing exosomes were protected from apoptosis through activation of AKT. Similar experiments with primary cultures showed protection and survival of peripheral blood mononuclear cells even in the absence of phytohemagglutinin/IL-2. Surviving cells contained more phosphorylated Rb, consistent with the role of Tax in regulation of the cell cycle. Collectively, these results suggest that exosomes may play an important role in extracellular delivery of functional HTLV-1 proteins and mRNA to recipient cells. PMID:24939845

  14. Cell-Free versus Cell-to-Cell Infection by Human Immunodeficiency Virus Type 1 and Human T-Lymphotropic Virus Type 1: Exploring the Link among Viral Source, Viral Trafficking, and Viral Replication.

    PubMed

    Dutartre, Hélène; Clavière, Mathieu; Journo, Chloé; Mahieux, Renaud

    2016-09-01

    Human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) are complex retroviruses mainly infecting CD4(+) T lymphocytes. In addition, antigen-presenting cells such as dendritic cells (DCs) are targeted in vivo by both viruses, although to a lesser extent. Interaction of HIV-1 with DCs plays a key role in viral dissemination from the mucosa to CD4(+) T lymphocytes present in lymphoid organs. While similar mechanisms may occur for HTLV-1 as well, most HTLV-1 data were obtained from T-cell studies, and little is known regarding the trafficking of this virus in DCs. We first compared the efficiency of cell-free versus cell-associated viral sources of both retroviruses at infecting DCs. We showed that both HIV-1 and HTLV-1 cell-free particles are poorly efficient at productively infecting DCs, except when DC-SIGN has been engaged. Furthermore, while SAMHD-1 accounts for restriction of cell-free HIV-1 infection, it is not involved in HTLV-1 restriction. In addition, cell-free viruses lead mainly to a nonproductive DC infection, leading to trans-infection of T-cells, a process important for HIV-1 spread but not for that of HTLV-1. Finally, we show that T-DC cell-to-cell transfer implies viral trafficking in vesicles that may both increase productive infection of DCs ("cis-infection") and allow viral escape from immune surveillance. Altogether, these observations allowed us to draw a model of HTLV-1 and HIV-1 trafficking in DCs.

  15. HTLV-I carrier mothers with high-titer antibody are at high risk as a source of infection.

    PubMed

    Hino, S; Doi, H; Yoshikuni, H; Sugiyama, H; Ishimaru, T; Yamabe, T; Tsuji, Y; Miyamoto, T

    1987-11-01

    High-titer antibody against HTLV-I in carrier mothers is proposed as a secondary parameter for risk of viral transmission to the children via milk. For titration of antibodies, a less expensive modified gelatin particle agglutination assay (approximately 40% of the standard cost) was developed. None of 11 carrier mothers with antibody titers of less than 4000 had carrier children, whereas 11 out of 17 mothers with titers of 256,000 or higher had carrier children. The antibody titer was correlated with antigen-bearing cells detectable in cultures of peripheral blood T-lymphocytes, which was previously described as a marker of risk for transferring HTLV-I to children.

  16. Challenge of chimpanzees (Pan troglodytes) immunized with human immunodeficiency virus envelope glycoprotein gp120.

    PubMed Central

    Arthur, L O; Bess, J W; Waters, D J; Pyle, S W; Kelliher, J C; Nara, P L; Krohn, K; Robey, W G; Langlois, A J; Gallo, R C

    1989-01-01

    The human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome, infects humans and chimpanzees. To determine the efficacy of immunization for preventing infection, chimpanzees were immunized with gp120 purified from human T-cell lymphotrophic virus type IIIB (HTLV-IIIB)-infected cell membranes and challenged with the homologous virus, HTLV-IIIB. A challenge stock of HTLV-IIIB was prepared by using unconcentrated HTLV-IIIB produced in H9 cells. The titer of the virus from this stock on human and chimpanzee peripheral blood mononuclear cells and in human lymphoid cell lines was determined; a cell culture infectivity of 10(4) was assigned. All chimpanzees inoculated intravenously with 40 cell culture infectious units or more became infected, as demonstrated by virus isolation and seroconversion. One of two chimpanzees inoculated with 4 cell culture infectious units became infected. Chimpanzees immunized with gp120 formulated in alum developed antibodies which precipitated gp120 and neutralized HTLV-IIIB. Peripheral blood mononuclear cells from gp120-vaccinated and HIV-infected animals showed a significantly greater response in proliferation assays with HIV proteins than did peripheral blood mononuclear cells from nonvaccinated and non-HIV-infected chimpanzees. Two of the gp120-alum-immunized chimpanzees were challenged with virus from the HTLV-IIIB stock. One animal received 400 cell culture infectious units, and one received 40 infectious units. Both animals became infected with HIV, indicating that the immune response elicited by immunization with gp120 formulated in alum was not effective in preventing infection with HIV-1. PMID:2555541

  17. Multiple sclerosis, tropical spastic paraparesis and HTLV-1 infection in Afro-Caribbean patients in the United Kingdom.

    PubMed Central

    Rudge, P; Ali, A; Cruickshank, J K

    1991-01-01

    Forty four consecutive patients of Afro-Caribbean origin resident in the United Kingdom (UK) were studied, based on a provisional diagnosis of myelopathy of unknown cause, tropical spastic paraparesis (TSP) or multiple sclerosis (MS). Of 30 patients with progressive paraparesis 27 had serum antibodies to HTLV-1 and were classified as having TSP. Fourteen patients fulfilled the criteria for MS and none of 12 tested had HTLV-1 antibodies. All the TSP patients and nine of those with MS were born in the West Indies. Five of the West Indianborn MS patients had migrated to the UK after adolescence but the duration of residence in the UK before symptoms of MS developed was similar to those born in the UK (average 18 years). The features that differentiated MS from TSP patients, apart from HTLV-1 status, included clinical evidence of cranial nerve involvement, more extensive abnormalities on the brain and cervical cord MRI and asymmetry of the VEP latency increase, all of which were more frequent in the MS group. Of the three patients without a diagnosis one, born in the UK, had marked abnormalities on MRI of the brain indistinguishable from those seen in MS. Images PMID:1940939

  18. Mice transgenic for HTLV-I LTR-tax exhibit tax expression in bone, skeletal alterations, and high bone turnover.

    PubMed

    Ruddle, N H; Li, C B; Horne, W C; Santiago, P; Troiano, N; Jay, G; Horowitz, M; Baron, R

    1993-11-01

    HTLV-I infection can result in adult T cell leukemia with accompanying hypercalcemia and increased bone resorption. A viral etiology has also been invoked for Paget's disease, a disease of high bone turnover. Delineation of pathogenetic mechanisms of viral-associated bone diseases has been impeded by the complexity of viral and host factors. In order to consider the relationship of HTLV-I infection to skeletal changes we have evaluated the role of a single viral gene in mice transgenic for HTLV-I tax under the control of the viral promoter. Tax mice exhibited severe skeletal abnormalities characterized by high bone turnover, increases in osteoblast and osteoclast numbers and activity, and myelofibrosis. These changes were apparent as early as two months of age. Tax mRNA and protein were highly expressed in bone but not in bone marrow nor in any other tissues except, as previously reported, salivary gland and neurofibromas when they did develop. Within bone, tax protein was detected in only two cell types, mature osteoclasts and spindle-shaped cells within the endosteal myelofibrosis. These observations suggest that local expression of the tax gene, which encodes a viral regulatory protein known to influence host gene expression, can induce within the bone environment marked changes in bone cell activity, resulting in profound skeletal alterations.

  19. A source of glycosylated human T-cell lymphotropic virus type 1 envelope protein: expression of gp46 by the vaccinia virus/T7 polymerase system.

    PubMed Central

    Arp, J; LeVatte, M; Rowe, J; Perkins, S; King, E; Leystra-Lantz, C; Foung, S K; Dekaban, G A

    1996-01-01

    Heterologous expression of the human T-cell lymphotropic virus type 1 (HTLV-1) envelope surface glycoprotein (gp46) in a vaccinia virus/T7 polymerase system resulted in the production of authentic recombinant gp46. Five differentially glycosylated forms of the surface envelope protein were produced by this mammalian system, as demonstrated by tunicamycin inhibition of N-glycosylation and N-glycan removal with endoglycosidase H and glycopeptidase F. These studies revealed that all four potential N-glycosylation sites in gp46 were used for oligosaccharide modification and that the oligosaccharides were mannose-rich and/or hybrid in composition. Conformational integrity of the recombinant HTLV-1 envelope protein was determined by the ability to bind to various HTLV-1-infected human sera and a panel of conformational-dependent human monoclonal antibodies under nondenaturing conditions. Furthermore, this recombinant gp46 was recognized by a series of HTLV-2-infected human sera and sera from a Pan paniscus chimpanzee infected with the distantly related simian T-cell lymphotropic virus STLVpan-p. Maintenance of highly conserved conformational epitopes in the recombinant HTLV-1 envelope protein structure suggests that it may serve as a useful diagnostic reagent and an effective vaccine candidate. PMID:8892853

  20. Integration site and clonal expansion in human chronic retroviral infection and gene therapy.

    PubMed

    Niederer, Heather A; Bangham, Charles R M

    2014-10-31

    Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety.

  1. Induction of IL-10- and IFN-gamma-producing T-cell responses by autoreactive T-cells expressing human T-cell leukemia virus type I Tax.

    PubMed

    Takatsuka, Natsuko; Hasegawa, Atsuhiko; Takamori, Ayako; Shimizu, Yukiko; Kato, Hirotomo; Ohashi, Takashi; Amagasa, Teruo; Masuda, Takao; Kannagi, Mari

    2009-09-01

    Human T-cell leukemia virus type I (HTLV-I) is associated with adult T-cell leukemia, HTLV-I-associated myelopathy/tropical spastic paraparesis and various autoimmune-like disorders. T-cell immune suppression is also associated with HTLV-I infection. Mechanisms of diverse immune dysregulation in HTLV-I infection are obscure. Here, we investigated a potential link between autoimmunity and immune suppression in HTLV-I infection. G14, an IL-2-dependent HTLV-I-negative CD4(+)CD8(+) T-cell line previously established from an HTLV-I-infected rat, constantly proliferated and produced IFN-gamma. IFN-gamma production by G14 cells was dependent on interactions between CD4 and MHC-II, suggesting that G14 cells recognized self-antigens presented by MHC-II on themselves. To examine immune response to G14 cells, we inoculated G14 cells into syngeneic naive rats. Interestingly, T-cells isolated from these rats vigorously proliferated when stimulated with G14-Tax cells that stably expressed HTLV-I Tax, but not with G14 cells. G14-Tax-mediated T-cell proliferation was abrogated by antibodies to CD80 and CD86 that were up-regulated in G14-Tax cells. T-cells propagated by repetitive G14-Tax cell stimulations in culture with IL-2 expressed CD4, CD25 and cytolytic T lymphocyte-associated antigen 4 (CTLA-4), produced abundant amounts of IL-10 and IFN-gamma in response to G14 cells and suppressed growth of G14 cells mainly through supernatant-mediated mechanisms. Similar IL-10- and IFN-gamma-producing CD4(+)CD25(+)CTLA-4(+) T-cells were predominantly induced in culture of splenocytes from HTLV-I-infected rats following stimulation with G14-Tax cells. These results implied that expression of Tax in the otherwise low immunogenic autoreactive T-cells induced IL-10- and IFN-gamma-producing T-cell responses with regulatory effects against the autoreactive cells. Our findings provide new insights into the complex immune conditions underlying HTLV-I-associated diseases. PMID:19654198

  2. Physiotherapy for human T-lymphotropic virus 1-associated myelopathy: review of the literature and future perspectives

    PubMed Central

    Sá, Katia N; Macêdo, Maíra C; Andrade, Rosana P; Mendes, Selena D; Martins, José V; Baptista, Abrahão F

    2015-01-01

    Human T-lymphotropic virus 1 (HTLV-1) infection may be associated with damage to the spinal cord – HTLV-associated myelopathy/tropical spastic paraparesis – and other neurological symptoms that compromise everyday life activities. There is no cure for this disease, but recent evidence suggests that physiotherapy may help individuals with the infection, although, as far as we are aware, no systematic review has approached this topic. Therefore, the objective of this review is to address the core problems associated with HTLV-1 infection that can be detected and treated by physiotherapy, present the results of clinical trials, and discuss perspectives on the development of knowledge in this area. Major problems for individuals with HTLV-1 are pain, sensory-motor dysfunction, and urinary symptoms. All of these have high impact on quality of life, and recent clinical trials involving exercises, electrotherapeutic modalities, and massage have shown promising effects. Although not influencing the basic pathologic disturbances, a physiotherapeutic approach seems to be useful to detect specific problems related to body structures, activity, and participation related to movement in HTLV-1 infection, as well as to treat these conditions. PMID:25759588

  3. Human T-lymphotropic virus infections in active component service members, U.S. Armed Forces, 2000-2008.

    PubMed

    Petruccelli, Bruno P; Murray, Clinton K; Davis, Kenneth W; McBride, Richard; Peel, Sheila A; Michael, Nelson; Scott, Paul T; Hakre, Shilpa

    2014-02-01

    Emergency whole blood transfusions may increase the risk of transmitting bloodborne pathogens, including human T-lymphotropic viruses (HTLVs). U.S. military personnel with any medical encounter for HTLV infection during 2000-2013;2008 were identified from surveillance data. Using both inclusive and restrictive case definitions, the incidence of diagnoses of HTLV infection was analyzed in relation to demographic factors and prior deployment. There were 247 "possible" cases of HTLV infection identified, or 1.88 cases per 100,000 person-years (p-yrs) (95% CI 1.66, 2.13). Seventy of these met the restrictive definition, translating to a rate of 0.53 per 100,000 p-yrs (95% CI 0.42, 0.67). Under the restrictive definition, a higher rate was noted among females versus males (RR 2.37; 95% CI 1.41, 3.98), service members with a healthcare occupation versus those who are primarily trained to engage in combat (RR 2.54; 95% CI 1.06, 6.10), and service members with any deployment experience (RR 8.98; 95% CI 5.61, 14.37). These findings, and a prior military case report of transfusion-transmitted HTLV-I, suggest a need to better define the epidemiology of HTLV in U.S. military personnel to further ensure emergency transfusion safety.

  4. Differential activation of the 21-base-pair enhancer element of human T-cell leukemia virus type I by its own trans-activator and cyclic AMP.

    PubMed Central

    Nakamura, M; Niki, M; Ohtani, K; Sugamura, K

    1989-01-01

    A transcriptional trans-acting factor p40tax of human T-cell leukemia virus type I (HTLV-I) functions as an inducer for expression of HTLV-I provirus via activation of the enhancer in the long terminal repeat of HTLV-I. In addition to p40tax and a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, we report here that forskolin, an activator of adenyl cyclase, also induces function of the HTLV-I enhancer. Experiments with mutants of the HTLV-I enhancer revealed that TPA-induced activation was not mediated by solely a 21-base-pair (bp) sequence that is repeated three times in the enhancer, whereas the 21-bp enhancer element can act as a sufficient cis-acting sequence for activation by both p40tax and forskolin. In addition, we found that nuclear factor(s) like the cyclic AMP-responsive element (CRE) binding factor could bind to the HTLV-I 21-bp enhancer element. However, a difference was found in sequences required for activation by p40tax and forskolin. A CRE related sequence present in the 21-bp enhancer element was enough for forskolin-induced activation. On the other hand, p40tax required a much longer sequence that is overlapping but not identical to the CRE related sequence, suggesting that the forskolin-induced cyclic AMP pathway may be partly involved in, but not sufficient for p40tax-mediating trans-activation of the HTLV-I enhancer. Images PMID:2548156

  5. Molecular cloning of human T-cell lymphotrophic virus type I-like proviral genome from the peripheral lymphocyte DNA of a patient with chronic neurologic disorders

    SciTech Connect

    Reddy, E.P.; Mettus, R.V.; DeFreitas, E.; Wroblewska, Z.; Cisco, M.; Koprowski, H. )

    1988-05-01

    Human T-cell lymphotropic virus type 1 (HTLV-I), the etiologic agent of human T-cell leukemia, has recently been shown to be associated with neurologic disorders such as tropical spastic paraparesis, HTLV-associated myelopathy, and possibly with multiple sclerosis. In this communication, the authors have examined one specific case of neurologic disorder that can be classified as multiple sclerosis or tropical spastic paraparesis. The patient suffering from chronic neurologic disorder was found to contain antibodies to HTLV-I envelope and gag proteins in his serum and cerebrospinal fluid. Lymphocytes from peripheral blood and cerebrospinal fluid of the patient were shown to express viral RNA sequences by in situ hybridization. Southern blot analysis of the patient lymphocyte DNA revealed the presence of HTLV-I-related sequences. Blot-hybridization analysis of the RNA from fresh peripheral lymphocytes stimulated with interleukin 2 revealed the presence of abundant amounts of genomic viral RNA with little or no subgenomic RNA. They have clones the proviral genome from the DNA of the peripheral lymphocytes and determined its restriction map. This analysis shows that this proviral genome is very similar if not identical to that of the prototype HTLV-I genome.

  6. [High prevalence of antiHTLV-1 antibodies in the Boni, an ethnic group of African origin isolated in French Guiana since the 18th century].

    PubMed

    Gessain, A; Calender, A; Strobel, M; Lefait-Robin, R; de Thé, G

    1984-01-01

    Antibodies to HTLV-1 (ELISA test using disrupted virus) were studied in different ethnic groups in French Guiana, including 135 blood donors from Cayenne, 97 Boni Blacks and 57 Wayana Indians from Maripasoula area, and 57 Hmong from Cacao village. We observed significant differences between Boni Blacks and Wayana Indians, having respectively 10.3% versus 0% of high antibody titers. The Hmong, recent refugees from Kampuchea, exhibited an intermediate level (3.5%) of infection. These results favour an African origin of HTLV-1 and raise, for the Hmong, the question of an infection acquired in Guiana.

  7. Oncogenic Human T-Cell Lymphotropic Virus Type 1 Tax Suppression of Primary Innate Immune Signaling Pathways

    PubMed Central

    Hyun, Jinhee; Ramos, Juan Carlos; Toomey, Ngoc; Balachandran, Siddharth; Lavorgna, Alfonso; Harhaj, Edward

    2015-01-01

    ABSTRACT Human T-cell lymphotropic virus type I (HTLV-1) is an oncogenic retrovirus considered to be the etiological agent of adult T-cell leukemia (ATL). The viral transactivator Tax is regarded as the oncoprotein responsible for contributing toward the transformation process. Here, we demonstrate that Tax potently inhibits the activity of DEx(D/H) box helicases RIG-I and MDA5 as well as Toll-dependent TIR-domain-containing adapter-inducing interferon-β (TRIF), which function as cellular sensors or mediators of viral RNA and facilitate innate immune responses, including the production of type I IFN. Tax manifested this function by binding to the RIP homotypic interaction motif (RHIM) domains of TRIF and RIP1 to disrupt interferon regulatory factor 7 (IRF7) activity, a critical type I IFN transcription factor. These data provide further mechanistic insight into HTLV-1-mediated subversion of cellular host defense responses, which may help explain HTLV-1-related pathogenesis and oncogenesis. IMPORTANCE It is predicted that up to 15% of all human cancers may involve virus infection. For example, human T-cell lymphotropic virus type 1 (HTLV-1) has been reported to infect up to 25 million people worldwide and is the causative agent of adult T-cell leukemia (ATL). We show here that HTLV-1 may be able to successfully infect the T cells and remain latent due to the virally encoded product Tax inhibiting a key host defense pathway. Understanding the mechanisms by which Tax subverts the immune system may lead to the development of a therapeutic treatment for HTLV-1-mediated disease. PMID:25694597

  8. Abnormal centrosome amplification in cells through the targeting of Ran-binding protein-1 by the human T cell leukemia virus type-1 Tax oncoprotein

    PubMed Central

    Peloponese, Jean-Marie; Haller, Kerstin; Miyazato, Akiko; Jeang, Kuan-Teh

    2005-01-01

    Human T cell leukemia virus type-1 (HTLV-1) is an oncogenic retrovirus etiologically causal of adult T cell leukemia. The virus encodes a Tax oncoprotein that functions in transcriptional regulation, cell cycle control, and transformation. Because adult T cell leukemia like many other human cancers is a disease of genomic instability with frequent gains and losses of chromosomes, to understand this disease it is important to comprehend how HTLV-1 engenders aneuploidy in host cells. In this regard, loss of cell cycle checkpoints permits tolerance of aneuploidy but does not explain how aneuploidy is created. We show here that HTLV-1 Tax causes abnormal centrosome fragmentation in the mitotic phase of the cell cycle. We report that Tax directly binds Ran and Ran-binding protein-1, locates to centrosomes/spindle poles, and causes supernumerary centrosomes. PMID:16365316

  9. Intracellular Distribution of Human T-Cell Leukemia Virus Type 1 Gag Proteins Is Independent of Interaction with Intracellular Membranes

    PubMed Central

    LeBlanc, Isabelle; Blot, Vincent; Bouchaert, Isabelle; Salamero, Jean; Goud, Bruno; Rosenberg, Arielle R.; Dokhélar, Marie-Christine

    2002-01-01

    Retrovirus Gag proteins are synthesized on free ribosomes, and are sufficient to govern the assembly and release of virus particles. Like type C retroviruses, human T-cell leukemia virus type 1 (HTLV-1) assembles and buds at the plasma membrane. After immunofluorescence staining, HTLV-1 Gag proteins appear as punctuated intracellular clusters, which suggests that they are associated either with intracellular membranes or with the plasma membrane. However, colocalization experiments using a panel of markers demonstrated that Gag proteins were not associated with the membranes involved in the secretory or endocytosis pathway. Small amounts of Gag proteins were detected at the plasma membrane and colocalized with the envelope glycoproteins. Moreover, Gag proteins were excluded from streptolysin-O permeabilized cells and in this respect behaved like cytoplasmic proteins. This suggests that the trafficking of HTLV-1 Gag proteins through the cytoplasm of the host cell is independent of any cell membrane system. PMID:11752179

  10. Tax unleashed: fulminant Tax-positive Adult T-cell Leukemia/Lymphoma after failed allogeneic stem cell transplantation.

    PubMed

    Ghez, David; Renand, Amédée; Lepelletier, Yves; Sibon, David; Suarez, Felipe; Rubio, Marie-Thérèse; Delarue, Richard; Buzyn, Agnès; Beljord, Kheira; Tanaka, Yuetsu; Varet, Bruno; Hermine, Olivier

    2009-12-01

    The human retrovirus HTLV-1 causes Adult T-cell Leukemia/Lymphoma (ATLL), a malignant lymphoproliferative disease of CD4+ T cells of dismal prognosis, in 3-5% of the 20 million infected individuals (Proietti et al.(1) and Bazarbachi et al.(2)). Infection with HTLV-1 represents a prototypical model of virus-mediated oncogenesis by virtue of the viral transactivator Tax, a potent oncogenic protein that exerts pleiotropic effects through its ability to deregulate the transcription of various cellular genes and signal transduction pathways and inhibit DNA repair enzymes, which are critical for T-cell homeostasis and genetic stability (Matsuoka and Jeang(3)) (et Boxus Retrovirology 2009). However, the oncogenic potential of Tax remains a conundrum. Tax protein expression is undetectable using conventional methods in freshly harvested ATLL cells and in non-malignant infected CD4+ T cells (Furukawa et al.(4)) but is up regulated after only a few hours of culture in vitro (Hanon et al.(5)). These observations strongly suggest that a host-derived mechanism is able to either actively repress the transcription of viral proteins in vivo or refrain the emergence of Tax-expressing cells, which would have a growth advantage. We report herein a unique case of CD4+ T-cell leukemia highly expressing Tax following rejection of an allogenic peripheral blood stem cell graft for an HTLV-1 associated lymphoma. PMID:19836302

  11. HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis Is Not Associated with SNP rs12979860 of the IL-28B Gene.

    PubMed

    Vallinoto, Antonio C R; Santana, Bárbara Brasil; Sá, Keyla S G; Ferreira, Tuane C S; Sousa, Rita Catarina M; Azevedo, Vânia N; Feitosa, Rosimar N M; Machado, Luiz Fernando A; Ishak, Marluísa O G; Ishak, Ricardo

    2015-01-01

    The present study investigated the association between the rs12979860 polymorphism in the IL-28B gene and HTLV-1 infection as well as the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-infected patients (26 HAM/TSP symptomatic and 53 asymptomatic) and 300 seronegative healthy controls were investigated. Plasma levels of the cytokines TNF-α, TNF-β, IL-8, IL-10, IL-6, and IFN-γ from infected patients were measured using an indirect enzyme-linked immunosorbent assay. The HTLV proviral load was measured using a real-time PCR assay, and T-cell subset counts were determined by flow cytometry. Real-time PCR was used to genotype the rs12979860 SNP. The allelic and genotypic distributions displayed no significant differences among the investigated groups. No significant association between the serum cytokine levels and the presence of the rs12979860 SNP in symptomatic and asymptomatic subjects was observed. A positive correlation (p = 0.0015) between TNF-β and IFN-γ was observed in the asymptomatic group, but a positive correlation was only observed (p = 0.0180) between TNF-α and IL-6 in the HAM/TSP group. The proviral load was significantly higher in HAM/TSP patients than in asymptomatic subjects. The present results do not support a previous report indicating an association between the SNP rs12979860 and HAM/TSP outcome. PMID:26609200

  12. HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis Is Not Associated with SNP rs12979860 of the IL-28B Gene

    PubMed Central

    Vallinoto, Antonio C. R.; Santana, Bárbara Brasil; Sá, Keyla S. G.; Ferreira, Tuane C. S.; Sousa, Rita Catarina M.; Azevedo, Vânia N.; Feitosa, Rosimar N. M.; Machado, Luiz Fernando A.; Ishak, Marluísa O. G.; Ishak, Ricardo

    2015-01-01

    The present study investigated the association between the rs12979860 polymorphism in the IL-28B gene and HTLV-1 infection as well as the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-infected patients (26 HAM/TSP symptomatic and 53 asymptomatic) and 300 seronegative healthy controls were investigated. Plasma levels of the cytokines TNF-α, TNF-β, IL-8, IL-10, IL-6, and IFN-γ from infected patients were measured using an indirect enzyme-linked immunosorbent assay. The HTLV proviral load was measured using a real-time PCR assay, and T-cell subset counts were determined by flow cytometry. Real-time PCR was used to genotype the rs12979860 SNP. The allelic and genotypic distributions displayed no significant differences among the investigated groups. No significant association between the serum cytokine levels and the presence of the rs12979860 SNP in symptomatic and asymptomatic subjects was observed. A positive correlation (p = 0.0015) between TNF-β and IFN-γ was observed in the asymptomatic group, but a positive correlation was only observed (p = 0.0180) between TNF-α and IL-6 in the HAM/TSP group. The proviral load was significantly higher in HAM/TSP patients than in asymptomatic subjects. The present results do not support a previous report indicating an association between the SNP rs12979860 and HAM/TSP outcome. PMID:26609200

  13. Mother-to-Child Transmission of Human T-Cell Lymphotropic Viruses-1/2: What We Know, and What Are the Gaps in Understanding and Preventing This Route of Infection

    PubMed Central

    Carneiro-Proietti, A. B. F.; Amaranto-Damasio, M. S.; Leal-Horiguchi, C. F.; Bastos, R. H. C.; Seabra-Freitas, G.; Borowiak, D. R.; Ribeiro, M. A.; Proietti, F. A.; Ferreira, A. S. D.; Martins, M. L.

    2014-01-01

    Although human T-cell lymphotropic viruses (HTLV-1/2) were described over 30 years ago, they are relatively unknown to the public and even to healthcare personnel. Although HTLV-1 is associated with severe illnesses, these occur in only approximately 10% of infected individuals, which may explain the lack of public knowledge about them. However, cohort studies are showing that a myriad of other disease manifestations may trouble infected individuals and cause higher expenditures with healthcare. Testing donated blood for HTLV-1/2 started soon after reliable tests were developed, but unfortunately testing is not available for women during prenatal care. Vertical transmission can occur before or after birth of the child. Before birth, it occurs transplacentally or by transfer of virus during cesarean delivery, but these routes of infection are rare. After childbirth, viral transmission occurs during breastfeeding and increases with longer breastfeeding and high maternal proviral load. Unlike the human immunodeficiency virus types 1 and 2, HTLV is transmitted primarily through breastfeeding and not transplacentally or during delivery. In this study, we review what is currently known about HTLV maternal transmission, its prevention, and the gaps still present in the understanding of this process. PMID:25232474

  14. Impairment of the humoral and CD4(+) T cell responses in HTLV-1-infected individuals immunized with tetanus toxoid.

    PubMed

    Souza, Anselmo; Santos, Silvane; Carvalho, Lucas P; Grassi, Maria Fernanda R; Carvalho, Edgar M

    2016-08-01

    T cells from HTLV-1-infected individuals have a decreased ability to proliferate after stimulation with recall antigens. This abnormality may be due to the production of regulatory cytokine or a dysfunctional antigen presentation. The aims of this study were to evaluate the antibody production and cytokine expression by lymphocytes before and after immunization with tetanus toxoid (TT) and to evaluate the immune response of monocytes after stimulation with TT and frequency of dendritic cells (DC) subsets. HTLV-1 carriers (HC) and uninfected controls (UC) with negative serology for TT were immunized with TT, and the antibody titers were determined by ELISA as well as the cell activation markers expression by monocytes. The frequencies of DC subsets were determined by flow cytometry. Following immunization, the IgG anti-TT titers and the frequency of CD4(+) T cells expressing IFN-γ, TNF-α and IL-10 in response to TT were lower in the HC than in the UC. Additionally, monocytes from HC did not exhibit increased HLA-DR expression after stimulation with TT, and presented low numbers of DC subsets, therefore, it's necessary to perform functional studies with antigen-presenting cells. Collectively, our finding suggests that HC present an impairment of the humoral and CD4(+) T cell immune responses after vaccination. PMID:27282836

  15. Impairment of the humoral and CD4(+) T cell responses in HTLV-1-infected individuals immunized with tetanus toxoid.

    PubMed

    Souza, Anselmo; Santos, Silvane; Carvalho, Lucas P; Grassi, Maria Fernanda R; Carvalho, Edgar M

    2016-08-01

    T cells from HTLV-1-infected individuals have a decreased ability to proliferate after stimulation with recall antigens. This abnormality may be due to the production of regulatory cytokine or a dysfunctional antigen presentation. The aims of this study were to evaluate the antibody production and cytokine expression by lymphocytes before and after immunization with tetanus toxoid (TT) and to evaluate the immune response of monocytes after stimulation with TT and frequency of dendritic cells (DC) subsets. HTLV-1 carriers (HC) and uninfected controls (UC) with negative serology for TT were immunized with TT, and the antibody titers were determined by ELISA as well as the cell activation markers expression by monocytes. The frequencies of DC subsets were determined by flow cytometry. Following immunization, the IgG anti-TT titers and the frequency of CD4(+) T cells expressing IFN-γ, TNF-α and IL-10 in response to TT were lower in the HC than in the UC. Additionally, monocytes from HC did not exhibit increased HLA-DR expression after stimulation with TT, and presented low numbers of DC subsets, therefore, it's necessary to perform functional studies with antigen-presenting cells. Collectively, our finding suggests that HC present an impairment of the humoral and CD4(+) T cell immune responses after vaccination.

  16. Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax.

    PubMed

    Higuchi, Masaya; Takahashi, Masahiko; Tanaka, Yuetsu; Fujii, Masahiro

    2014-12-01

    Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion-induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo.

  17. Circulating anti-Tax cytotoxic T lymphocytes from human T-cell leukemia virus type I-infected people, with and without tropical spastic paraparesis, recognize multiple epitopes simultaneously.

    PubMed Central

    Parker, C E; Nightingale, S; Taylor, G P; Weber, J; Bangham, C R

    1994-01-01

    CD8+ T cells were freshly isolated from a human T-cell leukemia virus type I (HTLV-I)-infected patient with tropical spastic paraparesis. These cells, which were specific for HTLV-I Tax, simultaneously recognized a minimum of five, and possibly as many as seven, distinct peptide epitopes within the protein. A further Tax epitope was recognized after a short period of culture without exogenous peptide stimulation. All but one of these epitopes were clustered in the N-terminal third of Tax, and one of the epitopes was clearly immunodominant on two separate occasions of testing. Recognition of the immunodominant epitope was restricted by human leukocyte antigen (HLA) B15, and recognition of all the others was by HLA A2. Similar patterns of cytotoxic T lymphocyte recognition of the HLA A2-restricted Tax peptides in two healthy HTLV-I-seropositive individuals, each of whom carried the HLA A2 allele, were observed. PMID:7512153

  18. Recombinant human T-cell leukemia virus types 1 and 2 Tax proteins induce high levels of CC-chemokines and downregulate CCR5 in human peripheral blood mononuclear cells.

    PubMed

    Barrios, Christy S; Abuerreish, Muna; Lairmore, Michael D; Castillo, Laura; Giam, Chou-Zen; Beilke, Mark A

    2011-12-01

    Human T-cell leukemia viruses types 1 (HTLV-1) and 2 (HTLV-2) produce key transcriptional regulatory gene products, known as Tax1 and Tax2, respectively. Tax1 and Tax2 transactivate multiple host genes involved in cellular immune responses within the cellular microenvironment, including induction of genes encoding expression of CC-chemokines. It is speculated that HTLV Tax proteins may act as immune modulators. In this study, recombinant Tax1 and Tax2 proteins were tested for their effects on the viability of cultured peripheral blood mononuclear cells (PBMCs), and their ability to induce expression of CC-chemokines and to downregulate the level of CCR5 expression in PBMCs. PBMCs obtained from uninfected donors were cultured in a range of Tax1 and Tax2 concentrations (10-100 pM), and supernatant fluids were harvested at multiple time points for quantitative determinations of MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5. Treatment of PBMCs with Tax1 and Tax2 proteins (100 pM) resulted in a significant increase in viability over a 7-d period compared to controls (p<0.01). Both Tax1 and Tax2 induced high levels of all three CC-chemokines over the dosing range compared to mock-treated controls (p<0.05). The gated population of lymphocytes treated with Tax2, as well as lymphocytes from HTLV-2-infected donors, showed a significantly lower percentage of CCR5-positive cells compared to those of uninfected donors and from mock-treated lymphocytes, respectively (p<0.05). These results suggest that Tax1 and Tax2 could promote innate immunity in the extracellular environment during HTLV-1 and HTLV-2 infections via CC-chemokine ligands and receptors. PMID:22111594

  19. Antibody reactivity to different regions of human T-cell leukemia virus type 1 gp61 in infected people.

    PubMed Central

    Chen, Y M; Lee, T H; Samuel, K P; Okayama, A; Tachibana, N; Miyoshi, I; Papas, T S; Essex, M

    1989-01-01

    The primary protein product of the human T-cell leukemia virus type 1 (HTLV-1) env gene, gp61, is cleaved to produce both the exterior (gp46) and the transmembrane (gp21) portions of the HTLV-1 envelope protein. To compare the reactivity with human antibodies of different regions of this gp61 protein, five plasmids (A, B, B1, C, and D) were constructed to express recombinant proteins (RPs) in Escherichia coli. RP-A, RP-B, RP-B1, and RP-C contain amino acid residues 26 to 165, 166 to 229, 166 to 201, and 229 to 308, respectively, of the exterior envelope protein gp46. Serum samples from HTLV-1-seropositive subjects were assayed for reactivity with these RPs by Western immunoblotting. The percentages of positive reactivity with each of the RPs were as follows: 18.9% (23 of 122) for RP-A, 89.6% (112 of 125) for RP-B, 70.2% (85 of 121) for RP-B1, and 92.9% (117 of 126) for RP-C. These results indicate that the C-terminal half of gp46 (RP-B plus RP-C) can detect 97.6% (123 of 126) of positive samples, while the N-terminal half of gp46 (RP-A) can only detect 18.9% of the HTLV-1-positive sera (P less than 0.005). Furthermore, RP-A, -B, and -C, which together span the entire length of gp46 except the first five amino acids at the N terminus and the last four amino acids at the C- terminus, detected 99.2% (125 of 126) of the HTLV-1-positive subjects. In contrast, RP-D, which contains the HTLV-1 transmembrane envelope protein gp21 minus the first amino acid at the N terminus, had a lower rate of antibody reactivity at 73.7% (84 of 114) (P less than 0.005). The difference in seropositive rates for RP-D between HTLV-1 carriers (55.6%) and adult T-cell leukemia patients (85.5%) is statistically significant (P less than 0.01). This study therefore indicates that the C-terminal half of gp46, especially the amino acid sequence from 200 to 308, contains the most reactive epitopes of the HTLV-1 gp61 envelope glycoprotein. Images PMID:2677406

  20. Prospective study of cytotoxic T lymphocyte responses to influenza and antibodies to human T lymphotropic virus-III in homosexual men. Selective loss of an influenza-specific, human leukocyte antigen-restricted cytotoxic T lymphocyte response in human T lymphotropic virus-III positive individuals with symptoms of acquired immunodeficiency syndrome and in a patient with acquired immunodeficiency syndrome.

    PubMed Central

    Shearer, G M; Salahuddin, S Z; Markham, P D; Joseph, L J; Payne, S M; Kriebel, P; Bernstein, D C; Biddison, W E; Sarngadharan, M G; Gallo, R C

    1985-01-01

    Peripheral blood leukocytes (PBL) from 18 homosexual men who did not have acquired immunodeficiency syndrome (AIDS) and from 9 heterosexual men were repetitively tested for their ability to generate HLA self-restricted cytotoxic T lymphocyte responses to influenza virus (flu-self) over a 2-yr period. The sera of the same donors were tested for antibodies to human T lymphotropic virus-III (HTLV-III). Six of the homosexual and none of the heterosexual donors consistently generated weak cytotoxic T lymphocyte responses to flu-self. Seven of the homosexual and none of the heterosexual donors were seropositive for antibodies to HTLV-III. No obvious correlation was detected between weak flu-self cytotoxic T lymphocyte responses and antibodies to HTLV-III. However, one homosexual donor generated no detectable cytotoxic T lymphocyte activity to flu-self, although he was a strong responder to HLA-alloantigens. This donor had an OKT4:OKT8 ratio of 0.4 and was seropositive for HTLV-III antigens; HTLV-III virus was identified in his PBL; and he developed AIDS during the course of this study. A second donor with lymphadenopathy and who was seropositive for HTLV-III antigens exhibited marginal cytotoxic T lymphocyte activity to flu-self which he subsequently lost. PBL from two patients, one with Kaposi's sarcoma and one with generalized lymphadenopathy, were also tested for cytotoxic T lymphocyte responses to flu-self and to alloantigens. Both donors failed to generate cytotoxic T lymphocyte to flu-self, but generated strong cytotoxic T lymphocyte responses to alloantigens. The selective loss of an HLA-restricted cytotoxic T lymphocyte response without loss of HLA alloantigenic cytotoxic T lymphocyte activity may be an important functional immunologic characteristic in the development of AIDS. PMID:2997287

  1. Median Nerve Somatosensory Evoked Potential in HTLV-I Associated Myelopathy

    PubMed Central

    Boostani, Reza; Poorzahed, Ali; Ahmadi, Zahra; Mellat, Ali

    2016-01-01

    Introduction HTLV-I Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a progressive Myelopathy that mainly involves the corticospinal tract. Despite pronounced involvement of the lower limbs, patients also have abnormalities in their upper limbs. So, we studied somatosensory-evoked potentials (SSEPs) of the median nerve in HAM/TSP patients to determine the extent of the involvement of the pathway of the central nervous system, especially the cervical spinal cord. Methods In this cross sectional study, 48 patients with HAM/TSP who were referred to Qaem Hospital in Mashhad from October 2010 to October 2011 were evaluated for various indices, including SSEPs of the median nerve for N9, N11, N13, and N20 waveforms and also N11–13 and N13–20 Inter Peak Latency (IPL), severity of disease (based on Osama criteria), disease duration (less or more than 2 years), age, and gender. SPSS software was used for data analysis. The t-test was used for quantitative data, and the chi-squared test was used for the qualitative variables. Results Thirty-four patients (70.2%) were females. The mean age was 45.6 ± 14.2 years. About SSEPs indices of the median nerve, N9 and N11 were normal in all patients, but N13 (50%), N20 (16.7%), IPL11–13 (58.3%), and IPL13–20 (22.9%) were abnormal. No significant relationships were found between age, gender, disease duration, and SSEPs indices (p > 0.05), but IPL11–13 and IPL13–20 had significant relationships with disease disability (p = 0.017 and p = 0.01, respectively). Conclusion Despite the lack of obvious complaints of upper limbs, SSEPs indices of the median nerve from the cervical spinal cord to the cortex were abnormal, which indicated extension of the lesion from the thoracic spinal cord up to the cervical spinal cord and thalamocortical pathways. Also, abnormalities in the cervical spinal cord had a direct correlation with the severity of disability in patients with HAM/TSP. PMID:27382445

  2. Serological responses in chimpanzees inoculated with human immunodeficiency virus glycoprotein (gp120) subunit vaccine

    SciTech Connect

    Arthur, L.O.; Pyle, S.W.; Nara, P.L.; Bess, J.W. Jr.; Gonda, M.A.; Kelliher, J.C.; Gilden, R.V.; Robey, W.G.; Bolognesi, D.P.; Gallo, R.C.

    1987-12-01

    The major envelope glycoprotein of a human immunodeficiency virus (HIV) has been purified and was utilized as a prototype vaccine in chimpanzees. The 120,000-dalton glycoprotein (gp120) was purified from membranes of human T-lymphotropic virus (HTLV)-IIIB-infected cells and the final preparation contained low levels to no detectable HTLV-IIIB core antigen (p24) and low levels of endotoxin. Chimpanzees inoculated with gp120 responded by developing antibodies that precipitated radiolabeled gp120 and neutralized in vitro infection of HTLV-IIIB. Antibodies to HTLV-IIIB p24 were not detected in the gp120-immunized chimpanzees. Peripheral blood leukocytes from the vaccinated animals were examined for T4/sup +/ and T8/sup +/ cells, and no decrease in the T4/T8 ratio was found, indicating that immunization with a ligand (gp120) that binds to T4 has not detectable adverse effect on the population of T4/sup +/ cells. The only current animal model that can be reproducibly infected with HIV is the chimpanzee. Immunization of chimpanzees with HIV proteins will provide an experimental system for testing the effectiveness of prototype vaccines for preventing HIV infection in vivo.

  3. Regulation of expression driven by human immunodeficiency virus type 1 and human T-cell leukemia virus type I long terminal repeats in pluripotential human embryonic cells

    SciTech Connect

    Maio, J.; Brown, F.L. )

    1988-04-01

    Human pluripotential embryonic teratocarcinoma cells differentially expressed gene activity controlled by the human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type I (HTLV-I) long terminal repeats (LTRs) when differentiation was induced by the morphogen all-trans retinoic acid. The alterations occurred after commitment and before the appearance of the multiple cell types characteristic of these pluripotential cells. After commitment, gene activity controlled by the HIV-1 LTR markedly increased, whereas that controlled by the HTLV-I LTR decreased. Steady-state mRNA levels and nuclear run-on transcription indicated that the increased HIV-1-directed activity during differentiation occurred posttranscriptionally, whereas the decreased HTLV-I activity was at the transcriptional level. Phorbol esters did not cause commitment but strongly enhanced expression by both viral LTRs at the transcriptional level. Differentiating cells gradually lost the ability to respond to phorbol ester stimulation. Experiments with a deletion mutant of the HIV-1 LTR suggested that this was due to imposition of negative regulation during differentiation that was not reversed by phorbol ester induction. Cycloheximide, with or without phorbol ester, slightly stimulated HIV-1-directed activity at the transcriptional level and massively increased the amounts of steady-state mRNA by posttranscriptional superinduction. It appeared, however, that new nuclear protein synthesis was required for maximal transcriptional stimulation by phorbol esters. Thus, changing cellular regulatory mechanisms influenced human retrovirus expression during human embryonic cell differentiation.

  4. Molecular detection of pre-ATL state among healthy HTLV-1 carriers in an endemic area of Japan.

    PubMed

    Chen, Y X; Ikeda, S; Mori, H; Hata, T; Tsukasaki, K; Momita, S; Yamada, Y; Kamihira, S; Mine, M; Tomonaga, M

    1995-03-16

    Adult T-cell leukemia/lymphoma (ATL) usually develops after age 40 in Japan, suggesting a long latency since HTLV-I is considered to be transmitted mainly from mothers to babies via breast milk. Our previous studies had suggested that HTLV-I carriers who have a monoclonal integration of HTLV-I proviral DNA in the peripheral blood cells, designated pre-ATL, account for about 2% of healthy carriers and are at high risk of developing ATL. Their ages ranged from 32 to 80 (median 57). Nevertheless, many cases of pre-ATL showed a long-lasting carrier state (10-year probability around 90%). In the present investigation we conducted a large-scale molecular detection of monoclonal integration in a population (481 cases) of healthy carriers with ages ranging from 16 to 82 (median 49) for the purpose of clarifying the earliest onset of this pre-ATL state. Southern-blot analysis of DNA extracted from peripheral blood mononuclear cells revealed 6 cases (1.2%) with a monoclonal band. All of these 6 were older than 40; no single positive case was found in 220 carriers under age 40. These results indicate that the molecularly detectable pre-ATL state also develops after a long latency. Thus the pre-ATL state seems to be a subtype of ATL showing an extremely indolent course of disease development, but not merely an early phase of all subtypes of ATL. We propose that, in order to reveal a promoter(s) responsible for the development of ATL from the pre-ATL state, intensive epidemiological investigation of life style, eating habits, occupation and exposure to carcinogens must be conducted on this unique group prone to ATL. It is also important to perform such an epidemiological study on the general population of carriers by paying special attention to the first 3-4 decades of each carrier's life in Japan and by comparing the data with those from carriers in different geographical areas of the world.

  5. Retroviruses and inflammatory myopathies in humans and primates.

    PubMed

    Dalakas, M C

    1993-11-01

    The human immunodeficiency virus (HIV), the human T cell lymphotropic virus (HTLV-1), the human foamy retrovirus and the simian immunodeficiency viruses have been associated with the development of an inflammatory myopathy in humans and primates. The myopathy caused by HIV and HTLV-1 is not due to direct infection of the muscle by these viruses, but rather due to an immunopathologic process triggered by the viruses, mediated by autoaggressive CD8+ cells in the context of MHC-class I antigen expression. This has been based on a series of studies utilizing immunocytochemistry, in situ hybridization, polymerase chain reaction, and co-cultivation of human myotubes with the viruses or with HIV-1 and HTLV-1-infected homologous lymphoid cells. Because the clinical, histological and immunological picture of patients with retroviral-associated inflammatory myopathies is identical to that of patients with retroviral-negative inflammatory myopathy, there is a reasonable possibility that retroviruses may be candidate viruses in triggering inflammatory myopathies. In recent years, the antiretroviral drug AZT (Zidovudine), commonly used for the treatment of AIDS, has been shown to cause a distinct mitochondrial myopathy characterized by depletion of the muscle mitochondrial DNA due to AZT's ability to inhibit the gamma-DNA polymerase of the mitochondrial matrix. Distinction of the AZT-myopathy is clinically important because it responds to discontinuation of AZT and to administration of another antiretroviral agent such as ddI or ddC.

  6. Among all human T-cell leukemia virus type 1 proteins, tax, polymerase, and envelope proteins are predicted as preferential targets for the HLA-A2-restricted cytotoxic T-cell response.

    PubMed Central

    Pique, C; Connan, F; Levilain, J P; Choppin, J; Dokhélar, M C

    1996-01-01

    The human T-cell leukemia virus type 1 (HTLV-1) is a human retrovirus associated with two diseases for which no successful treatment is yet available; the development of a vaccine is therefore an important issue. Since HTLV-1 is a persistent virus, an efficient vaccine will probably require a cytotoxic T-lymphocyte (CTL) response in addition to the production of antibodies. To identify potential CTL epitopes, we have selected, within all of the HTLV-1 proteins, nonapeptides containing anchor residues required for association with HLA-A2 molecules (residues at positions 2 and 9), which is the most frequently occurring A allele in all human populations. A set of 111 peptides was synthetized and tested in vitro in two assembly assays using processing-defective T2 cells. Anchor motifs selected were those containing two major anchor residues (L2/M2/12-V9/L9/I9) (one letter amino-acid code) and those including tolerated anchor residues (V2/A2/T2 and/or A9/M9/T9). The analysis of the binding capacity of the peptides confirms the high efficiency of the L2-V9 anchor motif and shows that a systematic research of potential binding peptides should exclude peptides containing known detrimental residues rather than select only peptides with known favored residues. We show that 39 peptides representative of all the HTLV-1 proteins are able to bind to HLA-A2 molecules. Strong binder peptides which are very likely good CTL epitopes were identified in three HTLV-1 proteins, Tax, envelope, and polymerase. Three of the strong binder peptides correspond to previously described HLA-A2-restricted CTL epitopes in the Tax protein, and two others are localized in a domain of the viral envelope recognized by natural neutralizing antibodies. This latter result has important implications for the development of an anti-HTLV-1 vaccine. PMID:8763995

  7. Human T-Lymphotropic Virus Type 1 and Type 2 Seroprevalence, Incidence, and Residual Transfusion Risk Among Blood Donors in Brazil During 2007–2009

    PubMed Central

    Sabino, Ester C.; Leão, Silvana; Salles, Nanci A.; Loureiro, Paula; Sarr, Moussa; Wright, David; Busch, Michael; Proietti, Fernando A.; Murphy, Edward L.

    2012-01-01

    Abstract Human T-lymphotropic virus type 1/2 (HTLV-1/2) infection is endemic in Brazil but representative donor prevalence and incidence data are lacking. All blood donations (2007–2009) from three blood centers in Brazil were studied. Samples reactive on one HTLV screening test (EIA) were retested with a different EIA; dual EIA reactivity correlated strongly with a confirmatory Western blot. Prevalence, incidence, and residual transfusion risk were calculated. Among 281,760 first-time donors, 363 were positive for HTLV on both EIAs (135 per 105, 95% CI 122–150). Prevalence differed considerably by region, from 83 to 222 per 105. Overall incidence rate was 3.6/105 person-years and residual transfusion risk was 5.0/106 per blood unit transfused. The logistic regression model showed significant associations with: age [adjusted odds ratio (aOR)=5.23 for age 50+ vs. <20], female sex (aOR=1.97), black (aOR=2.70 vs. white), and mixed skin colors (aOR=1.78 vs. white), and inversely with education (aOR=0.49, college vs. less than high school). HTLV testing with a dual-EIA strategy is feasible and can be useful in areas with low resources. Incidence and residual risk of HTLV-1 transmission by transfusion were relatively high and could be reduced by improving donor recruitment and selection in high prevalence areas. Blood center data may contribute to surveillance for HTLV infection. PMID:22324906

  8. High Endemicity of Human T-cell Lymphotropic Virus Type 1 Among Pregnant Women in Peru

    PubMed Central

    Alarcón, Jorge O.; Friedman, Heidi B.; Montano, Silvia M.; Zunt, Joseph R.; Holmes, King K.; Quinnan, Gerald V.

    2009-01-01

    Summary Human T-cell lymphotropic virus type 1(HTLV-1) is associated with adult T-cell leukemia, tropical spastic paraparesis, and other immune-mediated diseases. There are reports of groups with high prevalences of HTLV-1 infection in Peru, but there is limited knowledge of the epidemiology of infection or which routes of infection are most important. We studied 2492 women presenting to a large maternity hospital in Lima for prenatal, delivery, or abortion services. HTLV-1 seropositivity was confirmed in 42 women (1.7%; 95% confidence interval, 1.2–2.2). Seroprevalence increased with age but did not vary by region of birth or recency of migration to Lima. Age greater than 30 years and sexual intercourse before 20 years of age were strongly and independently associated with infection. History of abortion and history of transfusion were of borderline significance. Women whose male partner had a characteristic that might be a marker for risk of sexually transmitted infections were also more likely to be infected. HTLV-1 is common among Peruvians throughout the country and is maintained by a low level of neonatally acquired infection that is amplified by sexual transmission. In addition to screening of the blood supply, instituted in 1997, programs designed to reduce neonatal and sexual transmission should be effective. PMID:16773029

  9. High endemicity of human T-cell lymphotropic virus type 1 among pregnant women in peru.

    PubMed

    Alarcón, Jorge O; Friedman, Heidi B; Montano, Silvia M; Zunt, Joseph R; Holmes, King K; Quinnan, Gerald V

    2006-08-15

    Human T-cell lymphotropic virus type 1(HTLV-1) is associated with adult T-cell leukemia, tropical spastic paraparesis, and other immune-mediated diseases. There are reports of groups with high prevalences of HTLV-1 infection in Peru, but there is limited knowledge of the epidemiology of infection or which routes of infection are most important. We studied 2,492 women presenting to a large maternity hospital in Lima for prenatal, delivery, or abortion services. HTLV-1 seropositivity was confirmed in 42 women (1.7%; 95% confidence interval, 1.2-2.2). Seroprevalence increased with age but did not vary by region of birth or recency of migration to Lima. Age greater than 30 years and sexual intercourse before 20 years of age were strongly and independently associated with infection. History of abortion and history of transfusion were of borderline significance. Women whose male partner had a characteristic that might be a marker for risk of sexually transmitted infections were also more likely to be infected. HTLV-1 is common among Peruvians throughout the country and is maintained by a low level of neonatally acquired infection that is amplified by sexual transmission. In addition to screening of the blood supply, instituted in 1997, programs designed to reduce neonatal and sexual transmission should be effective.

  10. Anti-Human T-lymphotropic virus type-I antibodies in atomic-bomb survivors.

    PubMed

    Matsuo, T; Nakashima, E; Carter, R L; Neriishi, K; Mabuchi, K; Akiyama, M; Shimaoka, K; Kinoshita, K; Tomonaga, M; Ichimaru, M

    1995-03-01

    Adult T-cell leukemia (ATL), induced by human T- lymphotropic virus type-I (HTLV-I), is endemic in Nagasaki, Japan. To investigate the effects of atomic-bomb radiation on development of this specific type of leukemia, 6182 individuals in the Radiation Effects Research Foundation (RERF) Adult Health Study sample in Hiroshima and Nagasaki were examined for positive rate of HTLV-I antibody. Several lymphocyte parameters were also studied for 70 antibody- positive subjects in Nagasaki. The HTLV-I antibody-positive rate was higher in Nagasaki (6.36%) than in Hiroshima (0.79%) and significantly increased with increasing age, but no association was observed with radiation dose. Whether relationship existed between antibody titer levels and radiation dose among antibody-positive subjects was not The frequency of abnormal lymphocytes tended to be higher in antibody-positive subjects than in antibody-negative subjects, and higher in females than in males regardless of radiation dose. The lymphocyte count was lower in antibody-positive subjects than in antibody-negative subjects and lower in female than in male subjects. No evidence was found to suggest that atomic-bomb radiation plays an important role in HTLV-I infection.

  11. Human T-cell leukemia/lymphoma virus type 1 p30, but not p12/p8, counteracts toll-like receptor 3 (TLR3) and TLR4 signaling in human monocytes and dendritic cells.

    PubMed

    Fenizia, Claudio; Fiocchi, Martina; Jones, Kathryn; Parks, Robyn Washington; Ceribelli, Michele; Chevalier, Sebastien A; Edwards, Dustin; Ruscetti, Francis; Pise-Masison, Cynthia A; Franchini, Genoveffa

    2014-01-01

    The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) p30 protein, essential for virus infectivity in vivo, is required for efficient infection of human dendritic cells (DCs) but not B and T cells in vitro. We used a human monocytic cell line, THP-1, and dendritic cells to study the mechanism of p30 and p12/p8 requirements in these cell types. p30 inhibited the expression of interferon (IFN)-responsive genes (ISG) following stimulation by lipopolysaccharide (LPS) of Toll-like receptor 4 (TLR4) and by poly(I·C) of TLR3 but not of TLR7/8 with imiquimod. Results with THP-1 mirrored those for ex vivo human primary monocytes and monocyte-derived dendritic cells (Mo-mDC). The effect of p30 on TLR signaling was also demonstrated by ablating its expression within a molecular clone of HTLV-1. HTLV-1 infection of monocytes inhibited TLR3- and TLR4-induced ISG expression by 50 to 90% depending on the genes, whereas the isogenic clone p30 knockout virus was less effective at inhibiting TLR3 and TRL4 signaling and displayed lower infectivity. Viral expression and inhibition of ISG transcription was, however, rescued by restoration of p30 expression. A chromatin immunoprecipitation assay demonstrated that p30 inhibits initiation and elongation of PU.1-dependent transcription of IFN-α1, IFN-β, and TLR4 genes upon TLR stimulation. In contrast, experiments conducted with p12/p8 did not demonstrate an effect on ISG expression. These results provide a mechanistic explanation of the requirement of p30 for HTLV-1 infectivity in vivo, suggest that dampening interferon responses in monocytes and DCs is specific for p30, and represent an essential early step for permissive HTLV-1 infection and persistence.

  12. T helper cell activation and human retroviral pathogenesis.

    PubMed Central

    Copeland, K F; Heeney, J L

    1996-01-01

    T helper (Th) cells are of central importance in regulating many critical immune effector mechanisms. The profile of cytokines produced by Th cells correlates with the type of effector cells induced during the immune response to foreign antigen. Th1 cells induce the cell-mediated immune response, while Th2 cells drive antibody production. Th cells are the preferential targets of human retroviruses. Infections with human T-cell leukemia virus (HTLV) or human immunodeficiency virus (HIV) result in the expansion of Th cells by the action of HTLV (adult T-cell leukemia) or the progressive loss of T cells by the action of HIV (AIDS). Both retrovirus infections impart a high-level activation state in the host immune cells as well as systemically. However, diverging responses to this activation state have contrasting effects on the Th-cell population. In HIV infection, Th-cell loss has been attributed to several mechanisms, including a selective elimination of cells by apoptosis. The induction of apoptosis in HIV infection is complex, with many different pathways able to induce cell death. In contrast, infection of Th cells with HTLV-1 affords the cell a protective advantage against apoptosis. This advantage may allow the cell to escape immune surveillance, providing the opportunity for the development of Th-cell cancer. In this review, we will discuss the impact of Th-cell activation and general immune activation on human retrovirus expression with a focus upon Th-cell function and the progression to disease. PMID:8987361

  13. HIV-1, HBV, HCV, HTLV, HPV-16/18, and Treponema pallidum Infections in a Sample of Brazilian Men Who Have Sex with Men

    PubMed Central

    Soares, Caroline C.; Georg, Ingebourg; Lampe, Elisabeth; Lewis, Lia; Morgado, Mariza G.; Nicol, Alcina F.; Pinho, Adriana A.; Salles, Regina C. S.; Teixeira, Sylvia L. M.; Vicente, Ana Carolina P.; Viscidi, Raphael P.; Gomes, Selma A.

    2014-01-01

    Background Men who have sex with men (MSM) are more vulnerable to blood-borne infections and/or sexually-transmitted infections (STI). This study was conducted to estimate the prevalences of mono and co-infections of HIV-1 and other blood-borne/STIs in a sample of MSM in Campinas, Brazil. Methods Responding Driven Sampling (RDS) was used for recruitment of MSM. Serum samples collected from 558 MSM were analyzed for the presence of serological markers for HIV-1, HBV, HCV, HTLV, HPV-16/18, and T. pallidum infections. Results The highest prevalences of infection in serum samples were found for HPV-16 and 18 (31.9% and 20.3%, respectively). Approximately 8% of the study population showed infection with HIV-1, and within that group, 27.5% had recently become infected with HIV-1. HBV infection and syphilis were detected in 11.4% and 10% of the study population, respectively, and the rates of HTLV and HCV infection were 1.5% and 1%, respectively. With the exception of HTLV, all other studied infections were usually found as co-infections rather then mono-infections. The rates of co-infection for HCV, HPV-18, and HIV-1 were the highest among the studied infections (100%, 83%, and 85%, respectively). Interestingly, HTLV infection was usually found as a mono-infection in the study group, whereas HCV was found only as a co-infection. Conclusions The present findings highlight the need to educate the MSM population concerning their risk for STIs infections and methods of prevention. Campaigns to encourage vaccination against HBV and HPV could decrease the rates of these infections in MSM. PMID:25083768

  14. Human T cell leukemia virus-I-associated T-suppressor cell inhibition of erythropoiesis in a patient with pure red cell aplasia and chronic T gamma-lymphoproliferative disease.

    PubMed Central

    Levitt, L J; Reyes, G R; Moonka, D K; Bensch, K; Miller, R A; Engleman, E G

    1988-01-01

    Human retroviruses have recently been linked with T cell lymphoproliferative disorders and with the acquired immune deficiency syndrome. We investigated the mechanisms for acquired pure red cell aplasia and cutaneous anergy in a patient with the chronic T gamma-lymphoproliferative disease (T gamma-LPD) syndrome. Patient marrow erythroid progenitors (BFU-E) were 17 +/- 9% of control and were selectively increased to 88-102% of control after marrow T cell depletion. Patient Leu 2+ suppressor T cells spontaneously produced high titers of human gamma-interferon and resulted in a concentration-dependent selective inhibition (74-91%) of BFU-E when co-cultured with autologous or allogeneic marrow. Conditioned media (CM) derived from patient Leu 2+ T cells similarly inhibited growth of autologous or allogeneic marrow BFU-E. The inhibitory factor derived from patient CM was acid-labile (pH 2) and sensitive to trypsin; prior treatment of patient T cells with anti-HLA-DR monoclonal antibody plus complement abrogated the suppressive effect of T cell-derived CM. Patient peripheral blood mononuclear cells (PBMC) were unable to support growth of cultured interleukin 2 (IL 2)-dependent T cells, but responded to exogenous IL 2 in vitro with a 16-21-fold augmentation, relative to control, in mitogen-induced proliferation. Antibodies to HTLV-I core proteins p19 and p24 but not to HTLV-III proteins were detected in patient serum by Western blotting; patient cultured PBMC stained (7-11%) with antibodies to p19 and p24. Patient cultured PBMC demonstrated integrated HTLV-I genomic sequences by the Southern technique and expressed both specific HTLV-I genomic sequences by RNA dot blot plus reverse transcriptase activity. Utilizing a cloned DNA probe for the beta chain of the T cell receptor gene, patient PMBC demonstrated gene rearrangements providing presumptive evidence for clonality. The presence in serum of HTLV-I p19 and p24 antibodies, the expression of p19 and p24 core antigens on

  15. In vivo genomic variability of human T-cell leukemia virus type I depends more upon geography than upon pathologies.

    PubMed Central

    Komurian, F; Pelloquin, F; de Thé, G

    1991-01-01

    To investigate the geography- and disease-associated genomic variation of human T-cell leukemia virus type I (HTLV-I), we studied ex vivo DNA from peripheral blood lymphocytes from nine patients by polymerase chain reaction and direct DNA sequencing. For each viral strain, 1,917 bp was sequenced, including parts of the long terminal repeat, the env gene, and the px II, px III, and px IV coding frames of the px region. The number of genomic variations observed in the U3 region of the long terminal repeat was higher than that seen in the env and px genes. Very few mutations were present in the px II and px III genes. In contrast, the px IV open reading frame exhibited numerous single point mutations. While no specific mutation could be linked to any pathology (adult T-cell leukemia/lymphoma or tropical spastic paraparesis/HTLV-I-associated myelopathy), variations among HTLV-I isolates from different geographic areas (Ivory Coast, Caribbean, and Japan) existed. The Ivory Coast HTLV-I appeared to represent a group by itself. PMID:2041093

  16. Tax Gene Characterization of Human T-Lymphotropic Virus Type 1 Strains from Brazilian HIV-Coinfected Patients

    PubMed Central

    Magri, Mariana Cavalheiro; Brigido, Luis Fernando de Macedo; Rodrigues, Rosangela; Morimoto, Helena Kaminami

    2012-01-01

    Abstract The tax gene of human T-lymphotropic virus type 1 (HTLV-1) diverges among isolates according to geographic regions and has been classified into two genotypes: taxA and taxB. In Brazil, taxA is the most prevalent genotype in symptomatic and asymptomatic carriers. Few studies have been conducted in HIV-infected patients. The present study characterized the tax gene (1059 bp) in 13 Brazilian HIV-1/HTLV-1-coinfected patients from the south and southeast regions. The results confirmed the transcontinental HTLV-1 subgroup A of the Cosmopolitan subtype and showed high nucleotide similarity both among Brazilian sequences and in relation to the ATK prototype (99.5% and 99.2%, respectively). Six nucleotide substitutions were highly conserved among isolates, ranging from 76.9% to 100%: C7401T, T7914C, C7920T, C7982T, G8231A, and A8367C. The presence of the Brazilian molecular signature of genotype taxA was confirmed in all of the isolates, and they clustered into two Latin American clusters, which confirms the double introduction of HTLV-1 in Brazil. PMID:22449200

  17. Tax gene characterization of human T-lymphotropic virus type 1 strains from Brazilian HIV-coinfected patients.

    PubMed

    Magri, Mariana Cavalheiro; Brigido, Luis Fernando de Macedo; Rodrigues, Rosangela; Morimoto, Helena Kaminami; Caterino-de-Araujo, Adele

    2012-12-01

    The tax gene of human T-lymphotropic virus type 1 (HTLV-1) diverges among isolates according to geographic regions and has been classified into two genotypes: taxA and taxB. In Brazil, taxA is the most prevalent genotype in symptomatic and asymptomatic carriers. Few studies have been conducted in HIV-infected patients. The present study characterized the tax gene (1059 bp) in 13 Brazilian HIV-1/HTLV-1-coinfected patients from the south and southeast regions. The results confirmed the transcontinental HTLV-1 subgroup A of the Cosmopolitan subtype and showed high nucleotide similarity both among Brazilian sequences and in relation to the ATK prototype (99.5% and 99.2%, respectively). Six nucleotide substitutions were highly conserved among isolates, ranging from 76.9% to 100%: C7401T, T7914C, C7920T, C7982T, G8231A, and A8367C. The presence of the Brazilian molecular signature of genotype taxA was confirmed in all of the isolates, and they clustered into two Latin American clusters, which confirms the double introduction of HTLV-1 in Brazil.

  18. The risk of human T cell leukemia virus and viral hepatitis infection among US Marines stationed in Okinawa, Japan.

    PubMed

    Brodine, S K; Hyams, K C; Molgaard, C A; Ito, S I; Thomas, R J; Roberts, C R; Golbeck, A L; Oldfield, E C; Blattner, W A

    1995-03-01

    The prevalence and incidence of human T cell leukemia virus type I/II (HTLV-I/II) and hepatitis A, B, and C virus infection were determined among US Marines stationed in Okinawa, Japan. Of 2875 personnel, 2 (0.07%) had antibody to HTLV-I/II. After 1-3 years, no HTLV seroconversions were observed, although 23% reported sexual contact with Okinawans. Of 1010 hepatitis-tested marines, 121 (12%) had antibody to hepatitis A virus (anti-HAV), 26 (2.6%) had antibody to hepatitis B core antigen (anti-HBc), and 2 (0.2%) had antibody to hepatitis C virus (anti-HCV). On follow-up, 1 subject seroconverted to anti-HAV, 8 to anti-HBc, and none to anti-HCV. Most marines with recent hepatitis B infection were young, single, and enlisted and had been on short deployments to other countries in Southeast Asia. Marines stationed in Okinawa are not at high risk for HTLV infection but are at increased risk for hepatitis B infection and should be considered for vaccination. PMID:7876620

  19. Mechanisms of pathogenesis induced by bovine leukemia virus as a model for human T-cell leukemia virus

    PubMed Central

    Aida, Yoko; Murakami, Hironobu; Takahashi, Masahiko; Takeshima, Shin-Nosuke

    2013-01-01

    Bovine leukemia virus (BLV) and human T-cell leukemia virus type 1 (HTLV-1) make up a unique retrovirus family. Both viruses induce chronic lymphoproliferative diseases with BLV affecting the B-cell lineage and HTLV-1 affecting the T-cell lineage. The pathologies of BLV- and HTLV-induced infections are notably similar, with an absence of chronic viraemia and a long latency period. These viruses encode at least two regulatory proteins, namely, Tax and Rex, in the pX region located between the env gene and the 3′ long terminal repeat. The Tax protein is a key contributor to the oncogenic potential of the virus, and is also the key protein involved in viral replication. However, BLV infection is not sufficient for leukemogenesis, and additional events such as gene mutations must take place. In this review, we first summarize the similarities between the two viruses in terms of genomic organization, virology, and pathology. We then describe the current knowledge of the BLV model, which may also be relevant for the understanding of leukemogenesis caused by HTLV-1. In addition, we address our improved understanding of Tax functions through the newly identified BLV Tax mutants, which have a substitution between amino acids 240 and 265. PMID:24265629

  20. Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

    PubMed Central

    Tomita, Mariko; Semenza, Gregg L.; Michiels, Canine; Matsuda, Takehiro; Uchihara, Jun-Nosuke; Okudaira, Taeko; Tanaka, Yuetsu; Taira, Naoya; Ohshiro, Kazuiku; Mori, Naoki

    2007-01-01

    HTLV-1 (human T-cell leukaemia virus type 1) is the causative agent for ATL (adult T-cell leukaemia). HTLV-1 Tax can activate the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway, which is responsible for survival of HTLV-1-infected T-cells. HIFs (hypoxia-inducible factors) are transcriptional regulators that play a central role in the response to hypoxia. Overexpression of HIF-1α in many cancers is associated with a poor response to treatment and increased patient mortality. Our objectives in the present study were to investigate whether HIF-1 was activated in HTLV-1-infected T-cells and to elucidate the molecular mechanisms of HIF-1 activation by focusing on the PI3K/Akt signalling pathway. We detected a potent pathway that activated HIF-1 in the HTLV-1-infected T-cells under a normal oxygen concentration. Enhanced HIF-1α protein expression and HIF-1 DNA-binding activity were exhibited in HTLV-1-infected T-cell lines. Knockdown of HIF-1α by siRNA (small interfering RNA) suppressed the growth and VEGF (vascular endothelial growth factor) expression of the HTLV-1-infected T-cell line. HIF-1 protein accumulation and transcriptional activity were enhanced by Tax, which was inhibited by dominant-negative Akt. Importantly, mutant forms of Tax that are defective in activation of the PI3K/Akt pathway failed to induce HIF-1 transcriptional activity. The PI3K inhibitor LY294002 suppressed HIF-1α protein expression, HIF-1 DNA-binding and HIF-1 transcriptional activity in HTLV-1-infected T-cell lines. In primary ATL cells, HIF-1α protein levels were strongly correlated with levels of phosphorylated Akt. The results of the present study suggest that PI3K/Akt activation induced by Tax leads to activation of HIF-1. As HIF-1 plays a major role in tumour progression, it may represent a molecular target for the development of novel ATL therapeutics. PMID:17576198

  1. A cluster of human T-lymphotropic virus type-I carriers found in the southern district of Tokushima Prefecture.

    PubMed

    Kosaka, M; Iishi, Y; Horiuchi, N; Nakao, K; Okagawa, K; Saito, S; Minami, Y; Katoh, K

    1989-03-01

    Since we had experience of eight patients with adult T-cell leukemia lymphoma from 130 cases of non-Hodgkin's lymphoma between 1978 and 1986, a sero-epidemiological survey of anti human lymphotropic virus type-I (HTLV-I) antibody was performed using a gelatin particle agglutination test, an enzyme-linked immunosorbent assay and an indirect immunofluorescence assay for 2,190 adults (768 men and 1,422 women) aged between 21 and 86 years, in the southern district of Tokushima Prefecture. The inconclusive data obtained using the above mentioned methods have been re-examined by western blotting analysis using enzyme-labelled anti IgM and anti IgG. There was an overall prevalence rate of 6.0% (132/2, 190) but higher rate were found in village C (10.9%) and village D (14.2%). These two villages together with town K (6.1% seropositive) form one community unit with a small population in a mountain area, which could be prone to producing a cluster of HTLV-I carriers. Town G with 8.0% sero-positivity is on the Pacific Ocean coast neighboring one of the endemic areas in the eastern section of Kohchi Prefecture. Interestingly, only IgM antibody was detected in 17 of 137 carriers (13%), all females who had never had a blood transfusion, suggesting them to h ave been in a sort of immunodeficient state, as reported in cases of HTLV-I infection. In 13 of 29 HTLV-I carriers (44.8%) from villages C and D, the viral antigen was detected in 1-9% (0.41 +/- 0.19%) of the peripheral blood mononuclear cells after being cultured with phytohemagglutinin for three days. The data indicate that those carriers had evidently been infected with the HTLV-I virus.

  2. Role of protein kinase A in tax transactivation of the human T-cell leukemia virus type I long terminal repeat.

    PubMed Central

    Kadison, P; Poteat, H T; Klein, K M; Faller, D V

    1990-01-01

    The human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR) is inducible both by the retroviral tax gene product and by cyclic AMP in the murine thymoma S49 cell line. The cis-acting sequences that control transcriptional induction by tax and by cyclic AMP are in close proximity within the HTLV-I promoter. By using a protein kinase A (PKA)-deficient S49 mutant cell line, the response of the viral promoter to cyclic AMP was shown to depend on PKA, whereas the response to tax did not require the activity of this enzyme. Transactivation of the HTLV-I LTR by tax, however, decreased in PKA-deficient and adenylate cyclase-deficient cells. The evidence presented supports largely independent mechanisms of promoter induction by cyclic AMP and tax but also suggests a role for PKA-mediated phosphorylation in the regulation of HTLV-I LTR-driven gene expression by tax. Images PMID:2157876

  3. Sequence-specific interaction of the Ets1 protein with the long terminal repeat of the human T-lymphotropic virus type I.

    PubMed Central

    Gitlin, S D; Bosselut, R; Gégonne, A; Ghysdael, J; Brady, J N

    1991-01-01

    We recently demonstrated that members of the c-ets proto-oncogene family, Ets1 and Ets2, are sequence-specific transcriptional activators of the human T-lymphotropic virus type I (HTLV-I) long terminal repeat (LTR). We now report that the HTLV-I LTR contains two distinct Ets1-responsive regions, ERR-1 and ERR-2. Expression of Ets1 with reporter plasmids containing ERR-1 or ERR-2 upstream of a basal promoter resulted in an increase in transcriptional activity. By gel mobility shift assay, the interaction of Ets1 with the downstream ERR-1-binding region was found to be more stable than its interaction with the upstream ERR-2 region. By DNase I footprint, gel mobility shift, and methylation interference analyses, ERR-1 was found to contain two Ets1 binding sites, ERE-A and ERE-B. A recombinant Ets1 protein was found to bind with higher affinity to ERE-A than to ERE-B. Binding of Ets1 to these sites appears to result in a specific and sequential protection of a 37-nucleotide sequence of the HTLV-I LTR from -154 to -118. In view of the high-level expression of Ets1 in lymphoid cells, the c-ets proto-oncogenes encode transcription factors which could play an important role in both basal and Tax1-mediated HTLV-I transcription. Images PMID:1895400

  4. Transactivation of the proenkephalin gene promoter by the Tax sub 1 protein of human T-cell lymphotropic virus type I

    SciTech Connect

    Joshi, J.B. ); Dave, H.P.G. )

    1992-02-01

    Human T-cell lymphotropic virus type I (HTLV-I), an etiologic agent for adult T-cell leukemia, is strongly associated with certain neurological diseases. The HTLV-I genome encodes a protein, Tax{sub 1}, that transactivates viral gene transcription. CD4-positive T helper lymphocytes express the proenkephalin gene, and enkephalins have been implicated as neuroimmunomodulators. The authors have investigated the effect of Tax{sub 1} on the proenkephalin gene promoter in C6 rat glioma cells and demonstrated its transactivation. Analysis using 5{prime} deletion mutants of the promoter region showed that sequences upstream of base pair - 190 are necessary for maximal transactivation. Forskolin, a cAMP modulator, synergistically increased Tax{sub 1}-mediated transactivation of the proenkephalin promoter. Neither Tax{sub 1} transactivation alone nor Tax{sub 1}/cAMP synergism exclusively involved cAMP-responsive elements. Endogenous proenkephalin gene expression increased in Tax{sub 1}-expressing C6 cells. Since HTLV-I infects lymphocytes, which express proenkephalin mRNA, Tax{sub 1} transregulation of proenkephalin expression may provide bidirectional communication between the nervous and immune systems in HTLV-I-related diseases.

  5. cAMP inducibility of transcriptional repressor ICER in developing and mature human T lymphocytes.

    PubMed

    Bodor, J; Spetz, A L; Strominger, J L; Habener, J F

    1996-04-16

    Stimulation of the cAMP-dependent signaling pathway exerts an inhibitory effect on the proliferation and effector functions of T cells. The ability of T cells to form high intracellular levels of cAMP is acquired during development in the human thymus and is retained by the majority of mature peripheral T lymphocytes. Here we show that elevated cAMP levels in T cells correlate with the expression of the potent transcriptional repressor ICER (inducible cAMP early repressor) previously described in the hypothalamic-pituitary-gonadal axis. Further, in transcriptional assays in vivo, ICER inhibits calcineurin-mediated expression of the interleukin 2 promoter as well as Tax-mediated transactivation of the human T-lymphotropic virus type I (HTLV-I) promoter. Thus, the induction of ICER in T cells may play an important role in the cAMP-induced quiescence and the persistent latency of HTLV-I.

  6. Imbalanced expression of glutamate-glutamine cycle enzymes induced by human T-cell lymphotropic virus type 1 Tax protein in cultivated astrocytes.

    PubMed Central

    Akaoka, H; Hardin-Pouzet, H; Bernard, A; Verrier, B; Belin, M F; Giraudon, P

    1996-01-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent involved in the disease HTLV-1-associated myelopathy, or tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is poorly understood, but it is probable that viral infection has an indirect, deleterious effect on neural function. In this regard, dysfunction in astrocytes may be severely detrimental, as they supply neurons with metabolic precursors, control the extracellular levels of ion and excitatory neurotransmitters, and are electrically coupled with oligodendrocytes. In a model in vitro, we demonstrate that HTLV-1 induces an imbalance in the expression of two astrocyte enzymes, at both the transcriptional and translational levels. In both human astrocyte precursors and rat glial cells, the levels of expression of glutamine synthetase (GS) and glutamate dehydrogenase (GDH) were increased and decreased, respectively, after coculture with HTLV-1 T cells. The enhancement of GS expression may result from the action of the protein Tax, which is demonstrated to transactivate the GS gene promoter, while the decreased expression of GDH seems to reflect some compensatory mechanism in response to GS induction. GS and GDH are involved in the conversion of glutamate into glutamine or alpha-ketoglutarate, which then acts as a precursor for glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurons. Metabolism in astrocytes altered by Tax protein may lead to deleterious effects if it modifies the extracellular levels of glutamine, glutamate, and GABA and thus modulates neuronal excitability and osmotic equilibrium in the central nervous system of HTLV-1-infected patients. PMID:8971000

  7. High-Level Soluble Expression and One-step Purification of HTLV-I P19 Protein in Escherichia coli by Fusion Expression.

    PubMed

    Mosadeghi, Parvin; Zarnagh, Hafez Heydari; Mohammad-Zadeh, Mohammad; Salehi Moghaddam, Masoud

    2015-12-01

    Expression of HTLV-I p19 protein in an Escherichia coli expression system always leads to the formation of inclusion body. Solubilisation and refolding of the inclusion bodies is complex, time consuming and difficult during large-scale preparation. This study aimed to express and purify a soluble form of recombinant HTLV-I p19 protein in an E. coli expression system. The synthetic DNA encoding the p19 was subcloned into a pGS21a vector along with a His-GST solubility/purification tag. The recombinant pGS21a-p19 vector was then transformed into chemically competent E. coli BL21 (DE3) cells, and expression of the recombinant His-GST-p19 protein was induced by IPTG. Expression and distribution of the His-GST-p19 protein in soluble and insoluble fractions were evaluated using SDS-PAGE. Antigenicity of the His-GST-p19 protein was evaluated using ELISA after purifying the protein using Ni-NTA affinity chromatography, then compared to the results of synthetic immunodominant p19 peptide ELISA. The fusion His-GST-p19 protein accounted for 30% of the total cellular proteins. The SDS-PAGE results indicated that approximately 50% of the expressed His-GST-p19 proteins were soluble and accounted for 50% of the total soluble proteins. ELISA showed that the His-GST tag did not impair the antigenicity of the p19 protein and that the fusion protein reacted with HTLV-I antibodies in a concentration-dependent manner. The results of His-GST-p19 ELISA indicated that specificity of p19 reactivity was compatible to the results of p19 peptide ELISA. Combination of key strategies for the soluble expresion of proteins, like fusion with solubility/purification tags, low IPTG concentration and induction at low temperature, provide an efficient and facile platform for producing soluble  HTLV-I p19 protein.

  8. Impact of cellular autophagy on viruses: Insights from hepatitis B virus and human retroviruses

    PubMed Central

    2012-01-01

    Autophagy is a protein degradative process important for normal cellular metabolism. It is apparently used also by cells to eliminate invading pathogens. Interestingly, many pathogens have learned to subvert the cell’s autophagic process. Here, we review the interactions between viruses and cells in regards to cellular autophagy. Using findings from hepatitis B virus and human retroviruses, HIV-1 and HTLV-1, we discuss mechanisms used by viruses to usurp cellular autophagy in ways that benefit viral replication. PMID:23110561

  9. Studies of retroviral infection in humanized mice.

    PubMed

    Marsden, Matthew D; Zack, Jerome A

    2015-05-01

    Many important aspects of human retroviral infections cannot be fully evaluated using only in vitro systems or unmodified animal models. An alternative approach involves the use of humanized mice, which consist of immunodeficient mice that have been transplanted with human cells and/or tissues. Certain humanized mouse models can support robust infection with human retroviruses including different strains of human immunodeficiency virus (HIV) and human T cell leukemia virus (HTLV). These models have provided wide-ranging insights into retroviral biology, including detailed information on primary infection, in vivo replication and pathogenesis, latent/persistent reservoir formation, and novel therapeutic interventions. Here we describe the humanized mouse models that are most commonly utilized to study retroviral infections, and outline some of the important discoveries that these models have produced during several decades of intensive research.

  10. Studies of retroviral infection in humanized mice

    PubMed Central

    Marsden, Matthew D.; Zack, Jerome A.

    2015-01-01

    Many important aspects of human retroviral infections cannot be fully evaluated using only in vitro systems or unmodified animal models. An alternative approach involves the use of humanized mice, which consist of immunodeficient mice that have been transplanted with human cells and/or tissues. Certain humanized mouse models can support robust infection with human retroviruses including different strains of human immunodeficiency virus (HIV) and human T cell leukemia virus (HTLV). These models have provided wide-ranging insights into retroviral biology, including detailed information on primary infection, in vivo replication and pathogenesis, latent/persistent reservoir formation, and novel therapeutic interventions. Here we describe the humanized mouse models that are most commonly utilized to study retroviral infections, and outline some of the important discoveries that these models have produced during several decades of intensive research. PMID:25680625

  11. Application of targeted enrichment to next-generation sequencing of retroviruses integrated into the host human genome

    PubMed Central

    Miyazato, Paola; Katsuya, Hiroo; Fukuda, Asami; Uchiyama, Yoshikazu; Matsuo, Misaki; Tokunaga, Michiyo; Hino, Shinjiro; Nakao, Mitsuyoshi; Satou, Yorifumi

    2016-01-01

    The recent development and advancement of next-generation sequencing (NGS) technologies have enabled the characterization of the human genome at extremely high resolution. In the retrovirology field, NGS technologies have been applied to integration-site analysis and deep sequencing of viral genomes in combination with PCR amplification using virus-specific primers. However, virus-specific primers are not available for some epigenetic analyses, like chromatin immunoprecipitation sequencing (ChIP-seq) assays. Viral sequences are poorly detected without specific PCR amplification because proviral DNA is very scarce compared to human genomic DNA. Here, we have developed and evaluated the use of biotinylated DNA probes for the capture of viral genetic fragments from a library prepared for NGS. Our results demonstrated that viral sequence detection was hundreds or thousands of times more sensitive after enrichment, enabling us to reduce the economic burden that arises when attempting to analyze the epigenetic landscape of proviruses by NGS. In addition, the method is versatile enough to analyze proviruses that have mismatches compared to the DNA probes. Taken together, we propose that this approach is a powerful tool to clarify the mechanisms of transcriptional and epigenetic regulation of retroviral proviruses that have, until now, remained elusive. PMID:27321866

  12. Application of targeted enrichment to next-generation sequencing of retroviruses integrated into the host human genome.

    PubMed

    Miyazato, Paola; Katsuya, Hiroo; Fukuda, Asami; Uchiyama, Yoshikazu; Matsuo, Misaki; Tokunaga, Michiyo; Hino, Shinjiro; Nakao, Mitsuyoshi; Satou, Yorifumi

    2016-01-01

    The recent development and advancement of next-generation sequencing (NGS) technologies have enabled the characterization of the human genome at extremely high resolution. In the retrovirology field, NGS technologies have been applied to integration-site analysis and deep sequencing of viral genomes in combination with PCR amplification using virus-specific primers. However, virus-specific primers are not available for some epigenetic analyses, like chromatin immunoprecipitation sequencing (ChIP-seq) assays. Viral sequences are poorly detected without specific PCR amplification because proviral DNA is very scarce compared to human genomic DNA. Here, we have developed and evaluated the use of biotinylated DNA probes for the capture of viral genetic fragments from a library prepared for NGS. Our results demonstrated that viral sequence detection was hundreds or thousands of times more sensitive after enrichment, enabling us to reduce the economic burden that arises when attempting to analyze the epigenetic landscape of proviruses by NGS. In addition, the method is versatile enough to analyze proviruses that have mismatches compared to the DNA probes. Taken together, we propose that this approach is a powerful tool to clarify the mechanisms of transcriptional and epigenetic regulation of retroviral proviruses that have, until now, remained elusive. PMID:27321866

  13. Dual Simian Foamy Virus/Human Immunodeficiency Virus Type 1 Infections in Persons from Côte d’Ivoire

    PubMed Central

    Switzer, William M.; Tang, Shaohua; Zheng, HaoQiang; Shankar, Anupama; Sprinkle, Patrick S.; Sullivan, Vickie; Granade, Timothy C.; Heneine, Walid

    2016-01-01

    Zoonotic transmission of simian retroviruses in West-Central Africa occurring in primate hunters has resulted in pandemic spread of human immunodeficiency viruses (HIVs) and human T-lymphotropic viruses (HTLVs). While simian foamy virus (SFV) and simian T- lymphotropic virus (STLV)-like infection were reported in healthy persons exposed to nonhuman primates (NHPs) in West-Central Africa, less is known about the distribution of these viruses in Western Africa and in hospitalized populations. We serologically screened for SFV and STLV infection using 1,529 specimens collected between 1985 and 1997 from Côte d’Ivoire patients with high HIV prevalence. PCR amplification and analysis of SFV, STLV, and HIV/SIV sequences from PBMCs was used to investigate possible simian origin of infection. We confirmed SFV antibodies in three persons (0.2%), two of whom were HIV-1-infected. SFV polymerase (pol) and LTR sequences were detected in PBMC DNA available for one HIV-infected person. Phylogenetic comparisons with new SFV sequences from African guenons showed infection likely originated from a Chlorocebus sabaeus monkey endemic to Côte d’Ivoire. 4.6% of persons were HTLV seropositive and PCR testing of PBMCs from 15 HTLV seroreactive persons identified nine with HTLV-1 and one with HTLV-2 LTR sequences. Phylogenetic analysis showed that two persons had STLV-1-like infections, seven were HTLV-1, and one was an HTLV-2 infection. 310/858 (53%), 8/858 (0.93%), and 18/858 (2.1%) were HIV-1, HIV-2, and HIV-positive but undifferentiated by serology, respectively. No SIV sequences were found in persons with HIV-2 antibodies (n = 1) or with undifferentiated HIV results (n = 7). We document SFV, STLV-1-like, and dual SFV/HIV infection in Côte d’Ivoire expanding the geographic range for zoonotic simian retrovirus transmission to West Africa. These findings highlight the need to define the public health consequences of these infections. Studying dual HIV-1/SFV infections in

  14. Dual Simian Foamy Virus/Human Immunodeficiency Virus Type 1 Infections in Persons from Côte d'Ivoire.

    PubMed

    Switzer, William M; Tang, Shaohua; Zheng, HaoQiang; Shankar, Anupama; Sprinkle, Patrick S; Sullivan, Vickie; Granade, Timothy C; Heneine, Walid

    2016-01-01

    Zoonotic transmission of simian retroviruses in West-Central Africa occurring in primate hunters has resulted in pandemic spread of human immunodeficiency viruses (HIVs) and human T-lymphotropic viruses (HTLVs). While simian foamy virus (SFV) and simian T- lymphotropic virus (STLV)-like infection were reported in healthy persons exposed to nonhuman primates (NHPs) in West-Central Africa, less is known about the distribution of these viruses in Western Africa and in hospitalized populations. We serologically screened for SFV and STLV infection using 1,529 specimens collected between 1985 and 1997 from Côte d'Ivoire patients with high HIV prevalence. PCR amplification and analysis of SFV, STLV, and HIV/SIV sequences from PBMCs was used to investigate possible simian origin of infection. We confirmed SFV antibodies in three persons (0.2%), two of whom were HIV-1-infected. SFV polymerase (pol) and LTR sequences were detected in PBMC DNA available for one HIV-infected person. Phylogenetic comparisons with new SFV sequences from African guenons showed infection likely originated from a Chlorocebus sabaeus monkey endemic to Côte d'Ivoire. 4.6% of persons were HTLV seropositive and PCR testing of PBMCs from 15 HTLV seroreactive persons identified nine with HTLV-1 and one with HTLV-2 LTR sequences. Phylogenetic analysis showed that two persons had STLV-1-like infections, seven were HTLV-1, and one was an HTLV-2 infection. 310/858 (53%), 8/858 (0.93%), and 18/858 (2.1%) were HIV-1, HIV-2, and HIV-positive but undifferentiated by serology, respectively. No SIV sequences were found in persons with HIV-2 antibodies (n = 1) or with undifferentiated HIV results (n = 7). We document SFV, STLV-1-like, and dual SFV/HIV infection in Côte d'Ivoire expanding the geographic range for zoonotic simian retrovirus transmission to West Africa. These findings highlight the need to define the public health consequences of these infections. Studying dual HIV-1/SFV infections in

  15. The combination of IκB kinase β inhibitor and everolimus modulates expression of interleukin-10 in human T-cell lymphotropic virus type-1-infected T cells.

    PubMed

    Nishioka, Chie; Ikezoe, Takayuki; Yang, Jing; Udaka, Keiko; Yokoyama, Akihito

    2013-03-01

    Adult T-cell leukaemia-lymphoma (ATLL) is an aggressive malignancy of CD4(+)  CD25(+) T lymphocytes, characterized by a severely compromised immunosystem, in which the human T-cell lymphotropic virus type 1 (HTLV-1) has been recognized as the aetiological agent. This study found that an IκB kinase β (IKKβ) inhibitor Bay11-7082 inactivated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 and transcription factor nuclear factor-κB in HTLV-1-infected T cells; this was significantly enhanced in the presence of the mTOR inhibitor everolimus. In addition, Bay11-7082 decreased production of the immunosuppressive cytokine interleukin-10 (IL-10), which was further down-regulated when Bay11-7082 was combined with evelolimus in HTLV-1-infected T and ATLL cells isolated from patients. Interleukin-10 is known to inhibit maturation and the antigen-presenting function of dendritic cells (DCs). The culture media of HTLV-1-infected MT-1 cells, which contained a large amout of IL-10, hampered tumour necrosis factor-α-induced maturation of DCs isolated from healthy volunteers. Culture supernatant of MT-1 cells treated with a combination of Bay11-7082 and everolimus augmented maturation of DCs in association with a decrease in production of IL-10 and enhanced the allostimulatory function of DCs. Similarly, when DCs isolated from patients with ATLL were treated with the combination of Bay11-7082 and everolimus, they were fully matured and their capability to stimulate proliferation of lymphocytes was augmented. Taken together, the combination of Bay11-7082 and everolimus might exhibit immunostimulatory properties in HTLV-1-infected T and ATLL cells isolated from patients, and this combination may be potentially therapeutic to regain the compromised immunosystem in ATLL patients.

  16. Human T-cell lymphotropic virus type I-associated adult T-cell leukemia-lymphoma: new directions in clinical research.

    PubMed

    Tsukasaki, Kunihiro; Tobinai, Kensei

    2014-10-15

    Adult T-cell leukemia-lymphoma (ATL) is a distinct malignancy of regulatory T cell (Treg)/TH2 cells caused by human T-cell lymphotropic virus type I (HTLV-1), with a high frequency of expression of CD3/CD4/CD25/CCR4 and FoxP3 in about half of the cells. However, in primary ATL cells, although expression of the virus, including the Tax oncoprotein, appears just after an in vitro culture, integration sites of the provirus into the host genome are random, and chromosomal/genetic abnormalities are complex. ATL is thus a single disease entity that is caused by HTLV-1 and possesses diverse molecular features. The clinical features and prognosis of ATL vary, and this has led to subtypes classified into four categories: acute, lymphomatous, chronic, and smoldering types, based on lactate dehydrogenase and calcium values and organ involvement. Approximately 15 to 20 million individuals are infected with HTLV-1 worldwide, 1.1 million of whom reside in Japan, and the annual incidence of ATL has been estimated to be approximately 1,000. HTLV-1 infection early in life, mainly from breast feeding, is crucial for the development of ATL. The age-specific occurrence of ATL and complex genome abnormalities that accumulate with disease progression suggest a multistep carcinogenesis model following HTLV-1 infection. Various treatment options are available for ATL and consist of watchful waiting for indolent ATL, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation for aggressive ATL, and a combination of IFNα and zidovudine for ATL with leukemic manifestation. Several promising new agents, including an anti-CCR4 antibody, are currently undergoing clinical trials associated with translational research. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." PMID:25320371

  17. Temporal lesions and widespread involvement of white matter associated with multi-organ inflammatory disease in human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

    PubMed

    Mendes, Gustavo B; Kalil, Rosangela S; Rosadas, Carolina; de Freitas, Marcos R G; Puccioni-Sohler, Marzia

    2014-08-01

    Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the spinal cord, characterized by spastic paraparesis, back pain, and sphincter disorders. Involvement of multiple organs and encephalopathy are uncommon in HAM/TSP. Nonspecific small white matter lesions of unknown etiology, mainly in the periventricular and subcortical regions, have been found on brain magnetic resonance imaging of HAM/TSP patients. Bitemporal lesions have rarely been described. We report the case of a 54-year-old woman diagnosed with HAM/TSP who presented subclinical cognitive deficits associated with bitemporal and widespread white matter lesions. The cerebrospinal fluid (CSF) was inflammatory (blood-CSF barrier dysfunction, intrathecal synthesis of total and HTLV-1 IgG). The proviral load was higher in cerebrospinal fluid than in peripheral blood mononuclear cells. The neurological picture was complicated by multi-organ inflammatory disease (Hashimoto's thyroiditis, uveitis, anemia, and chronic renal failure). This case highlights the potential multisystem inflammatory nature of HTLV-1 infection, with a wide spectrum of manifestations. In cases of HAM/TSP with multi-organ inflammatory disease, encephalic involvement should be investigated, even in the absence of clinical manifestations. Also bitemporal lesions can be the consequence of intense and diffuse inflammation associated with HTLV-1 infection.

  18. Surveys of HIV-1, HTLV-I, and other sexually transmitted diseases in female sex workers in Taipei City, Taiwan, from 1993 to 1996.

    PubMed

    Chen, Y M; Yu, P S; Lin, C C; Jen, I

    1998-07-01

    Between 1993 and 1996 in Taipei, Taiwan, we studied the prevalences of HIV-1, HTLV-I, HSV-2, Chlamydia trachomatis, and syphilis infection in female commercial sex workers (CSW) and the pathogens' associated risk factors. Female CSW from nine massage parlors, two karaoke bars (KB), and 22 brothels in Taipei city participated in this study. Two of 557 (0.4%) KB CSWs from those who participated during the period from 1993 to 1994 had HIV-1 infection, whereas no KB CSWs in the periods 1994 to 1995 or 1995 to 1996 had HIV-1 infection. None of the 725 MP CSWs or 291 brothel CSWs who participated in the study between 1993 and 1996 had HIV-1 infection. In contrast, CSWs from brothels had elevated rates of both HTLV-I and active chlamydia infections compared with KB and MP CSWs (p < .05 and p < .005, respectively). KB CSWs showed an elevated rate of HSV-2 infection in the years 1993 and 1994 when compared with CSWs employed by brothels and MPs (p < .005). The prevalence rates of syphilis for CSWs from brothels dropped from 42.8% in the year 1993 to 1994 to 26.3% in the 1995 to 1996 period, whereas for KB and MP CSWs, the rates were < 6% in each of year studied.

  19. HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains.

    PubMed

    Wang, Chong; Long, Wenying; Peng, Chao; Hu, Lin; Zhang, Qiong; Wu, Ailing; Zhang, Xiaoqing; Duan, Xiaotao; Wong, Catherine C L; Tanaka, Yuetsu; Xia, Zongping

    2016-04-01

    The HTLV-1 oncoprotein Tax plays a key role in CD4+ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation.

  20. [Epidemiologic study of anti-HTLV-I/II antibodies in blood donors in metropolitan France. The Retrovirus Working Group of the National Blood Transfusion Society].

    PubMed

    Lemaire, J M; Coste, J; Barin, F; Couroucé, A M

    1991-01-01

    Between march and april 1989, the prevalence of HTLV-I/II antibodies was studied in a non selected population of 45,033 blood donors of Continental France. Serum samples were collected and screened by 12 Blood Banks located in different parts of the country. Screening was performed by 4 ELISAs (Abbott-Du Pont de Nemours-Organon-Pharmacia) and by gelatin particle agglutination (Fujirebio); the sensitivity of these tests was previously evaluated with an HTLV-I/II panel of the French National Society of Transfusion. The reproducibly reactive sera were confirmed by Western-Blot (Du Pont) and radioimmunoprecipitation assay. Five donors were confirmed positive: the global prevalence is 0.011%. This prevalence is one of the highest in Europe. Three of the five positive donors (0.007%) are white subjects. The other two are natives from the French West Indies (0.81%). Since may 1989 the Ministry of Health recommends for Continental France to test donors originating from endemic zones or to use their plasma for fractionation. The results obtained in this study show that the efficacy of these measures are incomplete since 0.007% donors (1 out of 15,000 blood donations) are not tracked down.

  1. HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains

    PubMed Central

    Wang, Chong; Long, Wenying; Peng, Chao; Hu, Lin; Zhang, Qiong; Wu, Ailing; Zhang, Xiaoqing; Duan, Xiaotao; Wong, Catherine C. L.; Tanaka, Yuetsu; Xia, Zongping

    2016-01-01

    The HTLV-1 oncoprotein Tax plays a key role in CD4+ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation. PMID:27082114

  2. Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program.

    PubMed

    Boxus, Mathieu; Twizere, Jean-Claude; Legros, Sébastien; Kettmann, Richard; Willems, Luc

    2012-01-01

    The Tax oncoprotein encoded by the human T-cell leukemia virus type 1 plays a pivotal role in viral persistence and pathogenesis. Human T-cell leukemia virus type 1-infected cells proliferate faster than normal lymphocytes, expand through mitotic division, and accumulate genomic lesions. Here, we show that Tax associates with the minichromosome maintenance MCM2-7 helicase complex and localizes to origins of replication. Tax modulates the spatiotemporal program of origin activation and fires supplementary origins at the onset of S phase. Thereby, Tax increases the DNA replication rate, accelerates S phase progression, but also generates a replicative stress characterized by the presence of genomic lesions. Mechanistically, Tax favors p300 recruitment and histone hyperacetylation at late replication domains, advancing their replication timing in early S phase. PMID:22058115

  3. Sexually Transmitted Diseases: from HPV to HTLV - clinical profile and associated factors*

    PubMed Central

    da Silveira, Fabíola Suris; Bonamigo, Renan Rangel

    2015-01-01

    The Brazilian Ministry of Health recommends the performance of serological tests in patients with clinical signs of Sexually Transmitted Diseases. However, data are lacking to affirm the necessity of testing these patients for human T-lymphotropic virus type 1 or type 2. This is a cross-sectional study with 120 patients seen at the Sexually Transmitted Diseases unit of the Sanitary Dermatology Outpatient Clinic of Rio Grande do Sul. The serum from none of the patients was positive for human T-lymphotropic virus type 1 or type 2. Viral warts were the most frequent diagnosis. Drug use was confirmed as a risk factor and high educational levels were found to be a protective factor against Sexually Transmitted Diseases. PMID:26734881

  4. Sexually Transmitted Diseases: from HPV to HTLV--clinical profile and associated factors.

    PubMed

    Silveira, Fabíola Suris da; Bonamigo, Renan Rangel

    2015-01-01

    The Brazilian Ministry of Health recommends the performance of serological tests in patients with clinical signs of Sexually Transmitted Diseases. However, data are lacking to affirm the necessity of testing these patients for human T-lymphotropic virus type 1 or type 2. This is a cross-sectional study with 120 patients seen at the Sexually Transmitted Diseases unit of the Sanitary Dermatology Outpatient Clinic of Rio Grande do Sul. The serum from none of the patients was positive for human T-lymphotropic virus type 1 or type 2. Viral warts were the most frequent diagnosis. Drug use was confirmed as a risk factor and high educational levels were found to be a protective factor against Sexually Transmitted Diseases. PMID:26734881

  5. Sexually Transmitted Diseases: from HPV to HTLV--clinical profile and associated factors.

    PubMed

    Silveira, Fabíola Suris da; Bonamigo, Renan Rangel

    2015-01-01

    The Brazilian Ministry of Health recommends the performance of serological tests in patients with clinical signs of Sexually Transmitted Diseases. However, data are lacking to affirm the necessity of testing these patients for human T-lymphotropic virus type 1 or type 2. This is a cross-sectional study with 120 patients seen at the Sexually Transmitted Diseases unit of the Sanitary Dermatology Outpatient Clinic of Rio Grande do Sul. The serum from none of the patients was positive for human T-lymphotropic virus type 1 or type 2. Viral warts were the most frequent diagnosis. Drug use was confirmed as a risk factor and high educational levels were found to be a protective factor against Sexually Transmitted Diseases.

  6. Induction of Adult T-Cell Leukemia-Like Lymphoproliferative Disease and Its Inhibition by Adoptive Immunotherapy in T-Cell-Deficient Nude Rats Inoculated with Syngeneic Human T-Cell Leukemia Virus Type 1-Immortalized Cells

    PubMed Central

    Ohashi, Takashi; Hanabuchi, Shino; Kato, Hirotomo; Koya, Yoshihiro; Takemura, Fumiyo; Hirokawa, Katsuiku; Yoshiki, Takashi; Tanaka, Yuetsu; Fujii, Masahiro; Kannagi, Mari

    1999-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) has been shown to be the etiologic agent of adult T-cell leukemia (ATL), but the in vivo mechanism by which the virus causes the malignant transformation is largely unknown. In order to investigate the mechanisms of HTLV-1 leukemogenesis, we developed a rat model system in which ATL-like disease was reproducibly observed, following inoculation of various rat HTLV-1-immortalized cell lines. When previously established cell lines, F344-S1 and TARS-1, but not TART-1 or W7TM-1, were inoculated, systemic multiple tumor development was observed in adult nude (nu/nu) rats. FPM1 cells, newly established from a heterozygous (nu/+) rat syngeneic to nu/nu rats, caused transient tumors only at the injection site in adult nu/nu rats, but could progressively grow in newborn nu/nu rats and metastasize in lymph nodes. The derivative cell line (FPM1-V1AX) serially passed through newborn nu/nu rats acquired the potency to grow in adult nu/nu rats. These results indicated that only some with additional changes but not all of the in vitro HTLV-1-immortalized cell lines possessed in vivo tumorigenicity. Using the syngeneic system, we further showed the inhibition of tumor development by transferring splenic T cells from immunized rats, suggesting the involvement of T cells in the regression of tumors. This novel and reproducible nude rat model of human ATL would be useful for investigation of leukemogenesis and antitumor immune responses in HTLV-1 infection. PMID:10364355

  7. GLUT-1-independent infection of the glioblastoma/astroglioma U87 cells by the human T cell leukemia virus type 1

    SciTech Connect

    Jin Qingwen; Agrawal, Lokesh; VanHorn-Ali, Zainab; Alkhatib, Ghalib . E-mail: galkhati@iupui.edu

    2006-09-15

    The human glucose transporter protein 1 (GLUT-1) functions as a receptor for human T cell leukemia virus (HTLV). GLUT-1 is a twelve-transmembrane cell surface receptor with six extracellular (ECL) and seven intracellular domains. To analyze HTLV-1 cytotropism, we utilized polyclonal antibodies to a synthetic peptide corresponding to the large extracellular domain of GLUT-1. The antibodies caused significant blocking of envelope (Env)-mediated fusion and pseudotyped virus infection of HeLa cells but had no significant effect on infection of U87 cells. This differential effect correlated with the detection of high-level surface expression of GLUT-1 on HeLa cells and very weak staining of U87 cells. To investigate this in terms of viral cytotropism, we cloned GLUT-1 cDNA from U87 cells and isolated two different versions of cDNA clones: the wild-type sequence (encoding 492 residues) and a mutant cDNA with a 5-base pair deletion (GLUT-1{delta}5) between nucleotides 1329 and 1333. The deletion, also detected in genomic DNA, resulted in a frame-shift and premature termination producing a truncated protein of 463 residues. Transfection of the wild-type GLUT-1 but not GLUT-1{delta}5 cDNA into CHO cells resulted in efficient surface expression of the human GLUT-1. Co-expression of GLUT-1 with GLUT-1{delta}5 produces a trans-inhibition by GLUT-1{delta}5 of GLUT-1-mediated HTLV-1 envelope (Env)-mediated fusion. Co-immunoprecipitation experiments demonstrated physical interaction of the wild-type and mutant proteins. Northern blot and RT-PCR analyses demonstrated lower GLUT-1 RNA expression in U87 cells. We propose two mechanisms to account for the impaired cell surface expression of GLUT-1 on U87 cells: low GLUT-1 RNA expression and the formation of GLUT-1/GLUT-1{delta}5 heterodimers that are retained intracellularly. Significant RNAi-mediated reduction of endogenous GLUT-1 expression impaired HTLV-1 Env-mediated fusion with HeLa cells but not with U87 cells. We propose a

  8. Infection of CD4{sup +} T lymphocytes by the human T cell leukemia virus type 1 is mediated by the glucose transporter GLUT-1: Evidence using antibodies specific to the receptor's large extracellular domain

    SciTech Connect

    Jin, Qingwen; Agrawal, Lokesh; VanHorn-Ali, Zainab; Alkhatib, Ghalib . E-mail: galkhati@iupui.edu

    2006-05-25

    To analyze HTLV-1 cytotropism, we developed a highly sensitive vaccinia virus-based assay measuring activation of a reporter gene upon fusion of two distinct cell populations. We used this system in a functional cDNA screening to isolate and confirm that the glucose transporter protein 1 (GLUT-1) is a receptor for HTLV-1. GLUT-1 is a ubiquitously expressed plasma membrane glycoprotein with 12 transmembrane domains and 6 extracellular loops (ECL). We demonstrate for the first time that peptide antibodies (GLUT-IgY) raised in chicken to the large extracellular loop (ECL1) detect GLUT-1 at the cell surface and inhibit envelope (Env)-mediated fusion and infection. Efficient GLUT-IgY staining was detected with peripheral blood CD4{sup +} lymphocytes purified by positive selection. Further, GLUT-IgY caused efficient inhibition of Env-mediated fusion and infection of CD4{sup +} T and significantly lower inhibition of CD8{sup +} T lymphocytes. The specificity of GLUT-IgY antibodies to GLUT-1 was demonstrated by ECL1 peptide competition studies. Grafting ECL1 of GLUT-1 onto the receptor-negative GLUT-3 conferred significant receptor activity. In contrast, grafting ECL1 of GLUT-3 onto GLUT-1 resulted in a significant loss of the receptor activity. The ECL1-mediated receptor activity was efficiently blocked with four different human monoclonal antibody (HMab) to HTLV-1 Env. The ECL1-derived peptide blocked HTLV-1 Env-mediated fusion with several nonhuman mammalian cell lines. The results demonstrate the utilization of cell surface GLUT-1 in HTLV-1 infection of CD4{sup +} T lymphocytes and implicate a critical role for the ECL1 region in viral tropism.

  9. Hypometabolism of watershed areas of the brain in HTLV-1-associated myelopathy/tropical spastic paraparesis.

    PubMed

    Taniguchi, Akitoshi; Mochizuki, Hitoshi; Nagamachi, Shigeki; Ebihara, Yuka; Ishii, Nobuyuki; Shiomi, Kazutaka; Nakazato, Masamitsu

    2015-11-01

    In previous studies of human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), areas of slow blood flow in the spinal cord were related to pathological changes. While the pathological changes in the brain are milder than those in the spinal cord, they are also more significant in sites with slow blood flow. In this study, we investigated brain glucose metabolism in slow blood flow areas using fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET). Clinical features and brain (18)F-FDG-PET parameters were analyzed in six patients with HAM/TSP. For comparison of PET data, eight healthy volunteers were enrolled as normal controls (NLs). Glucose metabolism in the watershed areas of the middle and posterior cerebral arteries, as compared with that in the occipital lobes as a control, was significantly lower in HAM/TSP patients than in NLs. This result confirmed the relationship between slow blood flow areas and hypometabolism in HAM/TSP, and is consistent with previous findings that pathological changes are accentuated in sites with slow blood flow.

  10. Clinical symptoms and the odds of human T-cell lymphotropic virus type 1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) in healthy virus carriers: application of best-fit logistic regression equation based on host genotype, age, and provirus load.

    PubMed

    Nose, Hirohisa; Saito, Mineki; Usuku, Koichiro; Sabouri, Amir H; Matsuzaki, Toshio; Kubota, Ryuji; Eiraku, Nobutaka; Furukawa, Yoshitaka; Izumo, Shuji; Arimura, Kimiyoshi; Osame, Mitsuhiro

    2006-06-01

    The authors have previously developed a logistic regression equation to predict the odds that a human T-cell lymphotropic virus type 1 (HTLV-1)-infected individual of specified genotype, age, and provirus load has HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in southern Japan. This study evaluated whether this equation is useful predictor for monitoring asymptomatic HTLV-1-seropositive carriers (HCs) in the same population. The authors genotyped 181 HCs for each HAM/TSP-associated gene (tumor necrosis factor [TNF]-alpha-863A/C, stromal cell-derived factor 1 (SDF-1) +801G/A, human leukocyte antigen [HLA]-A*02, HLA-Cw*08, HTLV-1 tax subgroup) and measured HTLV-1 provirus load in peripheral blood mononuclear cells using real-time polymerase chain reaction (PCR). Finally, the odds of HAM/TSP for each subject were calculated by using the equation and compared the results with clinical symptoms and laboratory findings. Although no clear difference was seen between the odds of HAM/TSP and either sex, family history of HAM/TSP or adult T-cell lenkemia (ATL), history of blood transfusion, it was found that brisk patellar deep tendon reflexes, which suggest latent central nervous system compromise, and flower cell-like abnormal lymphocytes, which is the morphological characteristic of ATL cells, were associated with a higher odds of HAM/TSP. The best-fit logistic regression equation may be useful for detecting subclinical abnormalities in HCs in southern Japan.

  11. Characterization of a novel baboon virus closely resembling human T-cell leukemia virus.

    PubMed

    Vincent, M J; Novembre, F J; Yamshchikov, V F; McClure, H M; Compans, R W

    1996-12-01

    We report the isolation of a virus from a baboon imported from Kenya and the analysis of the nucleotide sequence of the env gene. Comparison of the complete nucleotide sequence of the env gene of different HTLV-1 strains and the baboon T-cell leukemia virus (designated BTLV) indicated similarities ranging from 92.5 to 97.4%. In contrast, only 89.1% similarity was observed between the BTLV env sequence and that of simian T-cell leukemia virus (PtM3). The sequences corresponding to the glycosylation sites, endoproteolytic processing site, and major immunological determinants were strictly conserved between BTLV and HTLV-1. To characterize the expressed protein we used a vaccinia expression system, which indicated that a protein of 62 kDa is encoded by the envelope gene. The protein acquired mostly high mannose modifications and was localized predominantly in the endoplasmic reticulum. A fraction of the protein was expressed at the cell surface, where it could induce membrane fusion of target cells. The existence of HTLV-1-like viruses in baboons indicates the potential risk of transmission of such virus from these nonhuman primates to humans, thus highlighting the need for specific screening for such viruses during xenotransplantation.

  12. In vitro activation of transcription by the human T-cell leukemia virus type I Tax protein.

    PubMed Central

    Matthews, M A; Markowitz, R B; Dynan, W S

    1992-01-01

    The human T-cell leukemia virus type I (HTLV-I) regulatory protein Tax activates transcription of the proviral long terminal repeats and a number of cellular promoters. We have developed an in vitro system to characterize the mechanism by which Tax interacts with the host cell transcription machinery. Tax was purified from cells infected with a baculovirus expression vector. Addition of these Tax preparations to nuclear extracts from uninfected human T lymphocytes activated transcription of the HTLV-I long terminal repeat approximately 10-fold. Transcription-stimulatory activity copurified with the immunoreactive 40-kDa Tax polypeptide on gel filtration chromatography, and, as expected, the effect of recombinant Tax was diminished in HTLV-I-infected T-lymphocyte extracts containing endogenous Tax. Tax-mediated transactivation in vivo has been previously shown to require 21-bp-repeat Tax-responsive elements (TxREs) in the promoter DNA. Stimulation of transcription in vitro was also strongly dependent on these sequences. To investigate the mechanism of Tax transactivation, cellular proteins that bind the 21-bp-repeat TxREs were prepared by DNA affinity chromatography. Recombinant Tax markedly increased the formation of a specific host protein-DNA complex detected in an electrophoretic mobility shift assay. These data suggest that Tax activates transcription through a direct interaction with cellular proteins that bind to the 21-bp-repeat TxREs. Images PMID:1569936

  13. Alterations in T Cell Subsets in Human Immunodeficiency Virus–Infected Adults with Co-infections in Southern Mozambique

    PubMed Central

    Naniche, Denise; Letang, Emilio; Nhampossa, Tacilta; David, Catarina; Menendez, Clara; Alonso, Pedro

    2011-01-01

    T cell activation and depletion of naive T cells are hallmarks of human immunodeficiency virus (HIV) pathogenesis. This study explored the relationships between certain co-infections (including syphilis, hepatitis B and C, human T cell lymphotrophic viruses I and II [HTLV-I/II], Kaposi sarcoma–associated herpesvirus [KSHV], Plasmodium falciparum malaria, and tuberculosis), and levels of activated CD8 and CD4 T cell subsets as well as naive and memory CD4 T cells in HIV-infected adults in a rural area of southern Mozambique. We found that syphilis infection and to a lesser extent HTLV-I/II seropositivity were independently associated with higher CD8 T cell activation (CD8+ CD38+ HLA-DR+) whereas only syphilis was associated with higher CD4 T cell activation. Furthermore, KSHV and HTLV-I/II seropositivities were independently associated with a lower percentage of naive CD4 T cells (CD4+ CD45RA+ CD62L+). These results highlight the importance of screening and prompt treatment of syphilis, and raise questions as to whether HIV-positive persons with certain chronic viral co-infections should initiate combined antiretroviral therapy at higher CD4 cell counts. PMID:21976586

  14. Tax posttranslational modifications and interaction with calreticulin in MT-2 cells and human peripheral blood mononuclear cells of human T cell lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis patients.

    PubMed

    Medina, Fernando; Quintremil, Sebastian; Alberti, Carolina; Barriga, Andres; Cartier, Luis; Puente, Javier; Ramírez, Eugenio; Ferreira, Arturo; Tanaka, Yuetsu; Valenzuela, Maria Antonieta

    2014-04-01

    The human retrovirus human T cell lymphotropic virus type-I (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Axonal degeneration in HAM/TSP patients occurs without neuron infection, with the secreted viral Tax protein proposed to be involved. We previously found that Tax secreted into the culture medium of MT-2 cells (HTLV-1-infected cell line) produced neurite retraction in neuroblastoma cells differentiated to neuronal type. To assess the relevance of Tax posttranslational modifications on this effect, we addressed the question of whether Tax secreted by MT-2 cells and peripheral blood mononuclear cells (PBMCs) of HTLV-1-infected subjects is modified. The interaction of Tax with calreticulin (CRT) that modulates intracellular Tax localization and secretion has been described. We studied Tax localization and modifications in MT-2 cells and its interaction with CRT. Intracellular Tax in MT-2 cells was assessed by flow cytometry, corresponding mainly to a 71-kDa protein followed by western blot. This protein reported as a chimera with gp21 viral protein-confirmed by mass spectrometry-showed no ubiquitination or SUMOylation. The Tax-CRT interaction was determined by confocal microscopy and coimmunoprecipitation. Extracellular Tax from HAM/TSP PBMCs is ubiquitinated according to western blot, and its interaction with CRT was shown by coimmunoprecipitation. A positive correlation between Tax and CRT secretion was observed in HAM/TSP PBMCs and asymptomatic carriers. For both proteins inhibitors and activators of secretion showed secretion through the endoplasmic reticulum-Golgi complex. Tax, present in PBMC culture medium, produced neurite retraction in differentiated neuroblastoma cells. These results suggest that Tax, whether ubiquitinated or not, is active for neurite retraction. PMID:24321043

  15. Tax posttranslational modifications and interaction with calreticulin in MT-2 cells and human peripheral blood mononuclear cells of human T cell lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis patients.

    PubMed

    Medina, Fernando; Quintremil, Sebastian; Alberti, Carolina; Barriga, Andres; Cartier, Luis; Puente, Javier; Ramírez, Eugenio; Ferreira, Arturo; Tanaka, Yuetsu; Valenzuela, Maria Antonieta

    2014-04-01

    The human retrovirus human T cell lymphotropic virus type-I (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Axonal degeneration in HAM/TSP patients occurs without neuron infection, with the secreted viral Tax protein proposed to be involved. We previously found that Tax secreted into the culture medium of MT-2 cells (HTLV-1-infected cell line) produced neurite retraction in neuroblastoma cells differentiated to neuronal type. To assess the relevance of Tax posttranslational modifications on this effect, we addressed the question of whether Tax secreted by MT-2 cells and peripheral blood mononuclear cells (PBMCs) of HTLV-1-infected subjects is modified. The interaction of Tax with calreticulin (CRT) that modulates intracellular Tax localization and secretion has been described. We studied Tax localization and modifications in MT-2 cells and its interaction with CRT. Intracellular Tax in MT-2 cells was assessed by flow cytometry, corresponding mainly to a 71-kDa protein followed by western blot. This protein reported as a chimera with gp21 viral protein-confirmed by mass spectrometry-showed no ubiquitination or SUMOylation. The Tax-CRT interaction was determined by confocal microscopy and coimmunoprecipitation. Extracellular Tax from HAM/TSP PBMCs is ubiquitinated according to western blot, and its interaction with CRT was shown by coimmunoprecipitation. A positive correlation between Tax and CRT secretion was observed in HAM/TSP PBMCs and asymptomatic carriers. For both proteins inhibitors and activators of secretion showed secretion through the endoplasmic reticulum-Golgi complex. Tax, present in PBMC culture medium, produced neurite retraction in differentiated neuroblastoma cells. These results suggest that Tax, whether ubiquitinated or not, is active for neurite retraction.

  16. Meningitis associated with strongyloidiasis in an area endemic for strongyloidiasis and human T-lymphotropic virus-1: a single-center experience in Japan between 1990 and 2010.

    PubMed

    Sasaki, Y; Taniguchi, T; Kinjo, M; McGill, R L; McGill, A T; Tsuha, S; Shiiki, S

    2013-12-01

    Meningitis caused by enteric flora is a known complication of strongyloidiasis, and human T-lymphotropic virus-1 (HTLV-1) predisposes individuals to severe strongyloidiasis. We reviewed the clinical features of bacterial meningitis associated with strongyloidiasis seen at a single center in subtropical Japan, in an area endemic for both strongyloidiasis and HTLV-1. We found 33 episodes in 21 patients between 1990 and 2010. The results were remarkable for the high incidence of meningitis due to Gram-positive cocci (27.3 %), especially Streptococcus bovis, and culture-negative cases (42.4 %). Given the high incidence of Gram-positive meningitis, a modified approach to corticosteroid use would be advisable in areas where strongyloidiasis is endemic, due to the potentially adverse consequences of glucocorticoid therapy.

  17. Transdominant human T-cell lymphotropic virus type I TAX1 mutant that fails to localize to the nucleus.

    PubMed Central

    Gitlin, S D; Lindholm, P F; Marriott, S J; Brady, J N

    1991-01-01

    Human T-cell lymphotropic virus type I (HTLV-I) encodes a 40-kDa nuclear transactivating phosphoprotein, TAX1. The results presented in this study demonstrate that deletion of amino acids 2 through 59 of TAX1 (delta 58 TAX1) decreased transactivation of the HTLV-I long terminal repeat 10- to 20-fold. S1 nuclease analysis revealed that the decrease in transactivation of the HTLV-I long terminal repeat was associated with a lack of RNA synthesis. In contrast to the nuclear localization of the wild-type TAX1 protein, indirect immunofluorescence analysis demonstrated that delta 58 TAX1 failed to localize to the nucleus, indicating that the TAX1 nuclear localization sequence is present in amino acids 2 through 59. Cotransfection of wild-type and mutant TAX1 DNAs resulted in the cytoplasmic accumulation of TAX1 and a 25-fold decrease in transactivation. Although several possibilities which may account for this transdominant effect exist, we favor a model in which delta 58 TAX1 interferes with the nuclear localization of wild-type TAX1 protein, perhaps by forming heterodimer complexes. Images PMID:2016773

  18. Characterization of Envelope Glycoprotein Mutants for Human T-Cell Leukemia Virus Type 1 Infectivity and Immortalization

    PubMed Central

    Tsukahara, Tomonori; Wielgosz, Matthew M.; Ratner, Lee

    2001-01-01

    The human T-cell leukemia virus type 1 (HTLV-1) envelope protein is required for virus spread. This study further characterizes the role of the envelope protein in HTLV-1 immortalization. Viruses with single amino acid substitutions within the SU protein at residue 75, 81, 95, 101, 105, or 195 or with a C-terminal cytoplasmic domain truncation (CT), as well as an envelope-null (EN) virus, were generated within an infectious molecular clone, ACH. Transfection of 293T cells resulted in the release of similar amounts of virus particles from all of the mutants as determined by p19 enzyme-linked immunosorbent assay and immunoblot analysis of Gag in cell lysates and supernatants. The virus particles from all mutants except ACH-101, ACH-CT, and ACH-EN were infectious for B5 macaque cells in cell-free and cell-to-cell transmission assays and were capable of immortalizing transfected CD4+ lymphocytes. These results indicate that HTLV-1 spread is required for immortalization. PMID:11533220

  19. Mutational analysis of human T-cell leukemia virus type I Tax: regions necessary for function determined with 47 mutant proteins.

    PubMed Central

    Semmes, O J; Jeang, K T

    1992-01-01

    We have made 47 mutations that span the length of the human T-cell leukemia virus type I (HTLV-I) Tax open reading frame. Of the 47 mutations, 38 were substitutions of single amino acids, 5 were missense changes in two or more amino acids, and 4 were deletions. A subset of these mutations includes individual changes of all 26 naturally occurring serines to alanines. By assaying each mutant protein separately on the HTLV-I long terminal repeat (LTR) and the human immunodeficiency virus type 1 (HIV-1) LTR in parallel, we were able to identify regions of Tax selectively necessary for each promoter. A small region in the carboxyl terminus, amino acids 315 to 325, was found to be selectively important for activation of the HTLV-I LTR. Three changes at serine 113, serine 160, and serine 258 were found to specifically affect function on the HIV-1 LTR. Surprisingly, we found that the great preponderance of missense changes (32 of 42) in Tax did not affect function. Images PMID:1433511

  20. Human immunodeficiency virus contains an epitope immunoreactive with thymosin. cap alpha. /sub 1/ and the 30-amino acid synthetic p17 group-specific antigen peptide HGP-30

    SciTech Connect

    Naylor, P.H.; Naylor, C.W.; Badamchian, M.; Wada, S.; Goldstein, A.L.; Wang, S.S.; Sun, D.K.; Thornton, A.H.; Sarin, P.S.

    1987-05-01

    The authors have reported that an antiserum prepared against thymosin ..cap alpha../sub 1/ (which shares a region of homology with the p17 protein of the acquired immunodeficiency syndrome (AIDS)-associated human immunodeficiency virus) effectively neutralized the AIDs virus and prevented its replication in H9 cells. Using HPLC and immunoblot analysis, they have identified from a clone B, type III human T-lymphotropic virus (HTLV-IIIB) extracts a protein with a molecular weight of 17,000 that is immunoreactive with thymosin ..cap alpha../sub 1/. In contrast, no immunoreactivity was found in retroviral extracts from a number of nonhuman species including feline, bovine, simian, gibbon, and murine retroviruses. Heterologous antiserum prepared against a 30-amino acid synthetic peptide analogue (HGP-30) does not cross-react with thymosin ..cap alpha../sub 1/ but does react specifically with the p17 protein of the AIDS virus in a manner identical to that seen with an HTLV-IIIB p17-specific monoclonal antibody. The demonstration that this synthetic analogue is immunogenic and that antibodies to HGP-30 cross-react not only with synthetic peptide but also with the HTLV-IIIB p17 viral protein provides an additional, and potentially more specific, candidate for development of a synthetic peptide vaccine for AIDS. In addition, the p17 synthetic peptide (HGP-3) may prove to be useful in a diagnostic assay for the detection of AIDS virus infection in seronegative individuals.

  1. Comparison of immunofluorescence, particle agglutination, and enzyme immunoassays for detection of human T-cell leukemia virus type I antibody in African sera.

    PubMed

    Verdier, M; Denis, F; Leonard, G; Sangare, A; Patillaud, S; Prince-David, M; Essex, M

    1990-09-01

    The effectiveness of four screening tests for detecting antibody to human T-cell leukemia virus type I (HTLV-I) was determined by using 2,700 African serum specimens. The tests studied were indirect immunofluorescence, particle agglutination from Fujirebio, and two enzyme immunoassays, one from Abbott Laboratories that used virus lysate from HUT 102 cells and the other from Cambridge BioScience Corp. that used an env recombinant protein. Positive and doubtful sera were confirmed by Western immunoblot and radioimmunoprecipitation assay with Food and Drug Administration seropositivity criteria. The best results were obtained with the two enzyme immunoassays, which were more sensitive (100 and 98.6% [Abbott and Cambridge, respectively]) and more specific (98.7 and 96.5%). Indirect immunofluorescence exhibited difficulties for reading and interpretation. With particle agglutination, prozone was observed for 9 of 78 HTLV-I-positive serum specimens. False-positives in any of the tests were not linked to cross-reactions with human immunodeficiency viruses. However, confirmation tests remain necessary for HTLV-I screening.

  2. Identification of an osteoclast transcription factor that binds to the human T cell leukemia virus type I-long terminal repeat enhancer element.

    PubMed

    Inoue, D; Santiago, P; Horne, W C; Baron, R

    1997-10-01

    Transgenic mice expressing human T cell leukemia virus type I (HTLV-I)-tax under the control of HTLV-I-long terminal repeat (LTR) promoter develop skeletal abnormalities with high bone turnover and myelofibrosis. In these animals, Tax is highly expressed in bone with a pattern of expression restricted to osteoclasts and spindle-shaped cells within the endosteal myelofibrosis. To test the hypothesis that lineage-specific transcription factors promote transgene expression from the HTLV-I-LTR in osteoclasts, we first examined tax expression in transgenic bone marrow cultures. Expression was dependent on 1alpha,25-dihydroxycholecalciferol and coincided with tartrate-resistant acid phosphatase (TRAP) expression, a marker of osteoclast differentiation. Furthermore, Tax was expressed in vitronectin receptor-positive mononuclear precursors as well as in mature osteoclast-like cells (OCLs). Consistent with our hypothesis, electrophoretic mobility shift assays revealed the presence of an OCL nuclear factor (NFOC-1) that binds to the LTR 21-base pair direct repeat, a region critical for the promoter activity. This binding is further enhanced by Tax. Since NFOC-1 is absent in macrophages and conserved in osteoclasts among species including human, such a factor may play a role in lineage determination and/or in expression of the differentiated osteoclast phenotype.

  3. Characterization of the nuclear export signal of human T-cell lymphotropic virus type 1 Rex reveals that nuclear export is mediated by position-variable hydrophobic interactions.

    PubMed Central

    Kim, F J; Beeche, A A; Hunter, J J; Chin, D J; Hope, T J

    1996-01-01

    We previously determined that amino acids 64 to 120 of human T-cell lymphotropic virus type 1 (HTLV-1) Rex can restore the function of an effector domain mutant of human immunodeficiency virus type 1 (HIV-1) Rev (T. J. Hope, B. L. Bond, D. McDonald, N. P. Klein, and T. G. Parslow, J. Virol. 65:6001-6007, 1991). In this report, we (i) identify and characterize a position-independent 17-amino-acid region of HTLV-1 Rex that fully complements HIV-1 Rev effector domain mutants and (ii) show that this 17-amino-acid region and specific hydrophobic substitutions can serve as nuclear export signals. Mutagenesis studies revealed that four leucines within the minimal region were essential for function. Alignment of the minimal Rex region with the HIV-1 Rev effector domain suggested that the position of some of the conserved leucines is flexible. We found two of the leucines could each occupy one of two positions within the context of the full-length HTLV-1 Rex protein and maintain function. The idea of flexibility within the Rex effector domain was confirmed and extended by identifying functional substitutions by screening a library of effector domain mutants in which the two regions of flexibility were randomized. Secondly, the functional roles of the minimal Rex effector domain and hydrophobic substitutions were independently confirmed by demonstrating that these effector domains could serve as nuclear export signals when conjugated with bovine serum albumin. Nuclear export of the wild-type Rex conjugates was temperature dependent and sensitive to wheat germ agglutinin and was blocked by a 20-fold excess of unlabeled conjugates. Together, these studies reveal that position-variable hydrophobic interactions within the HTLV-1 Rex effector domain mediate nuclear export function. PMID:8756672

  4. Human T cell leukaemia virus type 2 tax protein mediates CC-chemokine expression in peripheral blood mononuclear cells via the nuclear factor kappa B canonical pathway.

    PubMed

    Barrios, C S; Castillo, L; Zhi, H; Giam, C-Z; Beilke, M A

    2014-01-01

    Retroviral co-infections with human immunodeficiency virus type-1 (HIV-1) and human T cell leukaemia virus type 1 (HTLV-1) or type 2 (HTLV-2) are prevalent in many areas worldwide. It has been observed that HIV-1/HTLV-2 co-infections are associated with slower rates of CD4(+) T cell decline and delayed progression to AIDS. This immunological benefit has been linked to the ability of Tax2, the transcriptional activating protein of HTLV-2, to induce the expression of macrophage inflammatory protein (MIP)-1α/CCL3, MIP-1β/CCL4 and regulated upon activation normal T cell expressed and secreted (RANTES)/CCL5 and to down-regulate the expression of the CCR5 co-receptor in peripheral blood mononuclear cells (PBMCs). This study aimed to assess the role of Tax2-mediated activation of the nuclear factor kappa B (NF-κB) signalling pathway on the production of the anti-viral CC-chemokines MIP-1α, MIP-1β and RANTES. Recombinant Tax1 and Tax2 proteins, or proteins expressed via adenoviral vectors used to infect cells, were tested for their ability to activate the NF-κB pathway in cultured PBMCs in the presence or absence of NF-κB pathway inhibitors. Results showed a significant release of MIP-1α, MIP-1β and RANTES by PBMCs after the activation of p65/RelA and p50. The secretion of these CC-chemokines was significantly reduced (P < 0·05) by canonical NF-κB signalling inhibitors. In conclusion, Tax2 protein may promote innate anti-viral immune responses through the activation of the canonical NF-κB pathway.

  5. APOBEC3G Generates Nonsense Mutations in Human T-Cell Leukemia Virus Type 1 Proviral Genomes In Vivo ▿ †

    PubMed Central

    Fan, Jun; Ma, Guangyong; Nosaka, Kisato; Tanabe, Junko; Satou, Yorifumi; Koito, Atsushi; Wain-Hobson, Simon; Vartanian, Jean-Pierre; Matsuoka, Masao

    2010-01-01

    Human T-cell leukemia virus type 1 (HTLV-1) induces cell proliferation after infection, leading to efficient transmission by cell-to-cell contact. After a long latent period, a fraction of carriers develop adult T-cell leukemia (ATL). Genetic changes in the tax gene in ATL cells were reported in about 10% of ATL cases. To determine genetic changes that may occur throughout the provirus, we determined the entire sequence of the HTLV-1 provirus in 60 ATL cases. Abortive genetic changes, including deletions, insertions, and nonsense mutations, were frequent in all viral genes except the HBZ gene, which is transcribed from the minus strand of the virus. G-to-A base substitutions were the most frequent mutations in ATL cells. The sequence context of G-to-A mutations was in accordance with the preferred target sequence of human APOBEC3G (hA3G). The target sequences of hA3G were less frequent in the plus strand of the HBZ coding region than in other coding regions of the HTLV-1 provirus. Nonsense mutations in viral genes including tax were also observed in proviruses from asymptomatic carriers, indicating that these mutations were generated during reverse transcription and prior to oncogenesis. The fact that hA3G targets the minus strand during reverse transcription explains why the HBZ gene is not susceptible to such nonsense mutations. HTLV-1-infected cells likely take advantage of hA3G to escape from the host immune system by losing expression of viral proteins. PMID:20463074

  6. Complement mediates human immunodeficiency virus type 1 infection of a human T cell line in a CD4- and antibody-independent fashion.

    PubMed

    Boyer, V; Desgranges, C; Trabaud, M A; Fischer, E; Kazatchkine, M D

    1991-05-01

    Incubation of the human T cell lymphotropic virus (HTLV)-IIIB and HTLV-RF strains of human immunodeficiency virus type 1 (HIV-1) with normal seronegative human serum under conditions that allow complement activation resulted in enhancement of infection of the MT2 human T cell line cultured in the presence of low amounts of virus. Infection of MT2 cells was assessed by measuring reverse transcriptase activity in supernatants at day 9 of culture. Complement activation by viral suspensions occurred through the alternative pathway. Opsonization of HTLV-RF viral particles with complement was sufficient to allow a productive infection to occur in cells exposed to suboptimal amounts of virus. Infection of MT2 cells with suboptimal amounts of serum-opsonized HIV-1 was suppressed by blocking the C3dg receptor (CR2, CD21) on MT2 cells with monoclonal anti-CR2 antibody and rabbit F(ab')2 anti-mouse immunoglobulin antibodies. Blocking of the gp120-binding site on CD4 under similar experimental conditions had no inhibitory effect on infection of MT2 cells with opsonized virus. Opsonization of HIV-1 with seronegative serum also resulted in a CR2-mediated enhancement of the infection of normal peripheral blood mononuclear cells and T lymphocytes. These results indicate that complement in the absence of antibody may enhance infection of C3 receptor-bearing T cells with HIV-1, and that the interaction of opsonized virus with the CR2 receptor may result by itself in the infection of target T cells in a CD4- and antibody-independent fashion. PMID:1827139

  7. Assessing Walking Ability in People with HTLV-1-Associated Myelopathy Using the 10 Meter Timed Walk and the 6 Minute Walk Test

    PubMed Central

    Adonis, Adine; Taylor, Graham P.

    2016-01-01

    Background Five to ten million persons, are infected by HTLV-1 of which 3% will develop HTLV-1-associated myelopathy (HAM) a chronic, disabling inflammation of the spinal cord. Walking, a fundamental, complex, multi-functional task is demanding of multiple body systems. Restricted walking ability compromises activity and participation levels in people with HAM (pwHAM). Therapy aims to improve mobility but validated measures are required to assess change. Study Design Prospective observational study. Objectives To explore walking capacity in pwHAM, walking endurance using the 6 minute walk (6MW), and gait speed, using the timed 10m walk (10mTW). Setting Out-patient setting in an inner London Teaching hospital. Methods Prospective documentation of 10mTW and 6MW distance; walking aid usage and pain scores measured twice, a median of 18 months apart. Results Data analysis was completed for twenty-six pwHAM, (8♂; 18♀; median age: 57.8 years; median disease duration: 8 years). Median time at baseline to: complete 10m was 17.5 seconds, versus 21.4 seconds at follow up; 23% completed the 6MW compared to 42% at follow up and a median distance of 55m was covered compared to 71m at follow up. Using the 10mTW velocity to predict the 6MW distance, overestimated the distance walked in 6 minutes (p<0.01). Functional decline over time was captured using the functional ambulation categories. Conclusions The 10mTW velocity underestimated the degree of disability. Gait speed usefully predicts functional domains, shows direction of functional change and comparison with published healthy age matched controls show that these patients have significantly slower gait speeds. The measured differences over 18 months were sufficient to reliably detect change and therefore these assessments can be useful to detect improvement or deterioration within broader disability grades. Walking capacity in pwHAM should be measured using the 10mTW for gait speed and the 6MW for endurance. PMID

  8. Failure in activation of the canonical NF-κB pathway by human T-cell leukemia virus type 1 Tax in non-hematopoietic cell lines

    SciTech Connect

    Mizukoshi, Terumi; Komori, Hideyuki; Mizuguchi, Mariko; Abdelaziz, Hussein; Hara, Toshifumi; Higuchi, Masaya; Tanaka, Yuetsu; Ohara, Yoshiro; Funato, Noriko; Fujii, Masahiro; Nakamura, Masataka

    2013-09-01

    Human T-cell leukemia virus type 1 (HTLV-1) Tax (Tax1) plays crucial roles in leukemogenesis in part through activation of NF-κB. In this study, we demonstrated that Tax1 activated an NF-κB binding (gpκB) site of the gp34/OX40 ligand gene in a cell type-dependent manner. Our examination showed that the gpκΒ site and authentic NF-κB (IgκB) site were activated by Tax1 in hematopoietic cell lines. Non-hematopoietic cell lines including hepatoma and fibroblast cell lines were not permissive to Tax1-mediated activation of the gpκB site, while the IgκB site was activated in those cells in association with binding of RelB. However RelA binding was not observed in the gpκB and IgκB sites. Our results suggest that HTLV-1 Tax1 fails to activate the canonical pathway of NF-κB in non-hematopoietic cell lines. Cell type-dependent activation of NF-κB by Tax1 could be associated with pathogenesis by HTLV-1 infection. - Highlights: • HTLV-1 Tax1 does not activate RelA of NF-κB in non-hematopoietic cell lines. • Tax1 activates the NF-κB non-canonical pathway in non-hematopoietic cell lines. • Tax1 does not induce RelA nuclear translocation in those cell lines, unlike TNFα. • The OX40L promoter κB site is activated by ectopic, but not endogenous, RelA.

  9. Tax and Semaphorin 4D Released from Lymphocytes Infected with Human Lymphotropic Virus Type 1 and Their Effect on Neurite Growth.

    PubMed

    Quintremil, Sebastián; Alberti, Carolina; Rivera, Matías; Medina, Fernando; Puente, Javier; Cartier, Luis; Ramírez, Eugenio; Tanaka, Yuetsu; Valenzuela, M Antonieta

    2016-01-01

    Human lymphotropic virus type 1 (HTLV-1) is a retrovirus causing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurodegenerative central nervous system (CNS) axonopathy. This virus mainly infects CD4(+) T lymphocytes without evidence of neuronal infection. Viral Tax, secreted from infected lymphocytes infiltrated in the CNS, is proposed to alter intracellular pathways related to axonal cytoskeleton dynamics, producing neurological damage. Previous reports showed a higher proteolytic release of soluble Semaphorin 4D (sSEMA-4D) from CD4(+) T cells infected with HTLV-1. Soluble SEMA-4D binds to its receptor Plexin-B1, activating axonal growth collapse pathways in the CNS. In the current study, an increase was found in both SEMA-4D in CD4(+) T cells and sSEMA-4D released to the culture medium of peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients compared to asymptomatic carriers and healthy donors. After a 16-h culture, infected PBMCs showed significantly higher levels of CRMP-2 phosphorylated at Ser(522). The effect was blocked either with anti-Tax or anti-SEMA-4D antibodies. The interaction of Tax and sSEMA-4D was found in secreted medium of PBMCs in patients, which might be associated with a leading role of Tax with the SEMA-4D-Plexin-B1 signaling pathway. In infected PBMCs, the migratory response after transwell assay showed that sSEMA-4D responding cells were CD4(+)Tax(+) T cells with a high CRMP-2 pSer(522) content. In the present study, the participation of Tax-sSEMA-4D in the reduction in neurite growth in PC12 cells produced by MT2 (HTLV-1-infected cell line) culture medium was observed. These results lead to the participation of plexins in the reported effects of infected lymphocytes on neuronal cells. PMID:26389656

  10. Low Proviral Load is Associated with Indeterminate Western Blot Patterns in Human T-Cell Lymphotropic Virus Type 1 Infected Individuals: Could Punctual Mutations be Related?

    PubMed Central

    Cánepa, Camila; Salido, Jimena; Ruggieri, Matías; Fraile, Sindy; Pataccini, Gabriela; Berini, Carolina; Biglione, Mirna

    2015-01-01

    Background: indeterminate Western blot (WB) patterns are a major concern for diagnosis of human T-cell lymphotropic virus type 1 (HTLV-1) infection, even in non-endemic areas. Objectives: (a) to define the prevalence of indeterminate WB among different populations from Argentina; (b) to evaluate if low proviral load (PVL) is associated with indeterminate WB profiles; and (c) to describe mutations in LTR and tax sequence of these cases. Results: Among 2031 samples, 294 were reactive by screening. Of them, 48 (16.3%) were WB indeterminate and of those 15 (31.3%) were PCR+. Quantitative real-time PCR (qPCR) was performed to 52 HTLV-1+ samples, classified as Group 1 (G1): 25 WB+ samples from individuals with pathologies; Group 2 (G2): 18 WB+ samples from asymptomatic carriers (AC); and Group 3 (G3): 9 seroindeterminate samples from AC. Median PVL was 4.78, 2.38, and 0.15 HTLV-1 copies/100 PBMCs, respectively; a significant difference (p=0.003) was observed. Age and sex were associated with PVL in G1 and G2, respectively. Mutations in the distal and central regions of Tax Responsive Elements (TRE) 1 and 2 of G3 were observed, though not associated with PVL.The 8403A>G mutation of the distal region, previously related to high PVL, was absent in G3 but present in 50% of WB+ samples (p = 0.03). Conclusions: indeterminate WB results confirmed later as HTLV-1 positive may be associated with low PVL levels. Mutations in LTR and tax are described;  their functional relevance remains to be determined. PMID:26516904

  11. A cluster of human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis in Jujuy, Argentina.

    PubMed

    Biglione, Mirna M; Pizarro, Manuel; Puca, Alberto; Salomón, Horacio E; Berría, Maria I

    2003-04-01

    Compared with other regions in Argentina, greater human T-cell lymphotropic virus type I (HTLV-I) seroprevalence has been reported in Jujuy Province, where it reaches 2.32% in the general population, so that a search for HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) cases deserved to be carried out. Accordingly, a clinically diagnosed and serologically confirmed cluster of cases in 1 man and 10 women, including 2 sisters, is described here. Most patients (9/11) were born in Cochinoca Department, located in an Andes highland area called Puna Jujeña, situated at more that 3400 m above sea level. No history of risk factors was disclosed, except for a single transfusion in 1 patient. In contrast to the Andean region of Bolivia, where high HTLV-I seroprevalence is in part attributable to Japanese immigrants, the Jujuy population mainly consists of aborigines, mestizos, and European descendants. Therefore, the long-term presence of virus in Jujuy natives may be taken for granted. Considering the HAM/TSP cluster described here plus previously reported isolated cases in neighboring Salta Province, we speculate that the Puna Jujeña region and regions in that vicinity would be a microepidemic focus of disease. To determine the role of possible pathogenic cofactors such as geographic, ethnic, genetic, and cultural features, further pertinent surveys are required in subtropical northwestern Argentina.

  12. Expansion of natural killer cells in peripheral blood in a Japanese elderly with human T-cell lymphotropic virus type 1-related skin lesions.

    PubMed

    Imashuku, Shinsaku; Kudo, Naoko; Kubo, Kagekatsu; Ohshima, Kouichi

    2014-01-01

    Natural killer (NK) cells were proposed to play an important role in the pathogenesis of human T-cell lymphotropic virus type 1- (HTLV-1-) associated neurologic disease. Our patient was a 77-year-old Japanese man, who had been treated for infective dermatitis associated with HTLV-1 for nearly 10 years. When referred to us, he had facial eczema/edema as well as extensive dermatitis at the neck/upper chest and nuchal area/upper back regions. Dermal lesions had CD3+CD4+ cells, but no NK cells. Flow cytometry of his peripheral blood showed a phenotype of CD2+ (97%), CD3+ (17%), CD4+ (12%), CD7+ (94%), CD8+ (6%), CD11c+ (70%), CD16+ (82%), CD19+ (0%), CD20+ (0%), CD56+ (67%), HLA-DR+ (68%), and NKp46+ (36%). Absolute numbers of CD56+NK cells in the peripheral blood were in a range of 986/μL-1,270/μL. The expanded NK cells in the peripheral blood are considered to be reactive, to maintain the confinement of the HTLV-1-positive CD4+ cells in the skin, and to prevent the progression of the disease.

  13. Antibody to the central region of human T-lymphotropic virus type 1 gp46 is associated with the progression of adult T-cell leukemia.

    PubMed

    Sagara, Yasuko; Inoue, Yukiko; Ohshima, Koichi; Kojima, Eijiro; Utsunomiya, Atae; Tsujimura, Mitsushi; Shiraki, Hiroshi; Kashiwagi, Seizaburo

    2007-02-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is an etiologic agent of adult T-cell leukemia/lymphoma (ATL). HTLV-1 is spread by cell-to-cell transmission via the gp46-197 region, Asp197 to Leu216, on the envelope protein gp46. In the present study, we revealed a positive correlation between the appearance of an antibody recognizing the gp46-197 region (anti-gp46-197 antibody) and the severity of ATL. The prevalence and titer of the anti-gp46-197 antibody were found to be elevated along with the progression of ATL. In serial samples obtained from a single patient, the anti-gp46-197 antibody was detected before treatment in acute phase, then diminished after allogeneic bone marrow transplantation, to which the patient had a complete response. However, the antibody appeared again before a relapse, along with an increase of the serum-soluble interleukin-2 receptor level and proviral load. The results from the other six patients also indicate that seroconversion of this antibody was synchronized with the deterioration of ATL. Taken together, the findings indicate that the anti-gp46-197 antibody may be a novel beacon for gauging the efficacy of therapeutic approaches to ATL, and a survey of this antibody would be useful for identifying asymptomatic carriers infected with HTLV-1 who are at high risk of developing ATL.

  14. MicroRNAs and human retroviruses

    PubMed Central

    Houzet, Laurent

    2011-01-01

    Summary MicroRNAs (miRNAs) are small non-coding RNAs that control a multitude of critical processes in mammalian cells. Increasing evidence has emerged that host miRNAs serve in animal cells to restrict viral infections. In turn, many viruses encode RNA silencing suppressors (RSS) which are employed to moderate the potency of the cell’s miRNA selection against viral replication. Some viruses also encode viral miRNAs. In this review, we summarize findings from human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1) that illustrate examples of host cell miRNAs that target the viruses, of RSS encoded by viruses, and of host cell miRNA profile changes that are seen in infected cells. PMID:21640212

  15. Human Viruses and Cancer

    PubMed Central

    Morales-Sánchez, Abigail; Fuentes-Pananá, Ezequiel M.

    2014-01-01

    The first human tumor virus was discovered in the middle of the last century by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt’s lymphoma. To date, seven viruses -EBV, KSHV, high-risk HPV, MCPV, HBV, HCV and HTLV1- have been consistently linked to different types of human cancer, and infections are estimated to account for up to 20% of all cancer cases worldwide. Viral oncogenic mechanisms generally include: generation of genomic instability, increase in the rate of cell proliferation, resistance to apoptosis, alterations in DNA repair mechanisms and cell polarity changes, which often coexist with evasion mechanisms of the antiviral immune response. Viral agents also indirectly contribute to the development of cancer mainly through immunosuppression or chronic inflammation, but also through chronic antigenic stimulation. There is also evidence that viruses can modulate the malignant properties of an established tumor. In the present work, causation criteria for viruses and cancer will be described, as well as the viral agents that comply with these criteria in human tumors, their epidemiological and biological characteristics, the molecular mechanisms by which they induce cellular transformation and their associated cancers. PMID:25341666

  16. Adenosine deaminase isoenzyme levels in patients with human T-cell lymphotropic virus type 1 and human immunodeficiency virus type 1 infections.

    PubMed Central

    Tsuboi, I; Sagawa, K; Shichijo, S; Yokoyama, M M; Ou, D W; Wiederhold, M D

    1995-01-01

    In serum, the enzyme adenosine deaminase (ADA) is known to be divided into two isoenzymes, ADA1 and ADA2, which have different molecular weights and kinetic properties. The present study investigated ADA isoenzyme levels in the sera of patients infected with retroviruses associated with adult T-cell leukemia (ATL), human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM), and AIDS, ADA isoenzyme activities were found to be significantly (P < 0.001) higher in the sera of patients with ATL, HAM, and AIDS than in the sera of healthy controls. In the case of the ADA subtypes in the sera of patients with ATL, ADA1 activity was significantly (P < 0.001) elevated in patients with the acute and lymphoma types of ATL compared with that in patients with the chronic and smoldering types of ATL. ADA2 activity was significantly elevated in the sera of patients with the acute, lymphoma, and chronic types of ATL (P < 0.001) compared with that in patients with smoldering ATL and HTLV-1 carriers. In the case of patients with human immunodeficiency virus type 1 (HIV-1) infection, ADA1 and ADA2 activities in the sera of patients with AIDS and HIV-1 antibody-positive individuals were significantly (P < 0.001) higher than those in the sera of HIV-1 antibody-negative individuals. A significant elevation in ADA2 activity was also seen in the sera of AIDS patients (P < 0.01) compared with that in the sera of HIV-1 antibody-positive individuals. These results suggest that the magnitude of elevation of ADA isoenzyme levels in serum correlates well with the clinical conditions of the patients with these diseases. Measurement of the activities of ADA isoenzymes may therefore provide an additional parameter for distinguishing the subtypes of ATL and may prove to be useful as prognostic and therapeutic monitors in diseases associated with HTLV-1 and HIV-1 infections. PMID:8548545

  17. Inhibition of proliferation by agricultural plant extracts in seven human adult T-cell leukaemia (ATL)-related cell lines.

    PubMed

    Kai, Hisahiro; Akamatsu, Ena; Torii, Eri; Kodama, Hiroko; Yukizaki, Chizuko; Sakakibara, Yoichi; Suiko, Masahito; Morishita, Kazuhiro; Kataoka, Hiroaki; Matsuno, Koji

    2011-07-01

    Adult T-cell leukaemia (ATL) is caused by human T-cell leukaemia virus type I (HTLV-I) infection and is resistant to conventional chemotherapy. We evaluated the inhibitory effects of agricultural plants on the proliferation of seven ATL-related human leukaemia cells, using three ATL cell lines (ED, Su9T01 and S1T), two human T-cell lines transformed by HTLV-I infection (HUT-102 and MT-2) and two HTLV-I-negative human T-cell acute lymphoblastic leukaemia cell lines (Jurkat and MOLT-4). A total of 52 samples of 80% ethanol extracts obtained from 30 types of agricultural plants were examined. On the basis of IC(50) values, we selected samples with greater activity than genistein, which was used as a positive control. The highest inhibitory effect was observed with extracts from leaves of Vaccinium virgatum Aiton (blueberry) on four cell lines (ED, Su9T01, HUT-102 and Jurkat); seeds of Momordica charantia L. (bitter gourd) exhibited the second highest activity. The bitter gourd seeds suppressed the proliferation of three cell lines (Su9T01, HUT-102 and Jurkat). The extracts from edible parts of Ipomea batatas LAM. (sweet potato), edible parts of Colocasia esculenta (L.) Schott (taro), skin of taro and seeds of Prunus mume Sieb. et Zucc. (mume) showed markedly greater inhibitory effects on Su9T01 than genistein. These findings suggest that ATL-preventative bioactive compounds may exist in these agricultural plants, which are considered to be functional foods. PMID:21293936

  18. The human T-cell leukemia/lymphotropic virus type 1 p12I proteins bind the interleukin-2 receptor beta and gammac chains and affects their expression on the cell surface.

    PubMed Central

    Mulloy, J C; Crownley, R W; Fullen, J; Leonard, W J; Franchini, G

    1996-01-01

    p12I is a small hydrophobic protein encoded by the human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) that interacts with the 16-kDa component of the H+ vacuolar ATPase and cooperates with bovine papillomavirus 1 E5 oncoprotein in cell transformation. Just as an important step in E5 action appears to be its binding to the platelet-derived growth factor receptor, it was found that p12I binds specifically to both the beta and gamma(c) chains of the interleukin-2 receptor (IL-2R). The IL-2R beta and gamma(c) chains associated with p12I are endoglycosidase-H sensitive, suggesting that their interaction occurs in a pre-Golgi compartment. p12I stabilizes the immature forms of the IL-2R beta and gamma(c) chains and decreases their cell surface expression. The interactions of p12I with IL-2R beta and gamma(c) may have important implications in the immunosuppressive effect of HTLV-1 in vivo as well as in the ligand-independent HTLV-1-mediated T-cell proliferation. PMID:8648694

  19. "Signal-on" photoelectrochemical biosensor for sensitive detection of human T-Cell lymphotropic virus type II DNA: dual signal amplification strategy integrating enzymatic amplification with terminal deoxynucleotidyl transferase-mediated extension.

    PubMed

    Shen, Qingming; Han, Li; Fan, Gaochao; Zhang, Jian-Rong; Jiang, Liping; Zhu, Jun-Jie

    2015-01-01

    A novel "signal-on" photoelectrochemical (PEC) biosensor for sensitive detection of human T-cell lymphotropic virus type II (HTLV-II) DNA was developed on the basis of enzymatic amplification coupled with terminal deoxynucleotidyl transferase (TdT)-mediated extension strategy. The intensity of the photocurrent signal was proportional to the concentration of the HTLV-II DNA-target DNA (tDNA) by dual signal amplification. In this protocol, GR-CdS:Mn/ZnS nanocomposites were used as photoelectric conversion material, while pDNA was used as the tDNA recognizing unit. Moreover, the TdT-mediated extension and the enzymatic signal amplification technique were used to enhance the sensitivity of detection. Using this novel dual signal amplification strategy, the prototype of PEC DNA sensor can detect as low as ∼0.033 fM of HTLV-II DNA with a linear range of 0.1-5000 fM, with excellent differentiation ability even for single-base mismatches. This PEC DNA assay opens a promising platform to detect various DNA targets at ultralow levels for early diagnoses of different diseases. PMID:25871300

  20. HTLV-1 Tax oncoprotein inhibits the estrogen-induced-ER α-Mediated BRCA1 expression by interaction with CBP/p300 cofactors.

    PubMed

    Shukrun, Meital; Jabareen, Azhar; Abou-Kandil, Ammar; Chamias, Rachel; Aboud, Mordechai; Huleihel, Mahmoud

    2014-01-01

    BRCA1 is a multifunctional tumor suppressor, whose expression is activated by the estrogen (E2)-liganded ERα receptor and regulated by certain recruited transcriptional co-activators. Interference with BRCA1 expression and/or functions leads to high risk of breast or/and ovarian cancer. Another multifunctional protein, HTLV-1Tax oncoprotein, is widely regarded as crucial for developing adult T-cell leukemia and other clinical disorders. Tax profile reveals that it can antagonize BRCA1 expression and/or functionality. Therefore, we hypothesize that Tax expression in breast cells can sensitize them to malignant transformation by environmental carcinogens. Here we examined Tax effect on BRCA1 expression by testing its influence on E2-induced expression of BRCA1 promoter-driven luciferase reporter (BRCA1-Luc). We found that E2 strongly stimulated this reporter expression by liganding to ERα, which consequently associated with BRCA1 promoter, while ERα concomitantly recruited CBP/p300 to this complex for co-operative enhancement of BRCA1 expression. Introducing Tax into these cells strongly blocked this E2-ERα-mediated activation of BRCA1 expression. We noted, also, that Tax exerted this inhibition by binding to CBP/p300 without releasing them from their complex with ERα. Chip assay revealed that the binding of Tax to the CBP/p300-ERα complex, prevented its link to AP1 site. Interestingly, we noted that elevating the intracellular pool of CBP or p300 to excessive levels dramatically reduced the Tax-mediated inhibition of BRCA1 expression. Exploring the mechanism of this reduction revealed that the excessive co-factors were sufficient to bind separately the free Tax molecules, thus lowering their amount in the CBP/p300-ERα complex and relieving, thereby, the inhibition of BRCA1 expression.

  1. [Frequency of HIV-1, rubella, syphilis, toxoplasmosis, cytomegalovirus, simple herpes virus, hepatitis B, hepatitis C, Chagas disease and HTLV I/II infection in pregnant women of State of Mato Grosso do Sul].

    PubMed

    Figueiró-Filho, Ernesto Antonio; Senefonte, Flávio Renato de Almeida; Lopes, Alessandro Henrique Antunes; de Morais, Orlando Oliveira; Souza Júnior, Virgílio Gonçalves; Maia, Tamara Lemos; Duarte, Geraldo

    2007-01-01

    It was aimed to estimate the frequency of syphilis, rubella, hepatitis B, hepatitis C, toxoplasmosis, Chagas disease, HTLV I/II, simple herpes virus, HIV-1 and cytomegalovirus in pregnant women and to evaluate the relationship between age and the frequency of the infections studied. A transversal study of 32,512 pregnant women submitted to pre-natal screening in the period of November 2002 to October 2003. The frequency of the tried infections among the pregnant women were 0.2% of HIV-1, 0.03% of rubella, 0.8% of syphilis, 0.4% of toxoplasmosis, 0.05% of cytomegalovirus, 0.02% of simple herpes virus, 0.3% of HBsAg, 0.1% of hepatitis C, 0.1% of HTLV and 0.1% of Chagas disease. There was significative statistical association between age and prenatal infection of rubella, cytomegalovirus, Chagas disease and herpes virus. The rates of frequency of rubella, syphilis, toxoplasmosis, Chagas disease and cytomegalovirus in pregnant women studied were lower than the compared rates.

  2. Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax.

    PubMed

    Chen, Li; Liu, Dan; Zhang, Yang; Zhang, Huan; Cheng, Hua

    2015-10-23

    The retroviral Tax proteins of human T cell leukemia virus type 1 and 2 (HTLV-1 and -2) are highly homologous viral transactivators. Both viral proteins can immortalize human primary CD4+ memory T cells, but when expressed alone they rarely transform T cells. In the present study, we found that the Tax proteins displayed a differential ability to immortalize human CD4+Foxp3+ T cells with characteristic expression of CTLA-4 and GITR. Because epidermal growth factor receptor (EGFR) was reportedly expressed and activated in a subset of CD4+Foxp3+ T cells, we introduced an activated EGFR into Tax-immortalized CD4+Foxp3+ T cells. We observed that these modified cells were grown independently of exogenous IL-2, correlating with a T cell transformation phenotype. In Tax-immortalized CD4+Foxp3- T cells, ectopic expression of Foxp3 was a prerequisite for Tax transformation of T cells. Accordingly, treatment of the transformed T cells with erlotinib, a selective inhibitor of EGFR, induced degradation of EGFR in lysosome, consequently causing T cell growth inhibition. Further, we identified autophagy as a crucial cellular survival pathway for the transformed T cells. Silencing key autophagy molecules including Beclin1, Atg5 and PI3 kinase class III (PI3KC3) resulted in drastic impairment of T cell growth. Our data, therefore, unveiled a previously unidentified role of Foxp3 in T cell transformation, providing a molecular basis for HTLV-1 transformation of CD4+Foxp3+ T cells.

  3. Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases.

    PubMed

    Gonçalves, Denise Utsch; Proietti, Fernando Augusto; Ribas, João Gabriel Ramos; Araújo, Marcelo Grossi; Pinheiro, Sônia Regina; Guedes, Antônio Carlos; Carneiro-Proietti, Anna Bárbara F

    2010-07-01

    Human T-cell leukemia virus type 1 (HTLV-1), the first human retrovirus to be discovered, is present in diverse regions of the world, where its infection is usually neglected in health care settings and by public health authorities. Since it is usually asymptomatic in the beginning of the infection and disease typically manifests later in life, silent transmission occurs, which is associated with sexual relations, breastfeeding, and blood transfusions. There are no prospects of vaccines, and screening of blood banks and in prenatal care settings is not universal. Therefore, its transmission is active in many areas such as parts of Africa, South and Central America, the Caribbean region, Asia, and Melanesia. It causes serious diseases in humans, including adult T-cell leukemia/lymphoma (ATL) and an incapacitating neurological disease (HTLV-associated myelopathy/tropical spastic paraparesis [HAM/TSP]) besides other afflictions such as uveitis, rheumatic syndromes, and predisposition to helminthic and bacterial infections, among others. These diseases are not curable as yet, and current treatments as well as new perspectives are discussed in the present review.

  4. Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro

    SciTech Connect

    Rubin, L.A.; Kurman, C.C.; Fritz, M.E.; Biddison, W.E.; Boutin, B.; Yarchoan, R.; Nelson, D.L.

    1985-11-01

    With the use of an enzyme-linked immunoabsorbent assay to measure soluble human interleukin 2 receptors (IL 2R), certain human T cell leukemia virus I (HTLV I)-positive T cell lines were found to spontaneously release large quantities of IL 2R into culture supernatants. This was not found with HTLV I-negative and IL 2 independent T cell lines, and only one of seven B cell-derived lines examined produced small amounts of IL 2R. In addition to this constitutive production of soluble IL 2R by certain cell lines, normal human peripheral blood mononuclear cells (PBMC) could be induced to release soluble IL 2R by plant lectins, the murine monoclonal antibody OKT3, tetanus toxoid, and allogeneic cells. Such activated cells also expressed cellular IL 2R measurable in detergent solubilized cell extracts. The generation of cellular and supernatant IL 2R was: dependent on cellular activation, rapid, radioresistant (3000 rad), and inhibited by cycloheximide treatment. NaDodSO4-polyacrylamide gel electrophoresis analysis of soluble IL 2R demonstrated molecules of apparent Mr = 35,000 to 40,000, and 45,000 to 50,000, respectively, somewhat smaller than the mature surface receptor on these cells. The release of soluble IL 2R appears to be a characteristic marker of T lymphocyte activation and might serve an immunoregulatory function during both normal and abnormal cell growth and differentiation.

  5. Triple infection with HIV-1, HTLV-1 and Strongyloides stercoralis, rendering CD4+ T-cell counts a misleading entity.

    PubMed

    Janssen, Saskia; Rossatanga, Elie G; Jurriaans, Suzanne; ten Berge, Ineke J M; Grobusch, Martin P

    2013-01-01

    We report the case of a Gabonese HIV-patient who presented with haemoptysis, weight loss, fulminant diarrhoea and subsequent ileus and elevated CD4+ T-cell counts. He was diagnosed with Strongyloides stercoralis and human T-lymphotrophic virus type-1 infection. After treatment of the strongyloides hyperinfection syndrome, his CD4+ T-cell counts dropped greatly. The initially elevated CD4+ T-cell counts were misleading to the clinicians with regard to decision-making on antiretroviral therapy initiation. PMID:24152969

  6. Induction of Cell Death in Growing Human T-Cells and Cell Survival in Resting Cells in Response to the Human T-Cell Leukemia Virus Type 1 Tax

    PubMed Central

    Mizuguchi, Mariko; Sasaki, Yuka; Hara, Toshifumi; Higuchi, Masaya; Tanaka, Yuetsu; Funato, Noriko; Tanaka, Nobuyuki; Fujii, Masahiro; Nakamura, Masataka

    2016-01-01

    Tax1 encoded by the human T-cell leukemia virus type 1 (HTLV-1) has been believed to dysregulate the expression of cellular genes involved in cell survival and mortality, leading to the development of adult T-cell leukemia (ATL). The function of Tax1 in ATL development however is still controversial, primarily because Tax1 induces cell cycle progression and apoptosis. To systemically understand cell growth phase-dependent induction of cell survival or cell death by Tax1, we established a single experimental system using an interleukin 2 (IL-2)-dependent human T-cell line Kit 225 that can be forced into resting phase by IL-2 deprivation. Introduction of Tax1 and HTLV-2 Tax (Tax2B) decreased mitochondrial activity alongside apoptosis in growing cells but not in resting cells. Cell cycle profile analysis indicated that Tax1 and Tax2B were likely to perturb the S phase in growing cells. Studies with Tax1 mutants and siRNA for NF-κB/RelA revealed that Tax1-mediated cell growth inhibition and apoptosis in growing Kit 225 cells depend on RelA. Interestingly, inactivation of the non-canonical NF-κB and p38 MAPK pathways relieved Tax1-mediated apoptosis, suggesting that the Tax1-NF-κB-p38 MAPK axis may be associated with apoptosis in growing cells. Inflammatory mediators such as CCL3 and CCL4, which are involved in oncogene-induced senescence (OIS), were induced by Tax1 and Tax2B in growing cells. In contrast, RelA silencing in resting cells reduced mitochondrial activity, indicating that NF-κB/RelA is also critical for Tax1-mediated cell survival. These findings suggest that Tax1-mediated cell survival and death depend on the cell growth phase. Both effects of Tax1 may be implicated in the long latency of HTLV-1 infection. PMID:26829041

  7. Physical and functional interaction between the human T-cell lymphotropic virus type 1 Tax1 protein and the CCAAT binding protein NF-Y.

    PubMed Central

    Pise-Masison, C A; Dittmer, J; Clemens, K E; Brady, J N

    1997-01-01

    Tax1, a potent activator of human T-cell lymphotropic virus type 1 (HTLV-1) transcription, has been shown to modulate expression of many cellular genes. Tax1 does not bind DNA directly but regulates transcription through protein-protein interactions with sequence-specific transcription factors. Using the yeast two-hybrid system to screen for proteins which interact with Tax1, we isolated the B subunit of the CCAAT binding protein NF-Y from a HeLa cDNA library. The interaction of Tax1 with NF-YB was specific in that NF-YB did not interact with a variety of other transcription factors, including human immunodeficiency virus Tat, human papillomavirus E6, and Bicoid, or with the M7 (amino acids 29CP-AS) Tax1 mutant. However, NF-YB did interact with the C-terminal Tax1 mutants M22 (130TL-AS) and M47 (319LL-RS). We also show that in vitro-translated NF-YB specifically bound to a glutathione S-transferase-Tax1 fusion protein. Further, Tax1 coimmunoprecipitated with NF-Y from nuclear extracts of HTLV-1-transformed cells, providing evidence for in vivo interaction of Tax1 and NF-YB. We further demonstrate that Tax1 specifically activated the NF-Y-responsive DQbeta promoter, as well as a minimal promoter which contains only the Y-box element. In addition, mutation of the Y-box element alone abrogated Tax1-mediated activation. Taken together, these data indicate that Tax1 interacts with NF-Y through the B subunit and that this interaction results in activation of the major histocompatibility complex class II promoter. Through activation of this and other NF-Y driven promoters, the Tax1-NF-Y interaction may play a critical role in causing cellular transformation and HTLV-1 pathogenesis. PMID:9032250

  8. Pooling of samples for seroepidemiological surveillance of human T-cell lymphotropic virus types I and II.

    PubMed

    Andersson, S; Gessain, A; Taylor, G P

    2001-10-30

    We evaluated a straight forward pooling strategy for antibody screening of HTLV-I/II, using panels of sera from various parts of the world including a total of 43 HTLV-I and 54 HTLV-II positive specimens. Four antibody screening assays were included in the evaluation: the HTLV-I/II GE 80/81 (Murex Diagnostics), the HTLV-I/HTLV-II Ab Capture ELISA (Ortho Diagnostics), the HTLV-I/II ELISA 3.0 (Genelabs Diagnostics) and the Serodia HTLV-I (Fujirebio). The Murex and Ortho assays represent a new generation of HTLV screening tests with a sandwich format incorporating both HTLV-I and HTLV-II synthetic and/or recombinant peptide antigens. The Genelabs assay is an indirect ELISA with recombinant HTLV-I and -II antigens and Serodia is a particle agglutination assay with HTLV-I whole viral lysate. Each HTLV-positive sample was included in pools of 1/1 up to 1/16, in two-fold steps made in normal HTLV-negative blood donor serum from one up to nine donors. For HTLV-I, with the exception of one false negative sample in dilution 1/16 with Genelabs ELISA, all assays were positive at all dilutions. The Murex assay had absorbance values at maximum levels for all samples at all dilutions. The other assays had gradually decreasing absorbance values although clearly above cut-off. For HTLV-II, the Murex assay correctly detected all samples to dilution 1/16 despite gradually decreasing signals. The Serodia assay had 100% sensitivity to dilution 1/4 while at 1/8 and 1/16 it decreased 82 and 80%, respectively. The Genelabs ELISA had gradually decreasing sensitivity for HTLV-II from 98 (1/1) to 33% (1/16) while the Ortho assay detected all specimens at all dilutions in a limited set of samples tested. Taken together, this evaluation has shown that pooling of samples may be an appropriate strategy for serosurveillance of HTLV. It is, however, crucial to limit the number of samples and to choose assays that allow the dilution caused by the pooling. Using the best performing assays in this

  9. The ectodomain of the human T-cell leukemia virus type 1 TM glycoprotein is involved in postfusion events.

    PubMed Central

    Rosenberg, A R; Delamarre, L; Pique, C; Pham, D; Dokhélar, M C

    1997-01-01

    To examine the contribution of the transmembrane envelope glycoprotein (TM) to the infectivity of the human T-cell leukemia virus type 1 (HTLV-1), single amino acid substitutions were introduced throughout its ectodomain. The mutated envelopes were tested for intracellular maturation and for functions, including ability to elicit syncytium formation and ability to mediate cell-to-cell transmission of the virus. Three major phenotypes, defining three functionally distinct regions, were identified. (i) Mutations causing defects in intracellular maturation of the envelope precursor are mostly distributed in the central portion of the TM ectodomain, containing the immunosuppressive peptide. This region, which includes vicinal cysteines thought to form an intramolecular disulfide bridge, is probably essential for correct folding of the protein. (ii) Mutations resulting in reduced syncytium-forming ability despite correct intracellular maturation are clustered in the amino-terminal part of the TM ectodomain, within the leucine zipper-like motif. Similar motifs with a propensity to form coiled-coil structures have been implicated in the fusion process driven by other viral envelope proteins, and HTLV-1 may thus conform to this general rule for viral fusion. (iii) Mutants with increased syncytium-forming ability define a region immediately amino-terminal to the membrane-spanning domain. Surprisingly, these mutants exhibited severe defects in infectivity, despite competence for fusion. Existence of this phenotype indicates that capacity for cell-to-cell fusion is not sufficient to ensure viral entry, even in cell-to-cell transmission. The ectodomain of the TM glycoprotein thus may be involved in postfusion events required for full infectivity of HTLV-1, which perhaps represents a unique feature of this poorly infectious retrovirus. PMID:9311790

  10. Influence of human T-cell leukemia virus type I tax and rex on interleukin-2 gene expression.

    PubMed Central

    McGuire, K L; Curtiss, V E; Larson, E L; Haseltine, W A

    1993-01-01

    The X region of human T-cell leukemia virus type I (HTLV-I) encodes two proteins that regulate viral gene expression. The tax protein is the product of the transactivator gene and has been shown to up-regulate the expression of some cellular genes controlling T-cell replication, including that of the interleukin-2 (IL-2) T-cell growth hormone and the alpha chain of its receptor (IL-2R). Several studies have shown that tax transactivation of the IL-2R alpha-chain promoter is mediated by binding sites for the transcriptional activator NF-kappa B, and this mechanism has also been implicated in the tax activation of IL-2 promoter activity. The rex gene product of HTLV-I regulates viral protein production by influencing mRNA expression and has been implicated in the stabilization of IL-2R alpha-chain mRNA. In the present studies, the ability of the tax and rex proteins to transactivate IL-2 gene expression has been reinvestigated. The ability of the tax protein to transactivate IL-2 promoter activity appears, at least in part, to be mediated by the recognition sequence for a DNA-binding complex known as CD28RC. Consistent with this hypothesis is the observation that tax-mediated activation of IL-2 gene expression is resistant to the immunosuppressive affects of cyclosporin A, a property postulated for the CD28RC binding complex. Unexpectedly, this tax-mediated up-regulation of IL-2 expression is synergized by the presence of the rex protein. These findings demonstrate that transactivation of IL-2 gene expression by tax is augmented by mechanisms distinct from NF-kappa B and raise the possibility that rex, as well as tax, contributes to the oncogenic capability of HTLV-I by altering the expression of the IL-2 gene in T cells infected with this retrovirus. Images PMID:8382312

  11. Human T-Lymphotropic Virus Type 1 Oncoprotein Tax Promotes S-Phase Entry but Blocks Mitosis

    PubMed Central

    Liang, Min-Hui; Geisbert, Thomas; Yao, Yao; Hinrichs, Steven H.; Giam, Chou-Zen

    2002-01-01

    Human T-lymphotropic virus type 1 (HTLV-1) Tax exerts pleiotropic effects on multiple cellular regulatory processes to bring about NF-κB activation, aberrant cell cycle progression, and cell transformation. Here we report that Tax stimulates cellular G1/S entry but blocks mitosis. Tax expression in naive cells transduced with a retroviral vector, pBabe-Tax, leads to a significant increase in the number of cells in the S phase, with an accompanying rise in the population of cells with a DNA content of 4N or more. In all cell types tested, including BHK-21, mouse NIH 3T3, and human diploid fibroblast WI-38, Tax causes an uncoupling of DNA synthesis from cell division, resulting in the formation of multinucleated giant cells and cells with decondensed, highly convoluted and lobulated nuclei that are reminiscent of the large lymphocytes with cleaved or cerebriform nuclei seen in HTLV-1-positive individuals. This contrasts with the Tax-transformed cell lines, PX1 (fibroblast) and MT4 (lymphocyte), which produce Tax at high levels, but without the accompanying late-stage cell cycle abnormalities. PX1 and MT4 may have been selected to harbor somatic mutations that allow a bypass of the Tax-induced block in mitosis. PMID:11907241

  12. Human retroviruses in leukaemia and AIDS: reflections on their discovery, biology and epidemiology.

    PubMed

    Karpas, Abraham

    2004-11-01

    The study of retroviruses has had a profound impact by unveiling an unusual form of viral replication: the multiplication of RNA viruses via a proviral DNA, for which Jan Svoboda provided the experimental model over forty years ago. In 1970 Temin, Mizutani and Baltimore discovered that this group of viruses contains a unique enzyme catalysing the synthesis of a DNA copy of the viral RNA: reverse transcriptase (RT). The discovery of RT has itself had an enormous impact on molecular biology in general, but also stimulated many premature claims of its detection in human disease. Claims by Gallo's laboratory that the cytoplasm of human leukaemia cells contained RT proved to be unfounded, as did his report in collaboration with Weiss that myeloid leukaemia contained HL23 virus, this organism proving not to be human but a laboratory contaminant of three monkey viruses. Conclusive demonstration of a retroviral involvement in human leukaemia was first provided in 1981 by Hinuma and his associates, showing that adult T-cell leukaemia (ATL), a rare form of leukaemia endemic to south-west Japan, is caused by a new retrovirus (ATLV). Other publications in December 1980 and through 1981 claimed the discovery of a new human T-cell leukaemia virus involved in mycosis fungoides (MF) and Sézary's syndrome (SS). This virus was termed HTLV by Gallo. The nucleotide sequence of ATLV is strongly conserved, that of my 1983 isolate from a black British ATL patient being practically identical with the Japanese virus isolates. After AIDS was recognised in 1981 by Gottlieb and coworkers as a new human disease, several papers were published by Gallo and his associates during 1983-4, invoking the oncovirus responsible for adult T-cell leukaemia as the cause of AIDS. In 1983 the French scientist Barré-Sinoussi and her colleagues succeeded in isolating a new agent in the disease, a lentivirus, which they named LAV. The French immunologist Klatzmann and his colleagues discovered that LAV killed

  13. The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transform