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Sample records for kaposis sarcoma-associated herpesvirus

  1. Molecular piracy of Kaposi's sarcoma associated herpesvirus.

    PubMed

    Choi, J; Means, R E; Damania, B; Jung, J U

    2001-01-01

    Kaposi's Sarcoma associated Herpesvirus (KSHV) is the most recently discovered human tumor virus and is associated with the pathogenesis of Kaposi's sarcoma, primary effusion lymphoma, and Multicentric Casttleman's disease. KSHV contains numerous open reading frames with striking homology to cellular genes. These viral gene products play a variety of roles in KSHV-associated pathogenesis by disrupting cellular signal transduction pathways, which include interferon-mediated anti-viral responses, cytokine-regulated cell growth, apoptosis, and cell cycle control. In this review, we will attempt to cover our understanding of how viral proteins deregulate cellular signaling pathways, which ultimately contribute to the conversion of normal cells to cancerous cells. PMID:11325605

  2. Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy.

    PubMed

    Dittmer, Dirk P; Damania, Blossom

    2016-09-01

    Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. This human gammaherpesvirus was discovered in 1994 by Drs. Yuan Chang and Patrick Moore. Today, there are over five thousand publications on KSHV and its associated malignancies. In this article, we review recent and ongoing developments in the KSHV field, including molecular mechanisms of KSHV pathogenesis, clinical aspects of KSHV-associated diseases, and current treatments for cancers associated with this virus. PMID:27584730

  3. Kaposi Sarcoma-associated Herpesvirus: mechanisms of oncogenesis.

    PubMed

    Schulz, Thomas F; Cesarman, Ethel

    2015-10-01

    Kaposi Sarcoma-associated Herpesvirus (KSHV, HHV8) causes three human malignancies, Kaposi Sarcoma (KS), an endothelial tumor, as well as Primary Effusion Lymphoma (PEL) and the plasma cell variant of Multicentric Castleman's Disease (MCD), two B-cell lymphoproliferative diseases. All three cancers occur primarily in the context of immune deficiency and/or HIV infection, but their pathogenesis differs. KS most likely results from the combined effects of an endotheliotropic virus with angiogenic properties and inflammatory stimuli and thus represents an interesting example of a cancer that arises in an inflammatory context. Viral and cellular angiogenic and inflammatory factors also play an important role in the pathogenesis of MCD. In contrast, PEL represents an autonomously growing malignancy that is, however, still dependent on the continuous presence of KSHV and the action of several KSHV proteins. PMID:26431609

  4. The chromatin landscape of Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Toth, Zsolt; Brulois, Kevin; Jung, Jae U

    2013-05-01

    Kaposi's sarcoma-associated herpesvirus is an oncogenic γ-herpesvirus that causes latent infection in humans. In cells, the viral genome adopts a highly organized chromatin structure, which is controlled by a wide variety of cellular and viral chromatin regulatory factors. In the past few years, interrogation of the chromatinized KSHV genome by whole genome-analyzing tools revealed that the complex chromatin landscape spanning the viral genome in infected cells has important regulatory roles during the viral life cycle. This review summarizes the most recent findings regarding the role of histone modifications, histone modifying enzymes, DNA methylation, microRNAs, non-coding RNAs and the nuclear organization of the KSHV epigenome in the regulation of latent and lytic viral gene expression programs as well as their connection to KSHV-associated pathogenesis. PMID:23698402

  5. Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6.

    PubMed

    Aoki, Y; Jones, K D; Tosato, G

    2000-04-01

    Since the discovery of the virus in 1994, the rapid pace with which Karposi's sarcoma-associated herpesvirus (KSHV) research has progressed has quickly led to a broad understanding of the structure of the virus and its biology and pathology in humans. Molecular piracy of potentially useful cellular genes has emerged as a characteristic feature of this virus. The viral homolog of human IL-6, vIL-6 is an example in kind. Studies in vitro and in vivo have shown that vIL-6 can stimulate the growth of KSHV-infected primary infusion lymphoma (PEL) cells, can promote hematopoiesis, and act as an angiogenic factor through the induction of vascular endothelial growth factor (VEGF). It is not difficult to envision how vIL-6, through these properties and perhaps others yet to be identified, can contribute to KSHV survival and spread in the human population. PMID:10813527

  6. Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

    PubMed Central

    Dourmishev, Lyubomir A.; Dourmishev, Assen L.; Palmeri, Diana; Schwartz, Robert A.; Lukac, David M.

    2003-01-01

    Kaposi's sarcoma had been recognized as unique human cancer for a century before it manifested as an AIDS-defining illness with a suspected infectious etiology. The discovery of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, in 1994 by using representational difference analysis, a subtractive method previously employed for cloning differences in human genomic DNA, was a fitting harbinger for the powerful bioinformatic approaches since employed to understand its pathogenesis in KS. Indeed, the discovery of KSHV was rapidly followed by publication of its complete sequence, which revealed that the virus had coopted a wide armamentarium of human genes; in the short time since then, the functions of many of these viral gene variants in cell growth control, signaling apoptosis, angiogenesis, and immunomodulation have been characterized. This critical literature review explores the pathogenic potential of these genes within the framework of current knowledge of the basic herpesvirology of KSHV, including the relationships between viral genotypic variation and the four clinicoepidemiologic forms of Kaposi's sarcoma, current viral detection methods and their utility, primary infection by KSHV, tissue culture and animal models of latent- and lytic-cycle gene expression and pathogenesis, and viral reactivation from latency. Recent advances in models of de novo endothelial infection, microarray analyses of the host response to infection, receptor identification, and cloning of full-length, infectious KSHV genomic DNA promise to reveal key molecular mechanisms of the candidate pathogeneic genes when expressed in the context of viral infection. PMID:12794189

  7. Molecular biology of Kaposi's sarcoma-associated herpesvirus and related oncogenesis.

    PubMed

    Cai, Qiliang; Verma, Suhbash C; Lu, Jie; Robertson, Erle S

    2010-01-01

    Kaposi's Sarcoma-associated Herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the most recently identified human tumor virus,and is associated with the pathogenesis of Kaposi's sarcoma and two lymphoproliferative disorders known to occur frequently in AIDS patients-primary effusion lymphoma and multicentric Castleman disease. In the 15 years since its discovery, intense studies have demonstrated an etiologic role for KSHV in the development of these malignancies. Here, we review the recent advances linked to understanding KSHV latent and lytic life cycle and the molecular mechanisms of KSHV-mediated oncogenesis in terms of transformation, cell signaling, cell growth and survival, angiogenesis, immune invasion and response to microenvironmental stress, and highlight the potential therapeutic targets for blocking KSHV tumorigenesis. PMID:21040832

  8. Molecular piracy: manipulation of the ubiquitin system by Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Fujimuro, Masahiro; Hayward, S Diane; Yokosawa, Hideyoshi

    2007-01-01

    Ubiquitination, one of several post-translational protein modifications, plays a key role in the regulation of cellular events, including protein degradation, signal transduction, endocytosis, protein trafficking, apoptosis and immune responses. Ubiquitin attachment at the lysine residue of cellular factors acts as a signal for endocytosis and rapid degradation by the 26S proteasome. It has recently been observed that viruses, especially oncogenic herpesviruses, utilise molecular piracy by encoding their own proteins to interfere with regulation of cell signalling. Kaposi's sarcoma- associated herpesvirus (KSHV) manipulates the ubiquitin system to facilitate cell proliferation, anti-apoptosis and evasion from immunity. In this review, we will describe the strategies used by KSHV at distinct stages of the viral life-cycle to control the ubiquitin system and promote oncogenesis and viral persistence. PMID:17688306

  9. STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

    PubMed Central

    Li, Xiaofan; Barbachano-Guerrero, Arturo

    2015-01-01

    ABSTRACT Lytic activation of Kaposi's sarcoma-associated herpesvirus (KSHV) from latency is a critical contributor to pathogenesis and progression of KSHV-mediated disease. Development of targeted treatment strategies and improvement of lytic-phase-directed oncolytic therapies, therefore, hinge on gaining a better understanding of latency-to-lytic-phase transition. A key observation in that regard, also common to other herpesviruses, is the partial permissiveness of latently infected cells to lytic-cycle-inducing agents. Here, we address the molecular basis of why only some KSHV-infected cells respond to lytic stimuli. Since cellular signal transducer and activator of transcription 3 (STAT3) is constitutively active in KSHV-associated cancers, KSHV activates STAT3, and STAT3 has been found to regulate lytic activation of Epstein-Barr virus (EBV)-infected cells, we asked if STAT3 contributes similarly to the life cycle of KSHV. We found that high levels of STAT3 correlate with the refractory state at the single-cell level under conditions of both spontaneous and induced lytic activation; importantly, STAT3 also regulates lytic susceptibility. Further, knockdown of STAT3 suppresses the cellular transcriptional corepressor Krüppel-associated box domain-associated protein 1 (KAP1; also known as TRIM28), and suppression of KAP1 activates lytic genes, including the viral lytic switch RTA, thereby linking STAT3 via KAP1 to regulation of the balance between lytic and latent cells. These findings, taken together with those from EBV-infected and, more recently, herpes simplex virus 1 (HSV-1)-infected cells, cement the contribution of host STAT3 to persistence of herpesviruses and simultaneously reveal an important lead to devise strategies to improve lytic-phase-directed therapies for herpesviruses. IMPORTANCE Lytic activation of the cancer-causing Kaposi's sarcoma-associated herpesvirus (KSHV) is vital to its life cycle and causation of disease. Like other herpesviruses

  10. A negative element involved in Kaposi's sarcoma-associated herpesvirus-encoded ORF11 gene expression

    SciTech Connect

    Chen, Lei

    2009-01-01

    The ORF11 of the Kaposi's sarcoma-associated herpesvirus (KSHV) is a lytic viral gene with delayed-early expression kinetics. How the ORF11 gene expression is regulated in the KSHV lytic cascade is largely unknown. Here we report that the deletion of the KSHV viral IL-6 gene from the viral genome leads to deregulated ORF11 gene expression. The KSHV-encoded viral IL-6 protein was found not to be essentially involved in the regulation of ORF11, suggesting a potential transcriptional cis-regulation. A negative element was identified downstream of the ORF11 gene, which suppresses the ORF11 basal promoter activity in a position-independent manner.

  11. Instigation of Notch signaling in the pathogenesis of Kaposi's sarcoma-associated herpesvirus and other human tumor viruses.

    PubMed

    Cheng, Fang; Pekkonen, Pirita; Ojala, Päivi M

    2012-10-01

    The Notch pathway is a highly conserved signaling circuit with a critical role in cell-fate determination and tumor initiation. Notch is reported to regulate various key events in tumor progression, such as angiogenesis, maintenance of cancer stem cells, resistance to therapeutic agents and metastasis. This review describes the intimate interplay of human tumor viruses with the Notch signaling pathway. Special attention is paid to Kaposi's sarcoma-associated herpesvirus, the etiological agent of Kaposi's sarcoma and rare lymphoproliferative disorders. The past decade of active research has led to significant advances in understanding how Kaposi's sarcoma-associated herpesvirus exploits the Notch pathway to regulate its replication phase and to modulate the host cellular microenvironment to make it more favorable for viral persistence and spreading. PMID:23030424

  12. Kaposi's Sarcoma-Associated Herpesvirus Induces Rapid Release of Angiopoietin-2 from Endothelial Cells

    PubMed Central

    Zhou, Fu-Chun; Nithianantham, Stanley; Chandran, Bala; Yu, Xiao-Lan; Weinberg, Aaron

    2013-01-01

    Kaposi sarcoma-associated herpesvirus (KSHV) stimulates proliferation, angiogenesis, and inflammation to promote Kaposi sarcoma (KS) tumor growth, which involves various growth factors and cytokines. Previously, we found that KSHV infection of human umbilical vein endothelial cells (HUVECs) induces a transcriptional induction of the proangiogenic and proinflammatory cytokine angiopoietin-2 (Ang-2). Here, we report that KSHV induces rapid release of Ang-2 that is presynthesized and stored in the Weibel-Palade bodies (WPB) of endothelial cells upon binding to its integrin receptors. Blocking viral binding to integrins inhibits Ang-2 release. KSHV binding activates the integrin tyrosine kinase receptor signaling pathways, leading to tyrosine phosphorylation of focal adhesion kinase (FAK), the tyrosine kinase Src, and the Calα2 subunit of the l-type calcium channel to trigger rapid calcium (Ca2+) influx. Pretreatment of endothelial cells with specific inhibitors of protein tyrosine kinases inhibits KSHV-induced Ca2+ influx and Ang-2 release. Inhibition of Ca2+ mobilization with calcium channel blockers also inhibits Ang-2 release. Thus, the interaction between KSHV and its integrin receptors plays a key role in regulating rapid Ang-2 release from endothelial cells. This finding highlights a novel mechanism of viral induction of angiogenesis and inflammation, which might play important roles in the early event of KS tumor development. PMID:23536671

  13. Detection of Kaposi's Sarcoma Associated Herpesvirus Nucleic Acids Using a Smartphone Accessory

    PubMed Central

    Mancuso, Matthew; Cesarman, Ethel; Erickson, David

    2014-01-01

    Kaposi's sarcoma (KS) is an infectious cancer occurring in immune-compromised patients, caused by Kaposi's sarcoma associated herpesvirus (KSHV). Our vision is to simplify the process of KS diagnosis through the creation of a smartphone based point-of-care system capable of yielding an actionable diagnostic readout starting from a raw biopsy sample. In this work we develop the sensing mechanism for the overall system, a smartphone accessory capable of detecting KSHV nucleic acids. The accessory reads out microfluidic chips filled with a colorimetric nanoparticle assay targeted at KSHV. We calculate that our final device can read out gold nanoparticle solutions with an accuracy of .05 OD, and we demonstrate that it can detect DNA sequences from KSHV down to 1 nM. We believe that through integration with our previously developed components, a smartphone based system like the one studied here can provide accurate detection information, as well as a simple platform for field based clinical diagnosis and research. PMID:25117534

  14. Kaposi's sarcoma-associated herpesvirus ORF6 gene is essential in viral lytic replication.

    PubMed

    Peng, Can; Chen, Jungang; Tang, Wei; Liu, Chunlan; Chen, Xulin

    2014-01-01

    Kaposi's sarcoma associated herpesvirus (KSHV) is associated with Kaposis's sarcoma (KS), primary effusion lymphoma and multicentric Castleman's disease. KSHV encodes at least 8 open reading frames (ORFs) that play important roles in its lytic DNA replication. Among which, ORF6 of KSHV encodes an ssDNA binding protein that has been proved to participate in origin-dependent DNA replication in transient assays. To define further the function of ORF6 in the virus life cycle, we constructed a recombinant virus genome with a large deletion within the ORF6 locus by using a bacterial artificial chromosome (BAC) system. Stable 293T cells carrying the BAC36 (wild type) and BACΔ6 genomes were generated. When monolayers of 293T-BAC36 and 293T-BACΔ6 cells were induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate, infectious virus was detected from the 293T-BAC36 cell supernatants only and not from the 293T- BACΔ6 cell supernatants. DNA synthesis was defective in 293T-BACΔ6 cells. Expression of ORF6 in trans in BACΔ6-containing cells was able to rescue both defects. Our results provide genetic evidence that ORF6 is essential for KSHV lytic replication. The stable 293T cells carrying the BAC36 and BACΔ6 genomes could be used as tools to investigate the detailed functions of ORF6 in the lytic replication of KSHV. PMID:24911362

  15. MicroRNAs encoded by Kaposi's sarcoma-associated herpesvirus regulate viral life cycle.

    PubMed

    Lu, Chih-Chung; Li, Zhonghan; Chu, Chia-Ying; Feng, Jiaying; Feng, Jun; Sun, Ren; Rana, Tariq M

    2010-10-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with Kaposi's sarcoma and lymphomas. The pathogenesis of KSHV depends on the balance between two phases of the viral cycle: latency and lytic replication. In this study, we report that KSHV-encoded microRNAs (miRNAs) function as regulators by maintaining viral latency and inhibiting viral lytic replication. MiRNAs are short, noncoding, small RNAs that post-transcriptionally regulate the expression of messenger RNAs. Of the 12 viral miRNAs expressed in latent KSHV-infected cells, we observed that expression of miR-K3 can suppress both viral lytic replication and gene expression. Further experiments indicate that miR-K3 can regulate viral latency by targeting nuclear factor I/B. Nuclear factor I/B can activate the promoter of the viral immediate-early transactivator replication and transcription activator (RTA), and depletion of nuclear factor I/B by short hairpin RNAs had similar effects on the viral life cycle to those of miR-K3. Our results suggest a role for KSHV miRNAs in regulating the viral life cycle. PMID:20847741

  16. Immunological and inflammatory features of Kaposi's sarcoma and other Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8-associated neoplasias.

    PubMed

    Riva, Giovanni; Barozzi, Patrizia; Torelli, Giuseppe; Luppi, Mario

    2010-01-01

    During the last 15 years, virologic and immunologic studies have provided a series of valuable clues on the modalities of gamma-herpesvirus-induced oncogenesis, which do not only consist of the direct subversion of intracellular signaling pathways, leading to a frank neoplastic molecular network in the infected cell, but also rely on viral manipulations of the cellular and cytokine microenvironment, especially in conditions of immunodeficiency in the host. At the virus-host interface, something iniquitous, strikingly favoring the aggressive expansion of human herpesvirus 8-infected lympho-endothelial clones, known as Kaposi's sarcoma, often occurs in different types of immunocompromised patients, able to establish a deleterious "pro-Kaposi's sarcoma" neo-angiogenic inflammatory network. However, these patients may control - or even resolve - the neoplastic burden as soon as an immunologic reassessment restores functional anti-Kaposi's sarcoma immune responses and reconstitutes a proper inflammatory environment. Indeed, the occurrence of iatrogenic Kaposi's sarcoma remissions, after the reduction or switch of immunosuppressive regimens, strongly suggests that the reset of immunologic constraints characterizing the Kaposi's sarcoma onco-pathogenic system may be sufficient to inhibit human herpesvirus 8-positive lympho-endothelial proliferations. Accordingly, immunologic reports all underline the pivotal protective role of anti-human herpesvirus 8 memory T-cells (harmonically, both CD8+ and CD4+ subsets), thus definitely implying a general requirement for an effective, antiviral immuno-inflammatory environment, based on correct and productive interactions between different compartments of dendritic, myeloid, and specific T-cells, in order to achieve and maintain optimal control on human herpesvirus 8-associated antigenic stimulations and Kaposi's sarcoma disease. In this review, we recapitulate some remarkable features about the outstanding immunologic issue raised by

  17. Identification and characterization of Kaposi's sarcoma-associated herpesvirus open reading frame 11 promotor activation

    SciTech Connect

    Chen, Lei

    2008-01-01

    Open reading frame 11 (ORF11) of Kaposi's sarcoma-associated herpesvirus belongs to a herpesviral homologous protein family shared by some members of the gamma- herpesvirus subfamily. Little is known about this ORF11 homologous protein family. We have characterized an unknown open reading frame, ORF11, located adjacent and in the opposite orientation to a well-characterized viral IL-6 gene. Northern blot analysis reveals that ORF11 is expressed during the KSHV lytic cycle with delayed-early transcription kinetics. We have determined the 5{prime} and 3{prime} untranslated region of the unspliced ORF11 transcript and identified both the transcription start site and the transcription termination site. Core promoter region, representing ORF11 promoter activity, was mapped to a 159nt fragment 5{prime} most proximal to the transcription start site. A functional TATA box was identified in the core promoter region. Interestingly, we found that ORF11 transcriptional activation is not responsive to Rta, the KSHV lytic switch protein. We also discovered that part of the ORF11 promoter region, the 209nt fragment upstream of the transcription start site, was repressed by phorbol esters. Our data help to understand transcription regulation of ORF11 and to elucidate roles of ORF11 in KSHV pathogenesis and life cycle.

  18. Next-Generation Sequencing in the Understanding of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Biology.

    PubMed

    Strahan, Roxanne; Uppal, Timsy; Verma, Subhash C

    2016-01-01

    Non-Sanger-based novel nucleic acid sequencing techniques, referred to as Next-Generation Sequencing (NGS), provide a rapid, reliable, high-throughput, and massively parallel sequencing methodology that has improved our understanding of human cancers and cancer-related viruses. NGS has become a quintessential research tool for more effective characterization of complex viral and host genomes through its ever-expanding repertoire, which consists of whole-genome sequencing, whole-transcriptome sequencing, and whole-epigenome sequencing. These new NGS platforms provide a comprehensive and systematic genome-wide analysis of genomic sequences and a full transcriptional profile at a single nucleotide resolution. When combined, these techniques help unlock the function of novel genes and the related pathways that contribute to the overall viral pathogenesis. Ongoing research in the field of virology endeavors to identify the role of various underlying mechanisms that control the regulation of the herpesvirus biphasic lifecycle in order to discover potential therapeutic targets and treatment strategies. In this review, we have complied the most recent findings about the application of NGS in Kaposi's sarcoma-associated herpesvirus (KSHV) biology, including identification of novel genomic features and whole-genome KSHV diversities, global gene regulatory network profiling for intricate transcriptome analyses, and surveying of epigenetic marks (DNA methylation, modified histones, and chromatin remodelers) during de novo, latent, and productive KSHV infections. PMID:27043613

  19. A novel mechanism inducing genome instability in Kaposi's sarcoma-associated herpesvirus infected cells.

    PubMed

    Jackson, Brian R; Noerenberg, Marko; Whitehouse, Adrian

    2014-05-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with multiple AIDS-related malignancies. Like other herpesviruses, KSHV has a biphasic life cycle and both the lytic and latent phases are required for tumorigenesis. Evidence suggests that KSHV lytic replication can cause genome instability in KSHV-infected cells, although no mechanism has thus far been described. A surprising link has recently been suggested between mRNA export, genome instability and cancer development. Notably, aberrations in the cellular transcription and export complex (hTREX) proteins have been identified in high-grade tumours and these defects contribute to genome instability. We have previously shown that the lytically expressed KSHV ORF57 protein interacts with the complete hTREX complex; therefore, we investigated the possible intriguing link between ORF57, hTREX and KSHV-induced genome instability. Herein, we show that lytically active KSHV infected cells induce a DNA damage response and, importantly, we demonstrate directly that this is due to DNA strand breaks. Furthermore, we show that sequestration of the hTREX complex by the KSHV ORF57 protein leads to this double strand break response and significant DNA damage. Moreover, we describe a novel mechanism showing that the genetic instability observed is a consequence of R-loop formation. Importantly, the link between hTREX sequestration and DNA damage may be a common feature in herpesvirus infection, as a similar phenotype was observed with the herpes simplex virus 1 (HSV-1) ICP27 protein. Our data provide a model of R-loop induced DNA damage in KSHV infected cells and describes a novel system for studying genome instability caused by aberrant hTREX. PMID:24788796

  20. Modulation of Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Function by Hypoxia-Upregulated Protein 1

    PubMed Central

    Giffin, Louise; Yan, Feng; Major, M. Ben

    2014-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8) is linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV expresses several proteins that modulate host cell signaling pathways. One of these proteins is viral interleukin-6 (vIL-6), which is a homolog of human IL-6 (hIL-6). vIL-6 is able to prevent apoptosis and promote proinflammatory signaling, angiogenesis, and cell proliferation. Although it can be secreted, vIL-6 is mainly an intracellular protein that is retained in the endoplasmic reticulum (ER). We performed affinity purification and mass spectrometry to identify novel vIL-6 binding partners and found that a cellular ER chaperone, hypoxia-upregulated protein 1 (HYOU1), interacts with vIL-6. Immunohistochemical staining reveals that both PEL and KS tumor tissues express significant amounts of HYOU1. We also show that HYOU1 increases endogenous vIL-6 protein levels and that HYOU1 facilitates vIL-6-induced JAK/STAT signaling, migration, and survival in endothelial cells. Furthermore, our data suggest that HYOU1 also modulates vIL-6's ability to induce CCL2, a chemokine involved in cell migration. Finally, we investigated the impact of HYOU1 on cellular hIL-6 signaling. Collectively, our data indicate that HYOU1 is important for vIL-6 function and may play a role in the pathogenesis of KSHV-associated cancers. IMPORTANCE KSHV vIL-6 is detectable in all KSHV-associated malignancies and promotes tumorigenesis and inflammation. We identified a cellular protein, called hypoxia-upregulated protein 1 (HYOU1), that interacts with KSHV vIL-6 and is present in KSHV-infected tumors. Our data suggest that HYOU1 facilitates the vIL-6-induced signaling, migration, and survival of endothelial cells. PMID:24920810

  1. Involvement of SSRP1 in Latent Replication of Kaposi's Sarcoma-Associated Herpesvirus

    PubMed Central

    Hu, Jianhong; Liu, Eugene; Renne, Rolf

    2009-01-01

    Kaposi's sarcoma-associated herpesvirus (also named human herpesvirus 8) is a γ-herpesvirus that undergoes both lytic and latent infection. During latent infection, two viral elements are required: latency-associated nuclear antigen (LANA), which functions as an origin binding protein, and the latent origin, which resides within the terminal repeats (TRs) of the viral genome. Previously, we identified two cis-elements within the TRs which are required for latent DNA replication: two LANA binding sites (LBS1 and LBS2 [LBS1/2]) and a GC-rich replication element (RE) upstream of LBS1/2. To further characterize the RE, we constructed a 71-bp minimal replicon (MR) and performed a detailed mutational analysis. Our data indicate that the first 8 nucleotides within the RE are critical for replication. Moreover, both the position and the distance between the RE and LBS1/2 can affect origin replication activity, suggesting that the RE may function as a loading pad for cellular proteins involved in replication. Using biotinylated DNA fragments of wild-type or mutant MRs as probes, we identified 30 proteins that preferentially bind to the origin. Among these proteins, structure-specific recognition protein 1 (SSRP1), a subunit of the FACT complex, and telomeric repeat binding factor 2 (TRF2) formed complexes with LANA at the MR region. Furthermore, the small interfering RNA-based knockdown of SSRP1, but not the dominant-negative-based knockdown of TRF2, significantly decreased the efficiency of LANA-dependent DNA replication. These results indicate that SSRP1 is a novel cellular protein involved in LANA-dependent DNA replication. PMID:19710137

  2. Efficient lytic induction of kaposi's sarcoma-associated herpesvirus (KSHV) by the anthracyclines

    PubMed Central

    Kim, Hyeongki; Choi, Miri; Lee, So-Young; Kim, Chonsaeng; Lee, Sang Jun; Song, Moon Jung; Kang, Hyojeung; Back, Sung Hoon; Han, Sang-Bae; Cho, Sungchan

    2014-01-01

    Lytic induction of latent Kaposi's sarcoma-associated herpesvirus (KSHV) has been considered as a therapeutic option for efficient treatment of several KSHV-associated malignancies. Here, we developed a robust high-throughput screening system that allows an easy and quantitative measurement of lytic induction of latent KSHV and discovered three anthracyclines as potent inducers from screen of FDA-approved drugs. Lytic induction of latent KSHV by three compounds was verified by the significant induction of lytic genes and subsequent production of infectious KSHV. Importantly, lytic induction by three compounds was much more efficient than that by sodium butyrate, a well-characterized inducer of KSHV lytic cycle. Mechanistically, the anthracyclines caused lytic induction of KSHV through apoptosis induced by their DNA intercalation rather than topoisomerase II inhibition. Consequently, our results clearly demonstrated a role of anthracyclines as effective lytic inducers of KSHV and also provided a molecular basis of their use for efficient treatment of diseases associated with KSHV infection. PMID:25237786

  3. Efficient lytic induction of Kaposi's sarcoma-associated herpesvirus (KSHV) by the anthracyclines.

    PubMed

    Kang, Hyunju; Song, Jaehyung; Choi, Kwangman; Kim, Hyeongki; Choi, Miri; Lee, So-Young; Kim, Chonsaeng; Lee, Sang Jun; Song, Moon Jung; Kang, Hyojeung; Back, Sung Hoon; Han, Sang-Bae; Cho, Sungchan

    2014-09-30

    Lytic induction of latent Kaposi's sarcoma-associated herpesvirus (KSHV) has been considered as a therapeutic option for efficient treatment of several KSHV-associated malignancies. Here, we developed a robust high-throughput screening system that allows an easy and quantitative measurement of lytic induction of latent KSHV and discovered three anthracyclines as potent inducers from screen of FDA-approved drugs. Lytic induction of latent KSHV by three compounds was verified by the significant induction of lytic genes and subsequent production of infectious KSHV. Importantly, lytic induction by three compounds was much more efficient than that by sodium butyrate, a well-characterized inducer of KSHV lytic cycle. Mechanistically, the anthracyclines caused lytic induction of KSHV through apoptosis induced by their DNA intercalation rather than topoisomerase II inhibition. Consequently, our results clearly demonstrated a role of anthracyclines as effective lytic inducers of KSHV and also provided a molecular basis of their use for efficient treatment of diseases associated with KSHV infection. PMID:25237786

  4. Role of heme oxygenase-1 in the pathogenesis and tumorigenicity of Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Dai, Lu; Qiao, Jing; Nguyen, David; Struckhoff, Amanda P; Doyle, Lisa; Bonstaff, Karlie; Del Valle, Luis; Parsons, Chris; Toole, Bryan P; Renne, Rolf; Qin, Zhiqiang

    2016-03-01

    Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation and lack effective therapeutic options. Heme oxygenase-1 (HO-1) has been reported as an important regulator of endothelial cell cycle control, proliferation and angiogenesis. HO-1 has also been found to be highly expressed in KSHV-infected endothelial cells and oral AIDS-KS lesions. We previously demonstrate that the multifunctional glycoprotein CD147 is required for KSHV/LANA-induced endothelial cell invasiveness. During the identification of CD147 controlled downstream genes by microarray analysis, we found that the expression of HO-1 is significantly elevated in both CD147-overexpressing and KSHV-infected HUVEC cells when compared to control cells. In the current study, we further identify the regulation of HO-1 expression and mediated cellular functions by both CD147 and KSHV-encoded LANA proteins. Targeting HO-1 by either RNAi or the chemical inhibitor, SnPP, effectively induces cell death of KSHV-infected endothelial cells (the major cellular components of KS) through DNA damage and necrosis process. By using a KS-like nude mouse model, we found that SnPP treatment significantly suppressed KSHV-induced tumorigenesis in vivo. Taken together, our data demonstrate the important role of HO-1 in the pathogenesis and tumorigenesis of KSHV-infected endothelial cells, the underlying regulatory mechanisms for HO-1 expression and targeting HO-1 may represent a promising therapeutic strategy against KSHV-related malignancies. PMID:26859574

  5. Regulation of viral and cellular gene expression by Kaposi's sarcoma-associated herpesvirus polyadenylated nuclear RNA.

    PubMed

    Rossetto, Cyprian C; Tarrant-Elorza, Margaret; Verma, Subhash; Purushothaman, Pravinkumar; Pari, Gregory S

    2013-05-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma and body cavity lymphoma. In cell culture, KSHV results in a latent infection, and lytic reactivation is usually induced with the expression of K-Rta or by treatment with phorbol 12-myristate 13-acetate (TPA) and/or n-butyrate. Lytic infection is marked by the activation of the entire viral genomic transcription cascade and the production of infectious virus. KSHV-infected cells express a highly abundant, long, noncoding transcript referred to as polyadenylated nuclear RNA (PAN RNA). PAN RNA interacts with specific demethylases and physically binds to the KSHV genome to mediate activation of viral gene expression. A recombinant BACmid lacking the PAN RNA locus fails to express K-Rta and does not produce virus. We now show that the lack of PAN RNA expression results in the failure of the initiation of the entire KSHV transcription program. In addition to previous findings of an interaction with demethylases, we show that PAN RNA binds to protein components of Polycomb repression complex 2 (PRC2). RNA-Seq analysis using cell lines that express PAN RNA shows that transcription involving the expression of proteins involved in cell cycle, immune response, and inflammation is dysregulated. Expression of PAN RNA in various cell types results in an enhanced growth phenotype, higher cell densities, and increased survival compared to control cells. Also, PAN RNA expression mediates a decrease in the production of inflammatory cytokines. These data support a role for PAN RNA as a major global regulator of viral and cellular gene expression. PMID:23468496

  6. Seroprevalence of Kaposi's sarcoma-associated herpesvirus among men who have sex with men in Japan.

    PubMed

    Katano, Harutaka; Yokomaku, Yoshiyuki; Fukumoto, Hitomi; Kanno, Takayuki; Nakayama, Tomoyuki; Shingae, Akitomo; Sugiura, Wataru; Ichikawa, Seiichi; Yasuoka, Akira

    2013-06-01

    Kaposi's sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi's sarcoma, causes malignancies frequently in patients with acquired immunodeficiency syndrome. In the United States and Europe, KSHV infection is common among men who have sex with men. However, the seroprevalence of KSHV among men who have sex with men in Japan is unknown. In the present study, the seroprevalence of KSHV was investigated among 230 men who have sex with men and 400 age- and area of residence-matched men (controls) using a mixed-antigen (KSHV-encoded K8.1, open reading frame 59, 65, and 73 proteins) enzyme-linked immunosorbent assay and an immunofluorescence assay. Among the Japanese men who have sex with men, serological assays revealed that 27 (11.7%) were seropositive for KSHV; 20 (5%) of the men in the control group were also KSHV seropositive. The seroprevalence of KSHV among men who have sex with men was significantly higher than in the control group (odds ratio = 2.52, 95% confidence intervals = 1.38-4.62, P = 0.0019, Chi-square test). Infection with the human immunodeficiency virus, Treponema pallidum, or hepatitis B and C virus did not correlate with KSHV infection. Furthermore, the association of KSHV seropositivity with specific sexual activities was not statistically significant. In conclusion, a higher KSHV seroprevalence was found among Japanese men who have sex with men than among the controls, suggesting that the circulation of KSHV infection is more efficient among men who have sex with men in Japan than among men who do not engage in such sexual activities. PMID:23588730

  7. An Alternative Kaposi's Sarcoma-Associated Herpesvirus Replication Program Triggered by Host Cell Apoptosis

    PubMed Central

    Prasad, Alka; Lu, Michael; Lukac, David M.

    2012-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to several neoplastic diseases: Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV replicates actively, via a controlled gene expression program, but can also remain latent. It had been thought that the transition from latent to lytic replication was controlled exclusively by the replication and transcription activator protein RTA (open reading frame 50 [ORF50] gene product). A dominant-negative (DN) ORF50 mutant, ORF50ΔSTAD, blocks gene expression and replication. We produced a PEL cell line derivative containing both latent KSHV genomes and an inducible ORF50ΔSTAD. We unexpectedly found that induction of apoptosis triggered high-level viral replication, even when DN ORF50ΔSTAD was present, suggesting that apoptosis triggers KSHV replication through a distinct RTA-independent pathway. We verified that apoptosis triggers KSHV replication independent of RTA using ORF50 small interfering RNA (siRNA) and also showed that caspase activity is required to trigger KSHV replication. We showed that when apoptosis triggers KSHV replication, the kinetics of late gene expression is accelerated by 12 to 24 h and that virus produced following apoptosis has reduced infectivity. KSHV therefore appears to replicate via two distinct pathways, a conventional pathway requiring RTA, with slower replication kinetics, producing virus with higher infectivity, and an alternative apoptosis-triggered pathway that does not require RTA, has faster replication kinetics, and produces virus with lower infectivity. The existence of a distinct apoptosis-triggered, accelerated replication pathway may have evolutionary advantages for the virus and clinical significance for the treatment of KSHV-associated neoplasms. It also provides further evidence that KSHV can sense and react to its environment. PMID:22345480

  8. Role of heme oxygenase-1 in the pathogenesis and tumorigenicity of Kaposi's sarcoma-associated herpesvirus

    PubMed Central

    Nguyen, David; Struckhoff, Amanda P.; Doyle, Lisa; Bonstaff, Karlie; Del Valle, Luis; Parsons, Chris; Toole, Bryan P.; Renne, Rolf; Qin, Zhiqiang

    2016-01-01

    Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several malignancies, including Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation and lack effective therapeutic options. Heme oxygenase-1 (HO-1) has been reported as an important regulator of endothelial cell cycle control, proliferation and angiogenesis. HO-1 has also been found to be highly expressed in KSHV-infected endothelial cells and oral AIDS-KS lesions. We previously demonstrate that the multifunctional glycoprotein CD147 is required for KSHV/LANA-induced endothelial cell invasiveness. During the identification of CD147 controlled downstream genes by microarray analysis, we found that the expression of HO-1 is significantly elevated in both CD147-overexpressing and KSHV-infected HUVEC cells when compared to control cells. In the current study, we further identify the regulation of HO-1 expression and mediated cellular functions by both CD147 and KSHV-encoded LANA proteins. Targeting HO-1 by either RNAi or the chemical inhibitor, SnPP, effectively induces cell death of KSHV-infected endothelial cells (the major cellular components of KS) through DNA damage and necrosis process. By using a KS-like nude mouse model, we found that SnPP treatment significantly suppressed KSHV-induced tumorigenesis in vivo. Taken together, our data demonstrate the important role of HO-1 in the pathogenesis and tumorigenesis of KSHV-infected endothelial cells, the underlying regulatory mechanisms for HO-1 expression and targeting HO-1 may represent a promising therapeutic strategy against KSHV-related malignancies. PMID:26859574

  9. Disintegrin-like domain of glycoprotein B regulates Kaposi's sarcoma-associated herpesvirus infection of cells.

    PubMed

    Walker, Lia R; Hussein, Hosni A M; Akula, Shaw M

    2014-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) glycoprotein B (gB) is a lytic structural protein expressed on the envelope of mature virions and on the membrane of cells supporting lytic infection. In addition to this viral glycoprotein's interaction with integrins via its RGD (Arg-Gly-Asp) motif, KSHV gB possesses a disintegrin-like domain (DLD), which binds integrins as well. Prior to this study, there has been minimal research involving the less common integrin-binding motif, DLD, of gB as it pertains to herpesvirus infection. By using phage display peptide library screening and molecular biology techniques, the DLD of KSHV gB was shown to interact specifically with non-RGD binding α9β1 integrins. Similarly, monitoring wild-type infection confirmed α9β1:DLD interactions to be critical to successful KSHV infection of human foreskin fibroblast (HFF) cells and human dermal microvascular endothelial cells (HMVEC-d) compared with 293 cells. To further demonstrate the importance of the DLD of gB in KSHV infection, two recombinant virus constructs were generated using a bacterial artificial chromosome (BAC) system harbouring the KSHV genome (BAC36): BAC36ΔD-KSHV (lacking a functionally intact DLD of gB and containing an introduced tetracycline cassette) and BAC36.T-KSHV (containing an intact DLD sequence and an introduced tetracycline cassette). Accordingly, BAC36ΔD-KSHV presented significantly lower infection rates in HFF and HMVEC-d cells compared with the comparable infection rates achieved by wild-type BAC36-KSHV and BAC36.T-KSHV. Thus, the present report has delineated a critical role for the DLD of gB in KSHV infection, which may lead to a broader knowledge regarding the sophisticated mechanisms utilized by virus-encoded structural proteins in KSHV entry and infection. PMID:24814923

  10. Kaposi's Sarcoma-Associated Herpesvirus Genome Replication, Partitioning, and Maintenance in Latency.

    PubMed

    Ohsaki, Eriko; Ueda, Keiji

    2012-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is thought to be an oncogenic member of the γ-herpesvirus subfamily. The virus usually establishes latency upon infection as a default infection pattern. The viral genome replicates according to the host cell cycle by recruiting the host cellular replication machinery. Among the latently expressing viral factors, LANA plays pivotal roles in viral genome replication, partitioning, and maintenance. LANA binds with two LANA-binding sites (LBS1/2) within a terminal repeat (TR) sequence and is indispensable for viral genome replication in latency. The nuclear matrix region seems to be important as a replication site, since LANA as well as cellular replication factors accumulate there and recruit the viral replication origin in latency (ori-P) by its binding activity to LBS. KSHV ori-P consists of LBS followed by a 32-bp GC-rich segment (32GC). Although it has been reported that LANA recruits cellular pre-replication complexes (pre-RC) such as origin recognition complexes (ORCs) to the ori-P through its interaction with ORCs, this mechanism does not account completely for the requirement of the 32GC. On the other hand, there are few reports about the partitioning and maintenance of the viral genome. LANA interacts with many kinds of chromosomal proteins, including Brd2/RING3, core histones, such as H2A/H2B and histone H1, and so on. The detailed molecular mechanisms by which LANA enables KSHV genome partitioning and maintenance still remain obscure. By integrating the findings reported thus far on KSHV genome replication, partitioning, and maintenance in latency, we will summarize what we know now, discuss what questions remain to be answered, and determine what needs to be done next to understand the mechanisms underlying viral replication, partitioning, and maintenance strategy. PMID:22291692

  11. Distinct Roles of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interferon Regulatory Factors in Inflammatory Response and Cancer

    PubMed Central

    Baresova, Petra; Pitha, Paula M.

    2013-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). Similar to other herpesviruses, KSHV has two life cycles, latency and lytic replication. In latency, the KSHV genome persists as a circular episome in the nucleus of the host cell and only a few viral genes are expressed. In this review, we focus on oncogenic, antiapoptotic, and immunomodulating properties of KSHV-encoded homologues of cellular interferon regulatory factors (IRFs)—viral IRF1 (vIRF1) to vIRF4—and their possible role in the KSHV-mediated antiviral response, apoptosis, and oncogenicity. PMID:23785197

  12. Intracellular-activated Notch1 can reactivate Kaposi's sarcoma-associated herpesvirus from latency

    SciTech Connect

    Lan, Ke; Murakami, Masanao; Choudhuri, Tathagata; Kuppers, Daniel A.; Robertson, Erle S. . E-mail: erle@mail.med.upenn.edu

    2006-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a predominantly latent infection in the infected host. Importantly, during latency, only a small number of viral encoded genes are expressed. This viral gene expression pattern contributes to the establishment of long-term infection as well as the ability of the virus to evade the immune system. Previous studies have been shown that the replication and transcription activator (RTA) encoded by ORF50 activates it downstream genes and initiates viral lytic reactivation through functional interaction with RBP-J{kappa}, the major downstream effector of the Notch signaling pathway. This indicates that RTA can usurp the conserved Notch signaling pathway and mimic the activities of intracellular Notch1 to modulate gene expression. In this report, we show that the activated intracellular domain of Notch1 (ICN) is aberrantly accumulated in KSHV latently infected pleural effusion lymphoma (PEL) cells. ICN activated the RTA promoter in a dose-dependent manner, and forced expression of ICN in latently infected KSHV-positive cells initiated full blown lytic replication with the production of infectious viral progeny. However, latency-associated nuclear antigen (LANA) which is predominantly expressed during latency can specifically down-modulate ICN-mediated transactivation of RTA and so control KSHV for lytic reactivation. These results demonstrate that LANA can inhibit viral lytic replication by antagonizing ICN function and suggest that LANA is a critical component of the regulatory control mechanism for switching between viral latent and lytic replication by directly interacting with effectors of the conserved cellular Notch1 pathway.

  13. Structural proteins of Kaposi's sarcoma-associated herpesvirus antagonize p53-mediated apoptosis.

    PubMed

    Chudasama, P; Konrad, A; Jochmann, R; Lausen, B; Holz, P; Naschberger, E; Neipel, F; Britzen-Laurent, N; Stürzl, M

    2015-01-29

    The tumor suppressor p53 is a central regulatory molecule of apoptosis and is commonly mutated in tumors. Kaposi's sarcoma-associated herpesvirus (KSHV)-related malignancies express wild-type p53. Accordingly, KSHV encodes proteins that counteract the cell death-inducing effects of p53. Here, the effects of all KSHV genes on the p53 signaling pathway were systematically analyzed using the reversely transfected cell microarray technology. With this approach we detected eight KSHV-encoded genes with potent p53 inhibiting activity in addition to the previously described inhibitory effects of KSHV genes ORF50, K10 and K10.5. Interestingly, the three most potent newly identified inhibitors were KSHV structural proteins, namely ORF22 (glycoprotein H), ORF25 (major capsid protein) and ORF64 (tegument protein). Validation of these results with a classical transfection approach showed that these proteins inhibited p53 signaling in a dose-dependent manner and that this effect could be reversed by small interfering RNA-mediated knockdown of the respective viral gene. All three genes inhibited p53-mediated apoptosis in response to Nutlin-3 treatment in non-infected and KSHV-infected cells. Addressing putative mechanisms, we could show that these proteins could also inhibit the transactivation of the promoters of apoptotic mediators of p53 such as BAX and PIG3. Altogether, we demonstrate for the first time that structural proteins of KSHV can counteract p53-induced apoptosis. These proteins are expressed in the late lytic phase of the viral life cycle and are incorporated into the KSHV virion. Accordingly, these genes may inhibit cell death in the productive and in the early entrance phase of KSHV infection. PMID:24469037

  14. Kaposi's Sarcoma-Associated Herpesvirus Encodes a Mimic of Cellular miR-23

    PubMed Central

    Manzano, Mark; Shamulailatpam, Priscilla; Raja, Archana N.

    2013-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) expresses ∼20 viral microRNAs (miRNAs) in latently infected cells. We have previously shown that two of these miRNAs function as mimics of the cellular miRNAs miR-155 and miR-142-3p. Two additional KSHV miRNAs, miR-K3+1 and miR-K3, share perfect and offset 5′ homology with cellular miR-23, respectively. Here, we report a single nucleotide polymorphism that causes miR-K3+1 expression in a subset of KSHV-infected primary effusion lymphoma cell lines as a consequence of altered processing of the primary transcript by the Microprocessor complex. We confirm that miR-K3+1 regulates miR-23 targets, which is expected because these miRNAs share the entire seed region (nucleotides 2 to 8). Surprisingly, we found that miR-K3 also regulates miR-23 targets, despite offset seed sequences. In addition, the offset homology of miR-K3 to miR-23 likely allows this viral miRNA to expand its target repertoire beyond the targets of miR-23. Because miR-23 is highly expressed in endothelial cells but expressed at only low levels in B cells, we hypothesize that miR-K3 may function to introduce miR-23-like activities into KSHV-infected B cells. Together, our data demonstrate that KSHV has evolved at least three distinct viral miRNAs to tap into evolutionarily conserved cellular miRNA-regulatory networks. Furthermore, our data allow fundamental insights into the generation and functional impact of miRNA 5′ end variation. PMID:23986579

  15. The Kaposi's Sarcoma-associated Herpesvirus-encoded vIRF-3 Inhibits Cellular IRF-5*S⃞

    PubMed Central

    Wies, Effi; Hahn, Alexander S.; Schmidt, Katharina; Viebahn, Cornelia; Rohland, Nadine; Lux, Anja; Schellhorn, Tim; Holzer, Angela; Jung, Jae U.; Neipel, Frank

    2009-01-01

    Kaposi's sarcoma-associated herpesvirus encodes four genes with homology to the family of interferon regulatory factors (IRFs). At least one of these viral IRFs, vIRF-3, is expressed in latently Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphoma (PEL) cells and is essential for the survival of PEL cells. We now report that vIRF-3 interacts with cellular IRF-5, thereby inhibiting binding of IRF-5 to interferon-responsive promoter elements. Consequently, vIRF-3 blocked IRF-5-mediated promoter activation. A central double helix motif present in vIRF-3 was sufficient to abrogate both DNA binding and transcriptional transactivation by IRF-5. Upon DNA damage or activation of the interferon or Toll-like receptor pathways, cytoplasmic IRF-5 has been reported to be translocated to the nucleus, which results in induction of both p53-independent apoptosis and p21-mediated cell cycle arrest. We report here that IRF-5 is present in the nuclei of PEL cells without interferon stimulation. Silencing of vIRF-3 expression in PEL cells was accompanied by increased sensitivity to interferon-mediated apoptosis and up-regulation of IRF-5 target genes. In addition, vIRF-3 antagonized IRF-5-mediated activation of the p21 promoter. The data presented here indicate that vIRF-3 contributes to immune evasion and sustained proliferation of PEL cells by releasing IRF-5 from transcription complexes. PMID:19129183

  16. The Crystal Structure of PF-8, the DNA Polymerase Accessory Subunit from Kaposi's Sarcoma-Associated Herpesvirus

    SciTech Connect

    Baltz, Jennifer L.; Filman, David J.; Ciustea, Mihai; Silverman, Janice Elaine Y.; Lautenschlager, Catherine L.; Coen, Donald M.; Ricciardi, Robert P.; Hogle, James M.

    2009-12-01

    Kaposi's sarcoma-associated herpesvirus is an emerging pathogen whose mechanism of replication is poorly understood. PF-8, the presumed processivity factor of Kaposi's sarcoma-associated herpesvirus DNA polymerase, acts in combination with the catalytic subunit, Pol-8, to synthesize viral DNA. We have solved the crystal structure of residues 1 to 304 of PF-8 at a resolution of 2.8 {angstrom}. This structure reveals that each monomer of PF-8 shares a fold common to processivity factors. Like human cytomegalovirus UL44, PF-8 forms a head-to-head dimer in the form of a C clamp, with its concave face containing a number of basic residues that are predicted to be important for DNA binding. However, there are several differences with related proteins, especially in loops that extend from each monomer into the center of the C clamp and in the loops that connect the two subdomains of each protein, which may be important for determining PF-8's mode of binding to DNA and to Pol-8. Using the crystal structures of PF-8, the herpes simplex virus catalytic subunit, and RB69 bacteriophage DNA polymerase in complex with DNA and initial experiments testing the effects of inhibition of PF-8-stimulated DNA synthesis by peptides derived from Pol-8, we suggest a model for how PF-8 might form a ternary complex with Pol-8 and DNA. The structure and the model suggest interesting similarities and differences in how PF-8 functions relative to structurally similar proteins.

  17. Whole-Genome Sequencing of Kaposi's Sarcoma-Associated Herpesvirus from Zambian Kaposi's Sarcoma Biopsy Specimens Reveals Unique Viral Diversity

    PubMed Central

    Olp, Landon N.; Jeanniard, Adrien; Marimo, Clemence; West, John T.

    2015-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS). Both KSHV and KS are endemic in sub-Saharan Africa where approximately 84% of global KS cases occur. Nevertheless, whole-genome sequencing of KSHV has only been completed using isolates from Western countries—where KS is not endemic. The lack of whole-genome KSHV sequence data from the most clinically important geographical region, sub-Saharan Africa, represents an important gap since it remains unclear whether genomic diversity has a role on KSHV pathogenesis. We hypothesized that distinct KSHV genotypes might be present in sub-Saharan Africa compared to Western countries. Using a KSHV-targeted enrichment protocol followed by Illumina deep-sequencing, we generated and analyzed 16 unique Zambian, KS-derived, KSHV genomes. We enriched KSHV DNA over cellular DNA 1,851 to 18,235-fold. Enrichment provided coverage levels up to 24,740-fold; therefore, supporting highly confident polymorphism analysis. Multiple alignment of the 16 newly sequenced KSHV genomes showed low level variability across the entire central conserved region. This variability resulted in distinct phylogenetic clustering between Zambian KSHV genomic sequences and those derived from Western countries. Importantly, the phylogenetic segregation of Zambian from Western sequences occurred irrespective of inclusion of the highly variable genes K1 and K15. We also show that four genes within the more conserved region of the KSHV genome contained polymorphisms that partially, but not fully, contributed to the unique Zambian KSHV whole-genome phylogenetic structure. Taken together, our data suggest that the whole KSHV genome should be taken into consideration for accurate viral characterization. IMPORTANCE Our results represent the largest number of KSHV whole-genomic sequences published to date and the first time that multiple genomes have been sequenced from sub-Saharan Africa, a geographic area

  18. Broad target cell selectivity of Kaposi's sarcoma-associated herpesvirus glycoprotein-mediated cell fusion and virion entry

    SciTech Connect

    Kaleeba, Johnan A.R.; Berger, Edward A. . E-mail: edward_berger@nih.gov

    2006-10-10

    The molecular mechanism of Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) entry is poorly understood. We tested a broad variety of cell types of diverse species and tissue origin for their ability to function as targets in a quantitative reporter gene assay for KSHV-glycoprotein-mediated cell fusion. Several human, non-human primate, and rabbit cell lines were efficient targets, whereas rodent and all human lymphoblastoid cell lines were weak targets. Parallel findings were obtained with a virion entry assay using a recombinant KSHV encoding a reporter gene. No correlation was observed between target cell activity and surface expression of {alpha}3{beta}1 integrin, a proposed KSHV receptor. We hypothesize that target cell permissiveness in both the cell fusion and virion entry assays reflects the presence of a putative KSHV fusion-entry receptor.

  19. Interaction of Kaposi's Sarcoma-Associated Herpesvirus ORF6 Protein with Single-Stranded DNA

    PubMed Central

    Ozgur, Sezgin

    2014-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) ORF6 is homologous to the herpes simplex virus 1 (HSV-1) ICP8 and Epstein-Barr virus (EBV) BALF2 proteins. Here, we describe its single-stranded DNA (ssDNA) binding properties. Based on previous findings with ICP8 and BALF2, a 60-amino-acid C-terminal deletion mutant of Orf6 was generated, and the protein was purified to explore the function of the C terminus in ssDNA binding. We showed that full-length ORF6 binds cooperatively to M13 ssDNA, disrupting its secondary structure and extending it to a length equivalent to that of duplex M13 DNA. The width of the ORF6-ssDNA filament is 9 nm, and a 7.3-nm repeat can be distinguished along the filament axis. Fluorescence polarization analysis revealed that the wild-type and C-terminal mutant ORF6 proteins bind equally well to short ssDNA substrates, with dissociation constant (Kd) values of 2.2 × 10−7M and 1.5 × 10−7M, respectively. These values were confirmed by electrophoretic mobility shift assay (EMSA) analysis, which also suggested that binding by the full-length protein may involve both monomers and small multimers. While no significant difference in affinities of binding between full-length ORF6 and the C-terminal deletion mutant were observed with the short DNAs, binding of the C-terminal mutant protein to M13 ssDNA showed a clear lack of cooperativity as seen by electron microscopy (EM). Incubation of a duplex DNA containing a long single-stranded tail with double-helical ORF6 protein filaments revealed that the ssDNA segment can be enveloped within the protein filament without disrupting the filament structure. IMPORTANCE This work describes the biochemical characterization of the single-stranded DNA binding protein of KSHV, ORF6, central to viral DNA replication in infected cells. A C-terminal deletion mutant protein was generated to aid in understanding the role of the C terminus in DNA binding. Here we analyze the binding of the wild-type and

  20. Killing of Kaposi's sarcoma-associated herpesvirus-infected fibroblasts during latent infection by activated natural killer cells

    PubMed Central

    Matthews, Nick C; Goodier, Martin R; Robey, Rebecca C; Bower, Mark; Gotch, Frances M

    2011-01-01

    Abstract Kaposi's sarcoma-associated herpesvirus (KSHV) establishes life-long infection by evading clearance by the host immune system. In de novo infection and lytic replication, KSHV escapes cytotoxic T cells and NK cells through downregulation of MHC class-I and ICAM-1 molecules and associated antigens involved in forming and sustaining the immunological synapse. However, the efficacy of such mechanisms in the context of the predominantly latent KSHV infection reported in Kaposi's sarcoma (KS) lesions is unclear. Using primary dermal fibroblasts in a novel in vitro model of chronic latent KSHV infection, we generated target cells with viral loads similar to those in spindle cells extracted from KS lesions. We show that latently KSHV-infected fibroblasts had normal levels of MHC-class I, ICAM-1, HLA-E and NKG2D ligand expression, were resistant to NK-cell natural cytotoxicity and were highly susceptible to killing by cytokine-activated immunocompetent NK cells. KSHV-infected fibroblasts expressed normal levels of IFN-γR1 and responded to exogenous IFN-γ by upregulating MHC class I, ICAM-1 and HLA-E and resisting activated NK-cell killing. These data demonstrate that physiologically relevant levels of latent KSHV infection in primary cells cause limited activation of resting NK cells and confer little specific resistance to control by activated NK cells. PMID:21509779

  1. Kaposi΄s sarcoma-associated herpesvirus ORF36 protein induces chromosome condensation and phosphorylation of histone H3.

    PubMed

    Kim, Sunmi; Cha, Seho; Jang, Jun Hyeong; Kim, Yejin; Seo, Taegun

    2013-01-01

    Kaposi΄s sarcoma-associated herpesvirus (KSHV) has been known as an agent causing Kaposi΄s sarcoma, primary effusion lymphoma, and multicentric Castleman΄s disease. In the lytic phase of the virus cycle, various viral genes are expressed, which causes host cell dysregulation. Among the lytic genes, viral protein kinase (vPK) encoded by ORF36 is a member of serine/threonine protein kinase (CHPK) family, which is involved in viral gene expression, viral DNA replication and encapsidation, and nuclear egress of virions. Recent studies have shown that the BGLF4 protein of Epstein-Barr virus (EBV), a member of the CHPK family, alters the host cell chromatin structure through phosphorylation of its key regulators. The role of KSHV ORF36 in cellular mitotic events, however, is not yet understood. In the current study, we showed that KSHV ORF36 induced chromosome condensation and phosphorylation of histone H3 on Ser 10, which are known as cellular mitosis markers. These processes have occurred in a kinase activity-dependent manner. PMID:23530827

  2. Evasion and subversion of interferon-mediated antiviral immunity by Kaposi's sarcoma-associated herpesvirus: an overview.

    PubMed

    Sathish, Narayanan; Yuan, Yan

    2011-11-01

    Viral invasion of a host cell triggers immune responses with both innate and adaptive components. The innate immune response involving the induction of type I interferons (alpha and beta interferons [IFN-α and -β]) constitutes the first line of antiviral defenses. The type I IFNs signal the transcription of a group of antiviral effector proteins, the IFN-stimulated genes (ISGs), which target distinct viral components and distinct stages of the viral life cycle, aiming to eliminate invading viruses. In the case of Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma (KS), a sudden upsurge of type I IFN-mediated innate antiviral signals is seen immediately following both primary de novo infection and viral lytic reactivation from latency. Potent subversion of these responses thus becomes mandatory for the successful establishment of a primary infection following viral entry as well as for efficient viral assembly and egress. This review gives a concise overview of the induction of the type I IFN signaling pathways in response to viral infection and provides a comprehensive understanding of the antagonizing effects exerted by KSHV on type I IFN pathways wielded at various stages of the viral life cycle. Information garnered from this review should result in a better understanding of KSHV biology essential for the development of immunotherapeutic strategies targeted toward KSHV-associated malignancies. PMID:21775463

  3. Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities

    SciTech Connect

    Togi, Sumihito; Nakasuji, Misa; Muromoto, Ryuta; Ikeda, Osamu; Okabe, Kanako; Kitai, Yuichi; Kon, Shigeyuki; Oritani, Kenji; Matsuda, Tadashi

    2015-07-31

    Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA), which interacts with cellular proteins, plays a central role in modification of viral and/or cellular gene expression. Here, we show that LANA associates with glucocorticoid receptor (GR), and that LANA enhances the transcriptional activity of GR. Co-immunoprecipitation revealed a physical interaction between LANA and GR in transiently transfected 293T and HeLa cells. In human B-lymphoma cells, LANA overexpression enhanced GR activity and cell growth suppression following glucocorticoid stimulation. Furthermore, confocal microscopy showed that activated GR was bound to LANA and accumulated in the nucleus, leading to an increase in binding of activated GR to the glucocorticoid response element of target genes. Taken together, KSHV-derived LANA acts as a transcriptional co-activator of GR. Our results might suggest a careful use of glucocorticoids in the treatment of patients with KSHV-related malignancies such as Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. - Highlights: • KSHV-LANA enhances the transcriptional activity of GR in 293T and HeLa cells. • KSHV-LANA physically associates with GR. • KSHV-LANA enhances GR activation and cell growth suppression in human B-lymphocytes. • KSHV-LANA influences the nuclear retention and DNA binding activity of GR.

  4. Identification, expression, and immunogenicity of Kaposi's sarcoma-associated herpesvirus-encoded small viral capsid antigen.

    PubMed Central

    Lin, S F; Sun, R; Heston, L; Gradoville, L; Shedd, D; Haglund, K; Rigsby, M; Miller, G

    1997-01-01

    We describe a recombinant antigen for use in serologic tests for antibodies to Kaposi's sarcoma (KS)-associated herpesvirus (KSHV). The cDNA for a small viral capsid antigen (sVCA) was identified by immunoscreening of a library prepared from the BC-1 body cavity lymphoma cell line induced into KSHV lytic gene expression by sodium butyrate. The cDNA specified a 170-amino-acid peptide with homology to small viral capsid proteins encoded by the BFRF3 gene of Epstein-Barr virus and the ORF65 gene of herpesvirus saimiri. KSHV sVCA was expressed from a 0.85-kb mRNA present late in lytic KSHV replication in BC-1 cells. This transcript was sensitive to phosphonoacetic acid and phosphonoformic acid, inhibitors of herpesvirus DNA replication. KSHV sVCA expressed in mammalian cells or Escherichia coli or translated in vitro was recognized as an antigen by antisera from KS patients. Rabbit antisera raised to KSHV sVCA expressed in E. coli detected a 22-kDa protein in KSHV-infected human B cells. Overexpressed KSHV sVCA purified from E. coli and used as an antigen in immunoblot screening assay did not cross-react with EBV BFRF3. Antibodies to sVCA were present in 89% of 47 human immunodeficiency virus (HIV)-positive patients with KS, in 20% of 54 HIV-positive patients without KS, but in none of 122 other patients including children born to HIV-seropositive mothers and patients with hemophilia, autoimmune disease, or nasopharyngeal carcinoma. Low-titer antibody was detected in three sera from 28 healthy subjects. Antibodies to recombinant sVCA correlate with KS in high-risk populations. Recombinant sVCA can be used to examine the seroepidemiology of infection with KSHV in the general population. PMID:9060668

  5. Kaposi's Sarcoma-Associated Herpesvirus gH/gL: Glycoprotein Export and Interaction with Cellular Receptors▿

    PubMed Central

    Hahn, Alexander; Birkmann, Alexander; Wies, Effi; Dorer, Dominik; Mahr, Kerstin; Stürzl, Michael; Titgemeyer, Fritz; Neipel, Frank

    2009-01-01

    The attachment, entry, and fusion of Kaposi's sarcoma-associated herpesvirus (KSHV) with target cells are mediated by complex machinery containing, among others, viral glycoprotein H (gH) and its alleged chaperone, gL. We observed that KSHV gH, in contrast to its homologues in several other herpesviruses, is transported to the cytoplasm membrane independently from gL, but not vice versa. Mutational analysis revealed that the N terminus of gH is sufficient for gL interaction. However, the entire extracellular part of gH is required for efficient gL secretion. The soluble ectodomain of gH was sufficient to interact with the surfaces of potential target cells in a heparin-dependent manner, and binding was further enhanced by coexpression of gL. Surface plasmon resonance revealed a remarkably high affinity of gH for glycosaminoglycans. Heparan sulfate (HS) proteoglycans of the syndecan family act as cellular receptors for the gH/gL complex. They promoted KSHV infection, and expression of gH/gL on target cells inhibited subsequent KSHV infection. Whereas gH alone was able to bind to HS, we observed that only the gH/gL complex adhered to heparan sulfate-negative cells at lamellipodium-like structures. PMID:18945775

  6. The Ubiquitin/Proteasome System Mediates Entry and Endosomal Trafficking of Kaposi's Sarcoma-Associated Herpesvirus in Endothelial Cells

    PubMed Central

    He, Meilan; Witt, Colleen; Ye, Fengchun; Gao, Shou-Jiang

    2012-01-01

    Ubiquitination, a post-translational modification, mediates diverse cellular functions including endocytic transport of molecules. Kaposi's sarcoma-associated herpesvirus (KSHV), an enveloped herpesvirus, enters endothelial cells primarily through clathrin-mediated endocytosis. Whether ubiquitination and proteasome activity regulates KSHV entry and endocytosis remains unknown. We showed that inhibition of proteasome activity reduced KSHV entry into endothelial cells and intracellular trafficking to nuclei, thus preventing KSHV infection of the cells. Three-dimensional (3-D) analyses revealed accumulation of KSHV particles in a cytoplasmic compartment identified as EEA1+ endosomal vesicles upon proteasome inhibition. KSHV particles are colocalized with ubiquitin-binding proteins epsin and eps15. Furthermore, ubiquitination mediates internalization of both KSHV and one of its receptors integrin β1. KSHV particles are colocalized with activated forms of the E3 ligase c-Cbl. Knock-down of c-Cbl or inhibition of its phosphorylation reduced viral entry and intracellular trafficking, resulting in decreased KSHV infectivity. These results demonstrate that ubiquitination mediates internalization of both KSHV and one of its cognate receptors integrin β1, and identify c-Cbl as a potential E3 ligase that facilitates this process. PMID:22615563

  7. PA-seq for Global Identification of RNA Polyadenylation Sites of Kaposi's Sarcoma-Associated Herpesvirus Transcripts.

    PubMed

    Ni, Ting; Majerciak, Vladimir; Zheng, Zhi-Ming; Zhu, Jun

    2016-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a human oncovirus linked to the development of several malignancies in immunocompromised patients. Like other herpesviruses, KSHV has a large DNA genome encoding more than 100 distinct gene products. Despite being transcribed and processed by cellular machinery, the structure and organization of KSHV genes in the virus genome differ from what is observed in cellular genes from the human genome. A typical feature of KSHV expression is the production of polycistronic transcripts initiated from different promoters but sharing the same polyadenylation site (pA site). This represents a challenge in determination of the 3' end of individual viral transcripts. Such information is critical for generation of a virus transcriptional map for genetic studies. Here we present PA-seq, a high-throughput method for genome-wide analysis of pA sites of KSHV transcripts in B lymphocytes with latent or lytic KSHV infection. Besides identification of all viral pA sites, PA-seq also provides quantitative information about the levels of viral transcripts associated with each pA site, making it possible to determine the relative expression levels of viral genes at various stages of infection. Due to the indiscriminate nature of PA-seq, the pA sites of host transcripts are also concurrently mapped in the testing samples. Therefore, this technology can simultaneously estimate the expression changes of host genes and RNA polyadenylation upon KSHV infection. © 2016 by John Wiley & Sons, Inc. PMID:27153384

  8. Modulation of Cellular and Viral Gene Expression by the Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus

    PubMed Central

    Renne, Rolf; Barry, Chris; Dittmer, Dirk; Compitello, Nicole; Brown, Patrick O.; Ganem, Don

    2001-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is the likely etiological agent of Kaposi's sarcoma and primary effusion lymphoma. Common to these malignancies is that tumor cells are latently infected with KSHV. Viral gene expression is limited to a few genes, one of which is the latency-associated nuclear antigen (LANA), the product of ORF73. Examination of the primary sequence of LANA reveals some structural features reminiscent of transcription factors, leading us to hypothesize that LANA may regulate viral and cellular transcription during latency. In reporter gene-based transient transfection assays, we found that LANA can have either positive or negative effects on gene expression. While expression of a reporter gene from several synthetic promoters was increased in the presence of LANA, expression from the human immunodeficiency virus (HIV) long terminal repeat (LTR)—and from NF-κB-dependent reporter genes—was reduced by LANA expression. In addition, the promoter of KSHV ORF73 itself is activated up to 5.5-fold by LANA. This autoregulation may be important in tumorigenesis, because two other genes (v-cyclin and v-FLIP) with likely roles in cell growth and survival are also controlled by this element. To identify cellular genes influenced by LANA, we employed cDNA array-based expression profiling. Six known genes (and nine expressed sequence tags) were found to be upregulated in LANA-expressing cell lines. One of these, Staf-50, is known to inhibit expression from the HIV LTR; most of the other known genes are interferon inducible, although the interferon genes themselves were not induced by LANA. These data demonstrate that LANA expression has effects on cellular and viral gene expression. We suggest that, whether direct or indirect in origin, these effects may play important roles in the pathobiology of KSHV infection. PMID:11119614

  9. Exploitation of the Complement System by Oncogenic Kaposi's Sarcoma-Associated Herpesvirus for Cell Survival and Persistent Infection

    PubMed Central

    Lee, Myung-Shin; Jones, Tiffany; Song, Dae-Yong; Jang, Jae-Hyuk; Jung, Jae U.; Gao, Shou-Jiang

    2014-01-01

    During evolution, herpesviruses have developed numerous, and often very ingenious, strategies to counteract efficient host immunity. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) eludes host immunity by undergoing a dormant stage, called latency wherein it expresses a minimal number of viral proteins to evade host immune activation. Here, we show that during latency, KSHV hijacks the complement pathway to promote cell survival. We detected strong deposition of complement membrane attack complex C5b-9 and the complement component C3 activated product C3b on Kaposi's sarcoma spindle tumor cells, and on human endothelial cells latently infected by KSHV, TIME-KSHV and TIVE-LTC, but not on their respective uninfected control cells, TIME and TIVE. We further showed that complement activation in latently KSHV-infected cells was mediated by the alternative complement pathway through down-regulation of cell surface complement regulatory proteins CD55 and CD59. Interestingly, complement activation caused minimal cell death but promoted the survival of latently KSHV-infected cells grown in medium depleted of growth factors. We found that complement activation increased STAT3 tyrosine phosphorylation (Y705) of KSHV-infected cells, which was required for the enhanced cell survival. Furthermore, overexpression of either CD55 or CD59 in latently KSHV-infected cells was sufficient to inhibit complement activation, prevent STAT3 Y705 phosphorylation and abolish the enhanced survival of cells cultured in growth factor-depleted condition. Together, these results demonstrate a novel mechanism by which an oncogenic virus subverts and exploits the host innate immune system to promote viral persistent infection. PMID:25254972

  10. Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

    PubMed Central

    Sun, Qiming; Tsurimoto, Toshiki; Juillard, Franceline; Li, Lin; Li, Shijun; De León Vázquez, Erika; Chen, She; Kaye, Kenneth

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) latently infects tumor cells and persists as a multiple-copy, extrachromosomal, circular episome. To persist, the viral genome must replicate with each cell cycle. The KSHV latency-associated nuclear antigen (LANA) mediates viral DNA replication and persistence, but little is known regarding the underlying mechanisms. We find that LANA recruits replication factor C (RFC), the DNA polymerase clamp [proliferating cell nuclear antigen (PCNA)] loader, to drive DNA replication efficiently. Mutated LANA lacking RFC interaction was deficient for LANA-mediated DNA replication and episome persistence. RFC depletion had a negative impact on LANA’s ability to replicate and maintain viral DNA in cells containing artificial KSHV episomes or in infected cells, leading to loss of virus. LANA substantially increased PCNA loading onto DNA in vitro and recruited RFC and PCNA to KSHV DNA in cells. These findings suggest that PCNA loading is a rate-limiting step in DNA replication that is incompatible with viral survival. LANA enhancement of PCNA loading permits efficient virus replication and persistence, revealing a previously unidentified mechanism for KSHV latency. PMID:25071216

  11. An Important Role for Mitochondrial Antiviral Signaling Protein in the Kaposi's Sarcoma-Associated Herpesvirus Life Cycle

    PubMed Central

    West, John A.; Wicks, Megan; Gregory, Sean M.; Chugh, Pauline; Jacobs, Sarah R.; Zhang, Zhigang; Host, Kurtis M.; Dittmer, Dirk P.

    2014-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) has been shown to be recognized by two families of pattern recognition receptors (PRRs), Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Here we show that MAVS and RIG-I (retinoic acid-inducible gene 1), an RLR family member, also have a role in suppressing KSHV replication and production. In the context of primary infection, we show that in cells with depleted levels of MAVS or RIG-I, KSHV transcription is increased, while beta interferon (IFN-β) induction is attenuated. We also observed that MAVS and RIG-I are critical during the process of reactivation. Depletion of MAVS and RIG-I prior to reactivation led to increased viral load and production of infectious virus. Finally, MAVS depletion in latent KSHV-infected B cells leads to increased viral gene transcription. Overall, this study suggests a role for MAVS and RIG-I signaling during different stages of the KSHV life cycle. IMPORTANCE We show that RIG-I and its adaptor protein, MAVS, can sense KSHV infection and that these proteins can suppress KSHV replication following primary infection and/or viral reactivation. PMID:24623417

  12. Ubiquitination of lysine-331 by Kaposi's sarcoma-associated herpesvirus protein K5 targets HFE for lysosomal degradation

    PubMed Central

    Rhodes, David A.; Boyle, Louise H.; Boname, Jessica M.; Lehner, Paul J.; Trowsdale, John

    2010-01-01

    The nonclassical MHC class I-related (MHC-I) molecule HFE controls cellular iron homeostasis by a mechanism that has not been fully elucidated. We examined the regulation of HFE by K5, the E3 ubiquitin ligase encoded by Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8), that is known to down-regulate classical MHC-I. K5 down-regulated HFE efficiently, using polyubiquitination of the membrane proximal lysine in the HFE cytoplasmic tail (K331), to target the molecule for degradation via ESCRT1/TSG101-dependent sorting from endosomes to multivesicular bodies (MVBs)/lysosomes. In the primary effusion lymphoma cell line BC-3, which carries latent KSHV, HFE was degraded rapidly upon virus reactivation. HFE was ubiquitinated on lysine-331 in unactivated BC-3 cells, conditions where K5 was not detectable, consistent with an endogenous E3 ubiquitin ligase controlling HFE expression. The results show regulated expression of HFE by ubiquitination, consistent with a role in cellular iron homeostasis, a molecular mechanism targeted by KSHV to achieve a positive iron balance. PMID:20805500

  13. A virally encoded small peptide regulates RTA stability and facilitates Kaposi's sarcoma-associated herpesvirus lytic replication.

    PubMed

    Jaber, Tareq; Yuan, Yan

    2013-03-01

    In both mammalian and viral genomes, a large proportion of sequences are transcribed and annotated as noncoding RNAs. A polyadenylated RNA of 3.0 kb (T3.0) is transcribed from the opposite strand of the open reading frame 50 (ORF50) DNA template in the genome of Kaposi's sarcoma-associated herpesvirus (KSHV) and has been annotated previously as a noncoding RNA. ORF50 encodes the replication and transcription activator (RTA), which controls the switch of the virus between the latent and lytic phases of the life cycle. Here we show that T3.0 encodes a small peptide of 48 amino acids (designated viral small peptide 1 [vSP-1]). vSP-1 interacts with RTA at the protein abundance regulatory signal (PARS) motifs, and the association prevents RTA from being subjected to degradation through the ubiquitin-proteasome pathway. As a consequence, vSP-1 facilitates KSHV gene expression and lytic replication. This finding reveals a novel mechanism of gene regulation in the viral life cycle. PMID:23302891

  14. Enhancement of autophagy during lytic replication by the Kaposi's sarcoma-associated herpesvirus replication and transcription activator.

    PubMed

    Wen, Hui-Ju; Yang, Zhilong; Zhou, You; Wood, Charles

    2010-08-01

    Autophagy is one of two major degradation systems in eukaryotic cells. The degradation mechanism of autophagy is required to maintain the balance between the biosynthetic and catabolic processes and also contributes to defense against invading pathogens. Recent studies suggest that a number of viruses can evade or subvert the host cell autophagic pathway to enhance their own replication. Here, we investigated the effect of autophagy on the KSHV (Kaposi's sarcoma-associated herpesvirus) life cycle. We found that the inhibition of autophagy reduces KSHV lytic reactivation from latency, and an enhancement of autophagy can be detected during KSHV lytic replication. In addition, RTA (replication and transcription activator), an essential viral protein for KSHV lytic reactivation, is able to enhance the autophagic process, leading to an increase in the number of autophagic vacuoles, an increase in the level of the lipidated LC3 protein, and the formation of autolysosomes. Moreover, the inhibition of autophagy affects RTA-mediated lytic gene expression and viral DNA replication. These results suggest that RTA increases autophagy activation to facilitate KSHV lytic replication. This is the first report demonstrating that autophagy is involved in the lytic reactivation of KSHV. PMID:20484505

  15. Productive Lytic Replication of a Recombinant Kaposi's Sarcoma-Associated Herpesvirus in Efficient Primary Infection of Primary Human Endothelial Cells

    PubMed Central

    Gao, Shou-Jiang; Deng, Jian-Hong; Zhou, Fu-Chun

    2003-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to the development of Kaposi's sarcoma (KS), a vascular spindle cell tumor primarily consisting of proliferating endothelial cells. Although KSHV has been shown to infect primary human endothelial cells and convert them into spindle shapes, KSHV infection is largely latent, and efforts to establish a highly efficient and sustainable infection system have been unsuccessful. A recombinant KSHV, BAC36, that has high primary-infection efficiency in 293 cells has been obtained (F. C. Zhou, Y. J. Zhang, J. H. Deng, X. P. Wang, H. Y. Pan, E. Hettler, and S. J. Gao, J. Virol. 76:6185-6196, 2002). BAC36 contains a green fluorescent protein cassette which can be used to conveniently monitor viral infection. Here, we describe the establishment of a KSHV lytic-replication-permissive infection cell model using BAC36 virions to infect primary human umbilical vein endothelial cell (HUVEC) cultures. BAC36 infection of HUVEC cultures has as high as 90% primary-infection efficiency and consists of two phases: a permissive phase, in which the cultures undergo active viral lytic replication, producing a large number of virions and concomitantly resulting in large-scale cell death, and a latent phase, in which the surviving cells from the permissive phase switch into latent infection, with a small number of cells undergoing spontaneous viral lytic replication, and proliferate into bundles of spindle cells with KS slit-like spaces. An assay for determining the KSHV titer in a virus preparation has also been developed. The cell model should be useful for examining KSHV infection and replication, as well as for understanding the development of KS. PMID:12941882

  16. Antiviral Activity of (+)-Rutamarin against Kaposi's Sarcoma-Associated Herpesvirus by Inhibition of the Catalytic Activity of Human Topoisomerase II

    PubMed Central

    Xu, Bo; Wang, Ling; González-Molleda, Lorenzo; Wang, Yan

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent of several AIDS-associated malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Its lytic replication cycle has been proven to be critical for the pathogenesis of KSHV-associated diseases. In KS lesions, lytic viral replication, production of virion particles, and reinfection of endothelial cells are essential to sustain the population of infected cells that otherwise would be quickly lost as spindle cells divide. Thus, antivirals that block KSHV replication could be a strategy in the treatment of KSHV-associated diseases. However, there is no effective anti-KSHV drug currently available. Our previous work showed that human topoisomerase II (Topo II) is indispensable for KSHV lytic replication and is suggested to be an effective target for antiviral drugs. Here, we report the discovery and characterization of a novel catalytic inhibitor of human Topo IIα, namely, (+)-rutamarin. The binding mode of (+)-rutamarin to the ATPase domain of human Topo IIα was established by docking and validated by molecular dynamics (MD) simulations. More importantly, (+)-rutamarin efficiently inhibits KSHV lytic DNA replication in BCBL-1 cells with a half-maximal inhibitory concentration (IC50) of 1.12 μM and blocks virion production with a half-maximal antiviral effective concentration (EC50) of 1.62 μM. It possesses low cytotoxicity, as indicated by the selectivity index (SI) of 84.14. This study demonstrated great potential for (+)-rutamarin to become an effective drug for treatment of human diseases associated with KSHV infection. PMID:24295975

  17. Conservation of the glycoprotein B homologs of the Kaposi׳s sarcoma-associated herpesvirus (KSHV/HHV8) and old world primate rhadinoviruses of chimpanzees and macaques.

    PubMed

    Bruce, A Gregory; Horst, Jeremy A; Rose, Timothy M

    2016-07-01

    The envelope-associated glycoprotein B (gB) is highly conserved within the Herpesviridae and plays a critical role in viral entry. We analyzed the evolutionary conservation of sequence and structural motifs within the Kaposi׳s sarcoma-associated herpesvirus (KSHV) gB and homologs of Old World primate rhadinoviruses belonging to the distinct RV1 and RV2 rhadinovirus lineages. In addition to gB homologs of rhadinoviruses infecting the pig-tailed and rhesus macaques, we cloned and sequenced gB homologs of RV1 and RV2 rhadinoviruses infecting chimpanzees. A structural model of the KSHV gB was determined, and functional motifs and sequence variants were mapped to the model structure. Conserved domains and motifs were identified, including an "RGD" motif that plays a critical role in KSHV binding and entry through the cellular integrin αVβ3. The RGD motif was only detected in RV1 rhadinoviruses suggesting an important difference in cell tropism between the two rhadinovirus lineages. PMID:27070755

  18. A hydrophobic domain within the small capsid protein of Kaposi's sarcoma-associated herpesvirus is required for assembly.

    PubMed

    Capuano, Christopher M; Grzesik, Peter; Kreitler, Dale; Pryce, Erin N; Desai, Keshal V; Coombs, Gavin; McCaffery, J Michael; Desai, Prashant J

    2014-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) capsids can be produced in insect cells using recombinant baculoviruses for protein expression. All six capsid proteins are required for this process to occur and, unlike for alphaherpesviruses, the small capsid protein (SCP) ORF65 is essential for this process. This protein decorates the capsid shell by virtue of its interaction with the capsomeres. In this study, we have explored the SCP interaction with the major capsid protein (MCP) using GFP fusions. The assembly site within the nucleus of infected cells was visualized by light microscopy using fluorescence produced by the SCP-GFP polypeptide, and the relocalization of the SCP to these sites was evident only when the MCP and the scaffold protein were also present - indicative of an interaction between these proteins that ensures delivery of the SCP to assembly sites. Biochemical assays demonstrated a physical interaction between the SCP and MCP, and also between this complex and the scaffold protein. Self-assembly of capsids with the SCP-GFP polypeptide was evident. Potentially, this result can be used to engineer fluorescent KSHV particles. A similar SCP-His6 polypeptide was used to purify capsids from infected cell lysates using immobilized affinity chromatography and to directly label this protein in capsids using chemically derivatized gold particles. Additional studies with SCP-GFP polypeptide truncation mutants identified a domain residing between aa 50 and 60 of ORF65 that was required for the relocalization of SCP-GFP to nuclear assembly sites. Substitution of residues in this region and specifically at residue 54 with a polar amino acid (lysine) disrupted or abolished this localization as well as capsid assembly, whereas substitution with non-polar residues did not affect the interaction. Thus, this study identified a small conserved hydrophobic domain that is important for the SCP-MCP interaction. PMID:24824860

  19. Kaposi's Sarcoma-Associated Herpesvirus ORF45 Interacts with Kinesin-2 Transporting Viral Capsid-Tegument Complexes along Microtubules

    PubMed Central

    Sathish, Narayanan; Zhu, Fan Xiu; Yuan, Yan

    2009-01-01

    Open reading frame (ORF) 45 of Kaposi's sarcoma-associated herpesvirus (KSHV) is a tegument protein. A genetic analysis with a null mutant suggested a possible role for this protein in the events leading to viral egress. In this study, ORF45 was found to interact with KIF3A, a kinesin-2 motor protein that transports cargoes along microtubules to cell periphery in a yeast two-hybrid screen. The association was confirmed by both co-immunoprecipitation and immunoflorescence approaches in primary effusion lymphoma cells following virus reactivation. ORF45 principally mediated the docking of entire viral capsid-tegument complexes onto the cargo-binding domain of KIF3A. Microtubules served as the major highways for transportation of these complexes as evidenced by drastically reduced viral titers upon treatment of cells with a microtubule depolymerizer, nocodazole. Confocal microscopic images further revealed close association of viral particles with microtubules. Inhibition of KIF3A–ORF45 interaction either by the use of a headless dominant negative (DN) mutant of KIF3A or through shRNA-mediated silencing of endogenous KIF3A expression noticeably decreased KSHV egress reflecting as appreciable reductions in the release of extracellular virions. Both these approaches, however, failed to impact HSV-1 egress, demonstrating the specificity of KIF3A in KSHV transportation. This study thus reports on transportation of KSHV viral complexes on microtubules by KIF3A, a kinesin motor thus far not implicated in virus transportation. All these findings shed light on the understudied but significant events in the KSHV life cycle, delineating a crucial role of a KSHV tegument protein in cellular transport of viral particles. PMID:19282970

  20. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes.

    PubMed

    You, Jianxin; Srinivasan, Viswanathan; Denis, Gerald V; Harrington, William J; Ballestas, Mary E; Kaye, Kenneth M; Howley, Peter M

    2006-09-01

    The latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is required for viral episome maintenance in host cells during latent infection. Two regions of the protein have been implicated in tethering LANA/viral episomes to the host mitotic chromosomes, and LANA chromosome-binding sites are subjects of high interest. Because previous studies had identified bromodomain protein Brd4 as the mitotic chromosome anchor for the bovine papillomavirus E2 protein, which tethers the viral episomes to host mitotic chromosomes (J. You, J. L. Croyle, A. Nishimura, K. Ozato, and P. M. Howley, Cell 117:349-360, 2004, and J. You, M. R. Schweiger, and P. M. Howley, J. Virol. 79:14956-14961, 2005), we examined whether KSHV LANA interacts with Brd4. We found that LANA binds Brd4 in vivo and in vitro and that the binding is mediated by a direct protein-protein interaction between the ET (extraterminal) domain of Brd4 and a carboxyl-terminal region of LANA previously implicated in chromosome binding. Brd4 associates with mitotic chromosomes throughout mitosis and demonstrates a strong colocalization with LANA and the KSHV episomes on host mitotic chromosomes. Although another bromodomain protein, RING3/Brd2, binds to LANA in a similar fashion in vitro, it is largely excluded from the mitotic chromosomes in KSHV-uninfected cells and is partially recruited to the chromosomes in KSHV-infected cells. These data identify Brd4 as an interacting protein for the carboxyl terminus of LANA on mitotic chromosomes and suggest distinct functional roles for the two bromodomain proteins RING3/Brd2 and Brd4 in LANA binding. Additionally, because Brd4 has recently been shown to have a role in transcription, we examined whether Brd4 can regulate the CDK2 promoter, which can be transactivated by LANA. PMID:16940503

  1. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen induction by hypoxia and hypoxia-inducible factors.

    PubMed

    Veeranna, Ravindra P; Haque, Muzammel; Davis, David A; Yang, Min; Yarchoan, Robert

    2012-01-01

    Hypoxia and hypoxia-inducible factors (HIFs) play an important role in the Kaposi's sarcoma-associated herpesvirus (KSHV) life cycle. In particular, hypoxia can activate lytic replication of KSHV and specific lytic genes, including the replication and transcription activator (RTA), while KSHV infection in turn can increase the levels and activity of HIFs. In the present study, we show that hypoxia increases the levels of mRNAs encoding KSHV latency-associated nuclear antigen (LANA) in primary effusion lymphoma (PEL) cell lines and also increases the levels of LANA protein. Luciferase reporter assays in Hep3B cells revealed a moderate activation of the LANA promoter region by hypoxia as well as by cotransfection with degradation-resistant HIF-1α or HIF-2α expression plasmids. Computer analysis of a 1.2-kb sequence upstream of the LANA translational start site identified six potential hypoxia-responsive elements (HRE). Sequential deletion studies revealed that much of this activity was mediated by one of these HREs (HRE 4R) oriented in the 3' to 5' direction and located between the constitutive (LTc) and RTA-inducible (LTi) mRNA start sites. Site-directed mutation of this HRE substantially reduced the response to both HIF-1α and HIF-2α in a luciferase reporter assay. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated binding of both HIF-1α and HIF-2α to this region. Also, HIF-1α was found to associate with RTA, and HIFs enhanced the activation of LTi by RTA. These results provide evidence that hypoxia and HIFs upregulate both latent and lytic KSHV replication and play a central role in the life cycle of this virus. PMID:22090111

  2. Functional characterization of Kaposi's sarcoma-associated herpesvirus open reading frame K8 by bacterial artificial chromosome-based mutagenesis.

    PubMed

    Wang, Yan; Sathish, Narayanan; Hollow, Charles; Yuan, Yan

    2011-03-01

    The open reading frame K8 of Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a basic leucine zipper (bZip) protein that binds to the origin of viral DNA replication and is an integral component of viral lytic DNA replication complex. Moreover, K8 physically interacts with replication and transcription activator (RTA) and represses its transactivation activity on several viral promoters. To investigate the role of this protein in viral life cycle, we constructed two K8-null recombinant mutant viruses (BAC-ΔK8 and BAC-stopK8) by using a bacterial artificial chromosome (BAC) system. Latent viral infection can be reconstituted in 293T and BJAB cells with wild-type and the K8-null recombinant viruses by introducing the cloned viral genomes into the cells. When the cells carrying these viruses were induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate, no significant difference was seen in overall viral gene expression between wild-type and K8-null viruses, with lytic DNA replication still active in the latter. However, 293T cells harboring K8-null mutant viruses, either BAC-ΔK8 or BAC-stopK8, displayed lower copy numbers of latent KSHV genome in comparison with wild-type viruses. Furthermore, although K8 deficiency appeared to not affect infectivity when K8-null viruses were used to infect 293T, primary human microvascular dermal endothelial and human foreskin fibroblast cells, they exhibited much lower viral genome copy numbers in all types of cell compared to wild-type viruses. Taken together, these data suggest a possible role of K8 in abortive lytic DNA replication occurring in early stages of de novo infection or in the maintenance of latent viral genomes. PMID:21159864

  3. Interaction between ORF24 and ORF34 in the Kaposi's Sarcoma-Associated Herpesvirus Late Gene Transcription Factor Complex Is Essential for Viral Late Gene Expression

    PubMed Central

    Davis, Zoe H.; Hesser, Charles R.; Park, Jimin

    2015-01-01

    Transcription of herpesviral late genes is stimulated after the onset of viral DNA replication but otherwise restricted. Late gene expression in gammaherpesviruses requires the coordination of six early viral proteins, termed viral transactivation factors (vTFs). Here, we mapped the organization of this protein complex for Kaposi's sarcoma-associated herpesvirus. Disruption of this complex via point mutation of the interaction interface between the open reading frame 24 (ORF24) and ORF34 vTFs ablated both late gene expression and viral replication. PMID:26468530

  4. Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) contains hypoxia response elements: relevance to lytic induction by hypoxia.

    PubMed

    Haque, Muzammel; Davis, David A; Wang, Victoria; Widmer, Isabelle; Yarchoan, Robert

    2003-06-01

    Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), also known as human herpesvirus 8, is an etiologic agent of KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease. We recently demonstrated that hypoxia can induce lytic replication of KSHV in PEL cell lines. Hypoxia induces the accumulation of hypoxia-inducible factors (HIF), and we hypothesized that the KSHV genome may respond to hypoxia through functional hypoxia response elements (HREs). Here, we demonstrate the presence of at least two promoters within the KSHV genome that are activated by hypoxia or hypoxia mimics. One is in the promoter region of the gene for Rta, the main lytic switch gene, and the other is within the promoter region of ORF34, a lytic gene of unknown function. The ORF34 promoter contains three putative consensus HREs oriented in the direction of the gene. Dissection and site-directed mutagenesis studies confirmed that one of the HREs of the ORF34 promoter is functional. Under conditions of hypoxia, the ORF34 promoter was strongly upregulated by HIF-1 alpha and HIF-2 alpha. By contrast, the promoter of the gene for Rta appeared to be preferentially upregulated by HIF-2 alpha. Reverse transcription-PCR analysis revealed that specific messages for ORF34 and ORF50 are upregulated in BCBL-1 cells exposed to hypoxia. An HIF-1 binding and competition assay demonstrated that the HRE sequence from the ORF34 promoter can compete for HIF-1 alpha binding to an erythropoietin HRE oligonucleotide while a mutant sequence cannot. Thus, we demonstrated that a viral gene can be activated by hypoxia through activation of a functional viral HRE. To our knowledge, this is the first example of a functional HRE in a viral promoter. PMID:12767996

  5. A rhesus macaque rhadinovirus related to Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 encodes a functional homologue of interleukin-6.

    PubMed

    Kaleeba, J A; Bergquam, E P; Wong, S W

    1999-07-01

    The rhesus rhadinovirus strain 17577 (RRV strain 17577) genome is essentially colinear with human herpesvirus 8 (HHV8)/Kaposi's sarcoma-associated herpesvirus (KSHV) and encodes several analogous open reading frames (ORFs), including the homologue of cellular interleukin-6 (IL-6). To determine if the RRV IL-6-like ORF (RvIL-6) is biologically functional, it was expressed either transiently in COS-1 cells or purified from bacteria as a glutathione S-transferase (GST)-RvIL-6 fusion and analyzed by IL-6 bioassays. Utilizing the IL-6-dependent B9 cell line, we found that both forms of RvIL-6 supported cell proliferation in a dose-dependent manner. Moreover, antibodies specific to the IL-6 receptor (IL-6R) or the gp130 subunit were capable of blocking the stimulatory effects of RvIL-6. Reciprocal titrations of GST-RvIL-6 against human recombinant IL-6 produced a more-than-additive stimulatory effect, suggesting that RvIL-6 does not inhibit but may instead potentiate normal cellular IL-6 signaling to B cells. These results demonstrate that RRV encodes an accessory protein with IL-6-like activity. PMID:10364379

  6. DNA-PK/Ku complex binds to latency-associated nuclear antigen and negatively regulates Kaposi's sarcoma-associated herpesvirus latent replication

    SciTech Connect

    Cha, Seho; Lim, Chunghun; Lee, Jae Young; Song, Yoon-Jae; Park, Junsoo; Choe, Joonho; Seo, Taegun

    2010-04-16

    During latent infection, latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) plays important roles in episomal persistence and replication. Several host factors are associated with KSHV latent replication. Here, we show that the catalytic subunit of DNA protein kinase (DNA-PKcs), Ku70, and Ku86 bind the N-terminal region of LANA. LANA was phosphorylated by DNA-PK and overexpression of Ku70, but not Ku86, impaired transient replication. The efficiency of transient replication was significantly increased in the HCT116 (Ku86 +/-) cell line, compared to the HCT116 (Ku86 +/+) cell line, suggesting that the DNA-PK/Ku complex negatively regulates KSHV latent replication.

  7. Propranolol Decreases Proliferation of Endothelial Cells Transformed by Kaposi's Sarcoma-Associated Herpesvirus and Induces Lytic Viral Gene Expression

    PubMed Central

    Hanson, Ryan S.; Manion, Rory D.

    2015-01-01

    Kaposi's sarcoma (KS) is common in Africa, but economic constraints hinder successful treatment in most patients. Propranolol, a generic β-adrenergic antagonist, decreased proliferation of KS-associated herpesvirus (KSHV)-infected cells. Downregulation of cyclin A2 and cyclin-dependent kinase 1 (CDK1) recapitulated this phenotype. Additionally, propranolol induced lytic gene expression in association with downregulation of CDK6. Thus, propranolol has diverse effects on KSHV-infected cells, and this generic drug has potential as a therapeutic agent for KS. PMID:26269192

  8. Generation of high-titre virus stocks using BrK.219, a B-cell line infected stably with recombinant Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Kati, Semra; Hage, Elias; Mynarek, Martin; Ganzenmueller, Tina; Indenbirken, Daniela; Grundhoff, Adam; Schulz, Thomas F

    2015-06-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a gamma-2-lymphotropic human oncogenic herpesvirus associated with Kaposi's sarcoma (KS) and two B-cell lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KSHV establishes latency soon after infection in vivo and in vitro. Consequently, it is technically difficult to generate high-titre virus stocks required for infection experiments in tissue culture. Currently used methods of KSHV stock production involve induction of the lytic/productive cycle in PEL cell lines or in adherent cell lines harbouring recombinant KSHV genomes. In this study, the BJAB-derived B-cell line BrK.219, which is infected latently with a recombinant KSHV (rKSHV.219), is used to produce high-titre virus stocks. BrK.219 cells enter the lytic KSHV replication cycle upon cross-linking of B-cell receptors (BCRs) with anti-IgM antibodies without the need for additional, potentially toxic chemical inducers. High cell concentrations can be cultured and induced easily in spinner flasks, saving time and resources. The established protocol allows the generation of KSHV virus stocks with titres of up to 10(6) IU/ml in unconcentrated culture supernatants, representing a 10(3)-10(4)-fold improvement compared to conventional methods. PMID:25736227

  9. Acetylation changes at lysine 5 of histone H4 associated with lytic gene promoters during reactivation of Kaposi's sarcoma-associated herpesvirus.

    PubMed

    Hwang, L R; Cha, S; Jong, J E; Jang, J H; Seo, T

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a pathogenic agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease in humans. Similarly to other gammaherpesviruses such as Epstein-Barr virus (EBV) and herpesvirus saimiri (HVS), KSHV displays two alternative life cycles, latent and lytic one. The transactivation from latency to the lytic phase is the result of transcriptional changes in the KSHV genome caused by the replication and transcriptional activator (RTA). During KSHV reactivation, epigenetic modifications of histone protein on the viral genome occur, which regulate the transcriptional activation of a number of lytic genes. The reactivation of EBV from latency to lytic cycle, induced by an immediate-early Zta protein, was shown to be accompanied by acetylation of specific lysines in histone H4. Accordingly, we hypothesized that the RTA-induced transactivation of KSHV could also be accompanied by histone acetylation. To validate this hypothesis, we assayed alterations of acetyl-histone H4-lysine 5 (acH4K5) during the RTA-mediated KSHV reactivation. While the modified histone protein in a total cell lysate was not distinguished between control and RTA-expressed cells, upregulated acH4K5 was detected on several lytic gene promoter regions during KSHV reactivation. Our results clearly indicate that this epigenetic change is related to transcription of genes expressed in the lytic cycle of KSHV. PMID:25283865

  10. Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein.

    PubMed

    Chatterjee, Deboeeta; Chandran, Bala; Berger, Edward A

    2012-01-01

    Kaposi sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) is etiologically associated with three neoplastic syndromes: Kaposi sarcoma and the uncommon HIV-associated B-cell lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. The incidence of the latter B-cell pathology has been increasing in spite of antiretroviral therapy; its association with lytic virus replication has prompted interest in therapeutic strategies aimed at this phase of the virus life cycle. We designed and expressed a recombinant immunotoxin (2014-PE38) targeting the gpK8.1A viral glycoprotein expressed on the surface of the virion and infected cells. We show that this immunotoxin selectively kills KSHV-infected cells in dose-dependent fashion, resulting in major reductions of infectious virus release. The immunotoxin and ganciclovir, an inhibitor of viral DNA replication, showed marked reciprocal potentiation of antiviral activities. These results suggest that the immunotoxin, alone or in combination, may represent a new approach to treat diseases associated with KSHV lytic replication. PMID:22377676

  11. The single RBP-Jkappa site within the LANA promoter is crucial for establishing Kaposi's sarcoma-associated herpesvirus latency during primary infection.

    PubMed

    Lu, Jie; Verma, Subhash C; Cai, Qiliang; Robertson, Erle S

    2011-07-01

    Kaposi's sarcoma-associated herpesvirus (KSHV; or human herpesvirus 8 [HHV8]) is implicated in the pathogenesis of many human malignancies including Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). KSHV infection displays two alternative life cycles, referred to as the latent and lytic or productive cycle. Previously, we have reported that the replication and transcription activator (RTA), a major lytic cycle transactivator, contributes to the development of KSHV latency by inducing latency-associated nuclear antigen (LANA) expression during early stages of infection by targeting RBP-Jκ, the master regulator of the Notch signaling pathway. Here, we generated a bacterial artificial chromosome (BAC) KSHV recombinant virus with a deletion of the RBP-Jκ site within the LANA promoter to evaluate the function of the RBP-Jκ cognate site in establishing primary latent infection. The results showed that genetic disruption of the RBP-Jκ binding site within the KSHV LANA promoter led to enhanced expression of the KSHV-encoded immediate early RTA, resulting in an increase in lytic replication during primary infection of human peripheral blood mononuclear cells (PBMCs). This system provides a powerful tool for use in indentifying additional cellular and viral molecules involved in LANA-mediated latency maintenance during the early stages of KSHV infection. PMID:21507979

  12. K1 and K15 of Kaposi's Sarcoma-Associated Herpesvirus Are Partial Functional Homologues of Latent Membrane Protein 2A of Epstein-Barr Virus

    PubMed Central

    Steinbrück, Lisa; Gustems, Montse; Medele, Stephanie; Schulz, Thomas F.; Lutter, Dominik

    2015-01-01

    ABSTRACT The human herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are associated with Hodgkin's lymphoma (HL) and Primary effusion lymphomas (PEL), respectively, which are B cell malignancies that originate from germinal center B cells. PEL cells but also a quarter of EBV-positive HL tumor cells do not express the genuine B cell receptor (BCR), a situation incompatible with survival of normal B cells. EBV encodes LMP2A, one of EBV's viral latent membrane proteins, which likely replaces the BCR's survival signaling in HL. Whether KSHV encodes a viral BCR mimic that contributes to oncogenesis is not known because an experimental model of KSHV-mediated B cell transformation is lacking. We addressed this uncertainty with mutant EBVs encoding the KSHV genes K1 or K15 in lieu of LMP2A and infected primary BCR-negative (BCR−) human B cells with them. We confirmed that the survival of BCR– B cells and their proliferation depended on an active LMP2A signal. Like LMP2A, the expression of K1 and K15 led to the survival of BCR− B cells prone to apoptosis, supported their proliferation, and regulated a similar set of cellular target genes. K1 and K15 encoded proteins appear to have noncomplementing, redundant functions in this model, but our findings suggest that both KSHV proteins can replace LMP2A's key activities contributing to the survival, activation and proliferation of BCR– PEL cells in vivo. IMPORTANCE Several herpesviruses encode oncogenes that are receptor-like proteins. Often, they are constitutively active providing important functions to the latently infected cells. LMP2A of Epstein-Barr virus (EBV) is such a receptor that mimics an activated B cell receptor, BCR. K1 and K15, related receptors of Kaposi's sarcoma-associated herpesvirus (KSHV) expressed in virus-associated tumors, have less obvious functions. We found in infection experiments that both viral receptors of KSHV can replace LMP2A and deliver functions

  13. Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins down regulate both DC-SIGN and DC-SIGNR.

    PubMed

    Lang, Sabine M; Bynoe, Meisha O F; Karki, Roshan; Tartell, Michael A; Means, Robert E

    2013-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of multicentric Castleman's disease, primary effusion lymphoma and Kaposi's sarcoma. In this study, we show that like the C-type lectin DC-SIGN, the closely related DC-SIGNR can also enhance KSHV infection. Following infection, they are both targeted for down modulation and our data indicate that the KSHV MARCH-family ubiquitin ligase K5 is mediating this regulation and subsequent targeting for degradation of DC-SIGN and DC-SIGNR in the context of the virus. The closely related viral K3 protein, is also able to target these lectins in exogenous expressions studies, but only weakly during viral infection. In addition to requiring a functional RING-CH domain, several protein trafficking motifs in the C-terminal region of both K3 and K5 are important in regulation of DC-SIGN and DC-SIGNR. Further exploration of this modulation revealed that DC-SIGN is endocytosed from the cell surface in THP-1 monocytes, but degraded from an internal location with minimal endocytosis in HEK-293 cells. Pull-down data indicate that both K3 and K5 preferentially associate with immature forms of the lectins, mediating their ubiquitylation and degradation. Together, these data emphasize the molecular complexities of K3 and K5, while expanding the repertoire of targets of these two viral proteins. PMID:23460925

  14. The Kaposi's Sarcoma-Associated Herpesvirus ORF34 Protein Binds to HIF-1α and Causes Its Degradation via the Proteasome Pathway

    PubMed Central

    Kousoulas, Konstantin G.

    2013-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi's sarcoma (KS) and two other lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Kaposi's sarcoma is a highly vascular tumor, and recently both hypoxia-inducible factor 1α (HIF-1α) and HIF-2α were detected in KS samples, indicating a role of HIFs in the KSHV life cycle. Previously, we showed that ORF34, a lytic gene of unassigned function, was activated by hypoxia and that ORF34 transcription was upregulated by both HIFs (M. Haque, D. A. Davis, V. Wang, I. Widmer, and R. Yarchoan, J Virol. 77:6761–6768, 2003). In the present study, we show that coexpression of ORF34 with HIF-1αm (degradation-resistant HIF-1α) caused substantial reduction in HIF-1α-dependent transcription, as evidenced by reporter assays. Two-way immunoprecipitation experiments revealed that ORF34 physically interacted with HIF-1αm in transient expression experiments. Deletion analysis revealed that three different ORF34 domains interacted with the amino-terminal domain of HIF-1α. Also, purified HIF-1α and ORF34 proteins interacted with each other. The observed transcriptional inhibition of HIF-1α-dependent promoters was attributed to degradation of HIF-1α after binding with ORF34, since the overall amount of wild-type HIF-1α but not the degradation-resistant one (HIF-1αm) was reduced in the presence of ORF34. Moreover, ORF34 caused degradation of HIF-1α in a dose-dependent manner. Inhibition of the ubiquitin-dependent pathway by the chemical proteasome inhibitor MG132 prevented HIF-1α degradation in the presence of ORF34. These results show that ORF34 binds to HIF-1α, leading to its degradation via the proteasome-dependent pathway. PMID:23221556

  15. The Kaposi's sarcoma-associated herpesvirus ORF34 protein binds to HIF-1α and causes its degradation via the proteasome pathway.

    PubMed

    Haque, Muzammel; Kousoulas, Konstantin G

    2013-02-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi's sarcoma (KS) and two other lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Kaposi's sarcoma is a highly vascular tumor, and recently both hypoxia-inducible factor 1α (HIF-1α) and HIF-2α were detected in KS samples, indicating a role of HIFs in the KSHV life cycle. Previously, we showed that ORF34, a lytic gene of unassigned function, was activated by hypoxia and that ORF34 transcription was upregulated by both HIFs (M. Haque, D. A. Davis, V. Wang, I. Widmer, and R. Yarchoan, J Virol. 77:6761-6768, 2003). In the present study, we show that coexpression of ORF34 with HIF-1αm (degradation-resistant HIF-1α) caused substantial reduction in HIF-1α-dependent transcription, as evidenced by reporter assays. Two-way immunoprecipitation experiments revealed that ORF34 physically interacted with HIF-1αm in transient expression experiments. Deletion analysis revealed that three different ORF34 domains interacted with the amino-terminal domain of HIF-1α. Also, purified HIF-1α and ORF34 proteins interacted with each other. The observed transcriptional inhibition of HIF-1α-dependent promoters was attributed to degradation of HIF-1α after binding with ORF34, since the overall amount of wild-type HIF-1α but not the degradation-resistant one (HIF-1αm) was reduced in the presence of ORF34. Moreover, ORF34 caused degradation of HIF-1α in a dose-dependent manner. Inhibition of the ubiquitin-dependent pathway by the chemical proteasome inhibitor MG132 prevented HIF-1α degradation in the presence of ORF34. These results show that ORF34 binds to HIF-1α, leading to its degradation via the proteasome-dependent pathway. PMID:23221556

  16. Seroprevalence and determinants of Kaposi sarcoma-associated human herpesvirus 8 in Indian HIV-infected males.

    PubMed

    Munawwar, Arshi; Sharma, Surendra K; Gupta, Somesh; Singh, Sarman

    2014-12-01

    In India Kaposi's sarcoma is rarely seen in AIDS patients. Hence the current belief is that the incidence of human herpesvirus-8 (HHV-8) is very low in this subcontinent, most probably due to the heterosexual route of HIV transmission. However, there is a scarcity of data on the prevalence of HHV-8 in India. In India the primary mode of HIV transmission is the heterosexual route. Therefore we aimed to determine the prevalence of antibodies against HHV-8 in North Indian HIV-infected men naive of antiretroviral therapy (ART). In a prospective study, 165 Indian adult males were recruited from an ART clinic. Blood samples were collected before administering any antiretroviral drug. The sera were tested for antibodies against HHV-8 using a commercial enzyme-linked immunosorbent assay (ELISA) kit, which detects IgG antibodies to lytic antigens of HHV-8. All positive samples were confirmed for the presence of anti-HHV-8 antibodies using an indirect immunofluorescence assay (IFA). The IFA kit is intended to detect primary, latent, persistent, or reactivated infection of HHV-8. Of the 165 males, 43 (26.06%) were positive by ELISA while 26 (15.8%) were also positive by IFA. Seroprevalence decreased with increasing age (p<0.05). Factors independently associated with HHV-8 infection were younger age group and alcohol consumption. These findings suggest that even in a heterosexual population, HHV-8 can be transmitted frequently. PMID:25375960

  17. Activation of p90 Ribosomal S6 Kinase by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus and Its Role in Viral Lytic Replication▿

    PubMed Central

    Kuang, Ersheng; Tang, Qiyi; Maul, Gerd G.; Zhu, Fanxiu

    2008-01-01

    The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway is essential for infection by a variety of viruses. The p90 ribosomal S6 kinases (RSKs) are direct substrates of ERK and functional mediators of ERK MAPK signaling, but their roles in viral infection have never been examined. We demonstrate that ORF45 of Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with RSK1 and RSK2 and strongly stimulates their kinase activities. The activation of RSK by ORF45 is correlated with ERK activation but does not require MEK. We further demonstrate that RSK1/RSK2 is activated during KSHV primary infection and reactivation from latency; a subset of RSK1/RSK2 is present in the viral replication compartment in the nucleus. Depletion of RSK1/RSK2 by small interfering RNA or the specific inhibitor BI-D1870 suppresses KSHV lytic gene expression and progeny virion production, suggesting an essential role of RSK1/RSK2 in KSHV lytic replication. PMID:18057234

  18. Kaposi's-sarcoma-associated-herpesvirus-activated dendritic cells promote HIV-1 trans-infection and suppress CD4{sup +} T cell proliferation

    SciTech Connect

    Liu, Wan; Qin, Yan; Bai, Lei; Lan, Ke; Wang, Jian-Hua

    2013-06-05

    Infection of Kaposi's sarcoma-associated herpesvirus (KSHV) is commonly occurred in AIDS patients. KSHV and HIV-1 act cooperatively in regulating infection with each other and in human carcinogenesis. Dendritic cells (DCs), as the pivotal cells in host immunity, may be modulated by both viruses, for immunoevasion and dissemination, therefore, the interaction between DCs and each virus has been a prior focus for pathogenesis elucidation. Here, we assessed the potential effect of KSHV on DC–HIV-1 interaction. We found that KSHV stimulation could promote maturation of monocyte-derived DCs (MDDCs) and impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} T cells, demonstrating the immunosuppression induced by KSHV. More importantly, KSHV-stimulated MDDCs could capture more HIV-1 and efficiently transferred these infectious viruses to Hut/CCR5 T cell line. Our results reveal the novel modulation of DC-mediated HIV-1 dissemination by KSHV, and highlight the importance of studying DC–HIV-1 interaction to elucidate HIV/AIDS pathogenesis. - Highlights: ► KSHV impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} T cells. ► KSHV stimulation matured MDDCs and enhanced HIV-1 endocytosis. ► KSHV stimulated MDDCs increased ICAM-1 expression and tighten contact with T cells. ► KSHV-stimulated MDDCs promoted HIV-1 trans-infection of CD4{sup +} T cells.

  19. A Kaposi's Sarcoma-Associated Herpesvirus MicroRNA and Its Variants Target the Transforming Growth Factor β Pathway To Promote Cell Survival

    PubMed Central

    Lei, Xiufen; Zhu, Ying; Jones, Tiffany; Bai, Zhiqiang; Huang, Yufei

    2012-01-01

    Transforming growth factor β (TGF-β) signaling regulates cell growth and survival. Dysregulation of the TGF-β pathway is common in viral infection and cancer. Latent infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is required for the development of several AIDS-related malignancies, including Kaposi's sarcoma and primary effusion lymphoma (PEL). KSHV encodes more than two dozen microRNAs (miRs) derived from 12 pre-miRs with largely unknown functions. In this study, we show that miR variants processed from pre-miR-K10 are expressed in KSHV-infected PEL cells and endothelial cells, while cellular miR-142-3p and its variant miR-142-3p_-1_5, which share the same seed sequence with miR-K10a_ +1_5, are expressed only in PEL cells and not in uninfected and KSHV-infected TIME cells. KSHV miR-K10 variants inhibit TGF-β signaling by targeting TGF-β type II receptor (TβRII). Computational and reporter mutagenesis analyses identified three functional target sites in the TβRII 3′ untranslated region (3′UTR). Expression of miR-K10 variants is sufficient to inhibit TGF-β-induced cell apoptosis. A suppressor of the miRs sensitizes latent KSHV-infected PEL cells to TGF-β and induces apoptosis. These results indicate that miR-K10 variants manipulate the TGF-β pathway to confer cells with resistance to the growth-inhibitory effect of TGF-β. Thus, KSHV miRs might target the tumor-suppressive TGF-β pathway to promote viral latency and contribute to malignant cellular transformation. PMID:22915806

  20. Long-Term-Infected Telomerase-Immortalized Endothelial Cells: a Model for Kaposi's Sarcoma-Associated Herpesvirus Latency In Vitro and In Vivo†

    PubMed Central

    An, Feng-Qi; Folarin, Hope Merlene; Compitello, Nicole; Roth, Justin; Gerson, Stanton L.; McCrae, Keith R.; Fakhari, Farnaz D.; Dittmer, Dirk P.; Renne, Rolf

    2006-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. Most KS tumor cells are latently infected with KSHV and are of endothelial origin. While PEL-derived cell lines maintain KSHV indefinitely, all KS tumor-derived cells to date have lost viral genomes upon ex vivo cultivation. To study KSHV latency and tumorigenesis in endothelial cells, we generated telomerase-immortalized human umbilical vein endothelial (TIVE) cells. TIVE cells express all KSHV latent genes 48 h postinfection, and productive lytic replication could be induced by RTA/Orf50. Similar to prior models, infected cultures gradually lost viral episomes. However, we also obtained, for the first time, two endothelial cell lines in which KSHV episomes were maintained indefinitely in the absence of selection. Long-term KSHV maintenance correlated with loss of reactivation in response to RTA/Orf50 and complete oncogenic transformation. Long-term-infected TIVE cells (LTC) grew in soft agar and proliferated under reduced-serum conditions. LTC, but not parental TIVE cells, formed tumors in nude mice. These tumors expressed high levels of the latency-associated nuclear antigen (LANA) and expressed lymphatic endothelial specific antigens as found in KS (LYVE-1). Furthermore, host genes, like those encoding interleukin 6, vascular endothelial growth factor, and basic fibroblast growth factor, known to be highly expressed in KS lesions were also induced in LTC-derived tumors. KSHV-infected LTCs represent the first xenograft model for KS and should be of use to study KS pathogenesis and for the validation of anti-KS drug candidates. PMID:16641275

  1. p53 Tumor Suppressor Protein Stability and Transcriptional Activity Are Targeted by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interferon Regulatory Factor 3

    PubMed Central

    Baresova, Petra; Musilova, Jana; Pitha, Paula M.

    2014-01-01

    Viruses have developed numerous strategies to counteract the host cell defense. Kaposi's sarcoma-associated herpesvirus (KSHV) is a DNA tumor virus linked to the development of Kaposi's sarcoma, Castleman's disease, and primary effusion lymphoma (PEL). The virus-encoded viral interferon regulatory factor 3 (vIRF-3) gene is a latent gene which is involved in the regulation of apoptosis, cell cycle, antiviral immunity, and tumorigenesis. vIRF-3 was shown to interact with p53 and inhibit p53-mediated apoptosis. However, the molecular mechanism underlying this phenomenon has not been established. Here, we show that vIRF-3 associates with the DNA-binding domain of p53, inhibits p53 phosphorylation on serine residues S15 and S20, and antagonizes p53 oligomerization and the DNA-binding affinity. Furthermore, vIRF-3 destabilizes p53 protein by increasing the levels of p53 polyubiquitination and targeting p53 for proteasome-mediated degradation. Consequently, vIRF-3 attenuates p53-mediated transcription of the growth-regulatory p21 gene. These effects of vIRF-3 are of biological relevance since the knockdown of vIRF-3 expression in KSHV-positive BC-3 cells, derived from PEL, leads to an increase in p53 phosphorylation, enhancement of p53 stability, and activation of p21 gene transcription. Collectively, these data suggest that KSHV evolved an efficient mechanism to downregulate p53 function and thus facilitate uncontrolled cell proliferation and tumor growth. PMID:24248600

  2. Interaction of Kaposi's sarcoma-associated herpesvirus ORF59 with oriLyt is dependent on binding with K-Rta.

    PubMed

    Rossetto, Cyprian C; Susilarini, Ni Ketut; Pari, Gregory S

    2011-04-01

    Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) displays two distinct life stages, latency and lytic reactivation. Progression through the lytic cycle and replication of the viral genome constitute an essential step toward the production of infectious virus and human disease. KSHV K-RTA has been shown to be the major transactivator required for the initiation of lytic reactivation. In the transient-cotransfection replication assay, K-Rta is the only noncore protein required for DNA synthesis. K-Rta was shown to interact with both C/EBPα binding motifs and the R response elements (RRE) within oriLyt. It is postulated that K-Rta acts in part to facilitate the recruitment of replication factors to oriLyt. In order to define the role of K-Rta in the initiation of lytic DNA synthesis, we show an interaction with ORF59, the DNA polymerase processivity factor (PF), one of the eight virally encoded proteins necessary for origin-dependent DNA replication. Using the chromatin immunoprecipitation (ChIP) assay, both K-Rta and ORF59 interact with the RRE and C/EBPα binding motifs within oriLyt in cells harboring the KSHV bacterial artificial chromosome (BAC). A transient-transfection ChIP assay demonstrated that the interaction of ORF59 with oriLyt is dependent on binding with K-Rta and that ORF59 fails to bind to oriLyt in the absence of K-Rta. Also, using the cotransfection replication assay, overexpression of the interaction domain of K-Rta with ORF59 has a dominant negative effect on oriLyt amplification, suggesting that the interaction of K-Rta with ORF59 is essential for DNA synthesis and supporting the hypothesis that K-Rta facilitates the formation of a replication complex at oriLyt. PMID:21289111

  3. A Structural Basis for BRD2/4-Mediated Host Chromatin Interaction and Oligomer Assembly of Kaposi Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus LANA Proteins

    PubMed Central

    Krausze, Joern; Richter, Ulrike; Adler, Heiko; Fedorov, Roman; Pietrek, Marcel; Rückert, Jessica; Ritter, Christiane; Schulz, Thomas F.; Lührs, Thorsten

    2013-01-01

    Kaposi sarcoma-associated herpesvirus (KSHV) establishes a lifelong latent infection and causes several malignancies in humans. Murine herpesvirus 68 (MHV-68) is a related γ2-herpesvirus frequently used as a model to study the biology of γ-herpesviruses in vivo. The KSHV latency-associated nuclear antigen (kLANA) and the MHV68 mLANA (orf73) protein are required for latent viral replication and persistence. Latent episomal KSHV genomes and kLANA form nuclear microdomains, termed ‘LANA speckles’, which also contain cellular chromatin proteins, including BRD2 and BRD4, members of the BRD/BET family of chromatin modulators. We solved the X-ray crystal structure of the C-terminal DNA binding domains (CTD) of kLANA and MHV-68 mLANA. While these structures share the overall fold with the EBNA1 protein of Epstein-Barr virus, they differ substantially in their surface characteristics. Opposite to the DNA binding site, both kLANA and mLANA CTD contain a characteristic lysine-rich positively charged surface patch, which appears to be a unique feature of γ2-herpesviral LANA proteins. Importantly, kLANA and mLANA CTD dimers undergo higher order oligomerization. Using NMR spectroscopy we identified a specific binding site for the ET domains of BRD2/4 on kLANA. Functional studies employing multiple kLANA mutants indicate that the oligomerization of native kLANA CTD dimers, the characteristic basic patch and the ET binding site on the kLANA surface are required for the formation of kLANA ‘nuclear speckles’ and latent replication. Similarly, the basic patch on mLANA contributes to the establishment of MHV-68 latency in spleen cells in vivo. In summary, our data provide a structural basis for the formation of higher order LANA oligomers, which is required for nuclear speckle formation, latent replication and viral persistence. PMID:24146614

  4. Kaposi's sarcoma-associated herpesvirus K-Rta exhibits SUMO-targeting ubiquitin ligase (STUbL) like activity and is essential for viral reactivation.

    PubMed

    Izumiya, Yoshihiro; Kobayashi, Keisuke; Kim, Kevin Y; Pochampalli, Mamata; Izumiya, Chie; Shevchenko, Bogdan; Wang, Don-Hong; Huerta, Steve B; Martinez, Anthony; Campbell, Mel; Kung, Hsing-Jien

    2013-01-01

    The small ubiquitin-like modifier (SUMO) is a protein that regulates a wide variety of cellular processes by covalent attachment of SUMO moieties to a diverse array of target proteins. Sumoylation also plays an important role in the replication of many viruses. Previously, we showed that Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a SUMO-ligase, K-bZIP, which catalyzes sumoylation of host and viral proteins. We report here that this virus also encodes a gene that functions as a SUMO-targeting ubiquitin-ligase (STUbL) which preferentially targets sumoylated proteins for degradation. K-Rta, the major transcriptional factor which turns on the entire lytic cycle, was recently found to have ubiquitin ligase activity toward a selected set of substrates. We show in this study that K-Rta contains multiple SIMs (SUMO interacting motif) and binds SUMOs with higher affinity toward SUMO-multimers. Like RNF4, the prototypic cellular STUbL, K-Rta degrades SUMO-2/3 and SUMO-2/3 modified proteins, including promyelocytic leukemia (PML) and K-bZIP. PML-NBs (nuclear bodies) or ND-10 are storage warehouses for sumoylated proteins, which negatively regulate herpesvirus infection, as part of the intrinsic immune response. Herpesviruses have evolved different ways to degrade or disperse PML bodies, and KSHV utilizes K-Rta to inhibit PML-NBs formation. This process depends on K-Rta's ability to bind SUMO, as a K-Rta SIM mutant does not effectively degrade PML. Mutations in the K-Rta Ring finger-like domain or SIM significantly inhibited K-Rta transactivation activity in reporter assays and in the course of viral reactivation. Finally, KSHV with a mutation in the Ring finger-like domain or SIM of K-Rta replicates poorly in culture, indicating that reducing SUMO-conjugates in host cells is important for viral replication. To our knowledge, this is the first virus which encodes both a SUMO ligase and a SUMO-targeting ubiquitin ligase that together may generate unique gene

  5. Kaposi's Sarcoma-Associated Herpesvirus K-Rta Exhibits SUMO-Targeting Ubiquitin Ligase (STUbL) Like Activity and Is Essential for Viral Reactivation

    PubMed Central

    Izumiya, Yoshihiro; Kobayashi, Keisuke; Kim, Kevin Y.; Pochampalli, Mamata; Izumiya, Chie; Shevchenko, Bogdan; Wang, Don-Hong; Huerta, Steve B.; Martinez, Anthony; Campbell, Mel; Kung, Hsing-Jien

    2013-01-01

    The small ubiquitin-like modifier (SUMO) is a protein that regulates a wide variety of cellular processes by covalent attachment of SUMO moieties to a diverse array of target proteins. Sumoylation also plays an important role in the replication of many viruses. Previously, we showed that Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a SUMO-ligase, K-bZIP, which catalyzes sumoylation of host and viral proteins. We report here that this virus also encodes a gene that functions as a SUMO-targeting ubiquitin-ligase (STUbL) which preferentially targets sumoylated proteins for degradation. K-Rta, the major transcriptional factor which turns on the entire lytic cycle, was recently found to have ubiquitin ligase activity toward a selected set of substrates. We show in this study that K-Rta contains multiple SIMs (SUMO interacting motif) and binds SUMOs with higher affinity toward SUMO-multimers. Like RNF4, the prototypic cellular STUbL, K-Rta degrades SUMO-2/3 and SUMO-2/3 modified proteins, including promyelocytic leukemia (PML) and K-bZIP. PML-NBs (nuclear bodies) or ND-10 are storage warehouses for sumoylated proteins, which negatively regulate herpesvirus infection, as part of the intrinsic immune response. Herpesviruses have evolved different ways to degrade or disperse PML bodies, and KSHV utilizes K-Rta to inhibit PML-NBs formation. This process depends on K-Rta's ability to bind SUMO, as a K-Rta SIM mutant does not effectively degrade PML. Mutations in the K-Rta Ring finger-like domain or SIM significantly inhibited K-Rta transactivation activity in reporter assays and in the course of viral reactivation. Finally, KSHV with a mutation in the Ring finger-like domain or SIM of K-Rta replicates poorly in culture, indicating that reducing SUMO-conjugates in host cells is important for viral replication. To our knowledge, this is the first virus which encodes both a SUMO ligase and a SUMO-targeting ubiquitin ligase that together may generate unique gene

  6. p130Cas Scaffolds the Signalosome To Direct Adaptor-Effector Cross Talk during Kaposi's Sarcoma-Associated Herpesvirus Trafficking in Human Microvascular Dermal Endothelial Cells

    PubMed Central

    Bandyopadhyay, Chirosree; Veettil, Mohanan Valiya; Dutta, Sujoy

    2014-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with cell surface receptors, such as heparan sulfate, integrins (α3β1, αVβ3, and αVβ5), and EphrinA2 (EphA2), and activates focal adhesion kinase (FAK), Src, phosphoinositol 3-kinase (PI3-K), c-Cbl, and RhoA GTPase signal molecules early during lipid raft (LR)-dependent productive macropinocytic entry into human dermal microvascular endothelial cells. Our recent studies have identified CIB1 as a signal amplifier facilitating EphA2 phosphorylation and subsequent cytoskeletal cross talk during KSHV macropinocytosis. Although CIB1 lacks an enzymatic activity and traditional adaptor domain or known interacting sequence, it associated with the KSHV entry signal complex and the CIB1-KSHV association was sustained over 30 min postinfection. To identify factors scaffolding the EphA2-CIB1 signal axis, the role of major cellular scaffold protein p130Cas (Crk-associated substrate of Src) was investigated. Inhibitor and small interfering RNA (siRNA) studies demonstrated that KSHV induced p130Cas in an EphA2-, CIB1-, and Src-dependent manner. p130Cas and Crk were associated with KSHV, LRs, EphA2, and CIB1 early during infection. Live-cell microscopy and biochemical studies demonstrated that p130Cas knockdown did not affect KSHV entry but significantly reduced productive nuclear trafficking of viral DNA and routed KSHV to lysosomal degradation. p130Cas aided in scaffolding adaptor Crk to downstream guanine nucleotide exchange factor phospho-C3G possibly to coordinate GTPase signaling during KSHV trafficking. Collectively, these studies demonstrate that p130Cas acts as a bridging molecule between the KSHV-induced entry signal complex and the downstream trafficking signalosome in endothelial cells and suggest that simultaneous targeting of KSHV entry receptors with p130Cas would be an attractive potential avenue for therapeutic intervention in KSHV infection. IMPORTANCE Eukaryotic cell adaptor molecules

  7. Accumulation of Heterochromatin Components on the Terminal Repeat Sequence of Kaposi's Sarcoma-Associated Herpesvirus Mediated by the Latency-Associated Nuclear Antigen

    PubMed Central

    Sakakibara, Shuhei; Ueda, Keiji; Nishimura, Ken; Do, Eunju; Ohsaki, Eriko; Okuno, Toshiomi; Yamanishi, Koichi

    2004-01-01

    In the latent infection of Kaposi's sarcoma-associated herpesvirus (KSHV), its 160-kb circularized episomal DNA is replicated and maintained in the host nucleus. KSHV latency-associated nuclear antigen (LANA) is a key factor for maintaining viral latency. LANA binds to the terminal repeat (TR) DNA of the viral genome, leading to its localization to specific dot structures in the nucleus. In such an infected cell, the expression of the viral genes is restricted by a mechanism that is still unclear. Here, we found that LANA interacts with SUV39H1 histone methyltransferase, a key component of heterochromatin formation, as determined by use of a DNA pull-down assay with a biotinylated DNA fragment that contained a LANA-specific binding sequence and a maltose-binding protein pull-down assay. The diffuse localization of LANA on the chromosomes of uninfected cells changed to a punctate one with the introduction of a bacterial artificial chromosome containing most of the TR region, and SUV39H1 clearly colocalized with the LANA-associated dots. Thus, the LANA foci in KSHV-infected cells seemed to include SUV39H1 as well as heterochromatin protein 1. Furthermore, a chromatin immunoprecipitation assay revealed that the TR and the open reading frame (ORF) K1 and ORF50/RTA genes, but not the ORF73/LANA gene, lay within the heterochromatin during KSHV latency. Taken together, these observations indicate that LANA recruits heterochromatin components to the viral genome, which may lead to the establishment of viral latency and govern the transcription program. PMID:15220403

  8. Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

    PubMed Central

    Sun, Zhiguo; Jha, Hem Chandra

    2015-01-01

    ABSTRACT Latent DNA replication of Kaposi's sarcoma-associated herpesvirus (KSHV) initiates at the terminal repeat (TR) element and requires trans-acting elements, both viral and cellular, such as ORCs, MCMs, and latency-associated nuclear antigen (LANA). However, how cellular proteins are recruited to the viral genome is not very clear. Here, we demonstrated that the host cellular protein, Bub1, is involved in KSHV latent DNA replication. We show that Bub1 constitutively interacts with proliferating cell nuclear antigen (PCNA) via a highly conserved PIP box motif within the kinase domain. Furthermore, we demonstrated that Bub1 can form a complex with LANA and PCNA in KSHV-positive cells. This strongly indicated that Bub1 serves as a scaffold or molecular bridge between LANA and PCNA. LANA recruited PCNA to the KSHV genome via Bub1 to initiate viral replication in S phase and interacted with PCNA to promote its monoubiquitination in response to UV-induced damage for translesion DNA synthesis. This resulted in increased survival of KSHV-infected cells. IMPORTANCE During latency in KSHV-infected cells, the viral episomal DNA replicates once each cell cycle. KSHV does not express DNA replication proteins during latency. Instead, KSHV LANA recruits the host cell DNA replication machinery to the replication origin. However, the mechanism by which LANA mediates replication is uncertain. Here, we show that LANA is able to form a complex with PCNA, a critical protein for viral DNA replication. Furthermore, our findings suggest that Bub1, a spindle checkpoint protein, serves as a scaffold or molecular bridge between LANA and PCNA. Our data further support a role for Bub1 and LANA in PCNA-mediated cellular DNA replication processes as well as monoubiquitination of PCNA in response to UV damage. These data reveal a therapeutic target for inhibition of KSHV persistence in malignant cells. PMID:26223641

  9. The minimal replicator element of the Kaposi's sarcoma-associated herpesvirus terminal repeat supports replication in a semiconservative and cell-cycle-dependent manner.

    PubMed

    Verma, Subhash C; Choudhuri, Tathagata; Robertson, Erle S

    2007-04-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) persists as episomes in infected cells by circularizing at the terminal repeats (TRs). The KSHV episome carries multiple reiterated copies of the terminal repeat, and each copy is capable of supporting replication. Expression of the latency-associated nuclear antigen (LANA) is critical for the replication of TR-containing plasmids. A 32-bp sequence upstream of LANA binding site 1 (LBS1), referred to as RE (replication element), along with LANA binding sites 1 and 2 (RE-LBS1/2), is sufficient to support replication (J. Hu and R. Renne, J. Virol. 79:2637-2642, 2005). In this report we demonstrate that the minimal replicator element (RE-LBS1/2) replicates in synchrony with the host cellular DNA, and only once, in a cell-cycle-dependent manner. Overexpression of the mammalian replication inhibitor geminin blocked replication of the plasmid containing the minimal replicator element, confirming the involvement of the host cellular replication control mechanism, and prevented rereplication of the plasmid in the same cell cycle. Overexpression of Cdt1 also rescued the replicative ability of the RE-LBS1/2-containing plasmids. A chromatin immunoprecipitation assay performed using anti-origin recognition complex 2 (alpha-ORC2) and alpha-LANA antibodies from cells transfected with RE-LBS1/2, RE-LBS1, LBS1, or RE showed the association of ORC2 with the RE region. Expression of LANA increased the number of copies of chromatin-bound DNA of replication elements, suggesting that LANA is important for the recruitment of ORCs and may contribute to the stabilization of the replication protein complexes at the RE site. PMID:17151118

  10. Latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus interacts with origin recognition complexes at the LANA binding sequence within the terminal repeats.

    PubMed

    Verma, Subhash C; Choudhuri, Tathagata; Kaul, Rajeev; Robertson, Erle S

    2006-03-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) DNA persists in latently infected cells as an episome via tethering to the host chromosomes. The latency-associated nuclear antigen (LANA) of KSHV binds to the cis-acting elements in the terminal repeat (TR) region of the genome through its carboxy terminus. Previous studies have demonstrated that LANA is important for episome maintenance and replication of the TR-containing plasmids. Here we report that LANA associates with origin recognition complexes (ORCs) when bound to its 17-bp LANA binding cognate sequence (LBS). Chromatin immunoprecipitation of multiple regions across the entire genome from two KSHV-infected cell lines, BC-3 and BCBL-1, revealed that the ORCs predominantly associated with the chromatin structure at the TR as well as two regions within the long unique region of the genome. Coimmunoprecipitation of ORCs with LANA-specific antibodies shows that ORCs can bind and form complexes with LANA in cells. This association was further supported by in vitro binding studies which showed that ORCs associate with LANA predominantly through the carboxy-terminal DNA binding region. KSHV-positive BC-3 and BCBL-1 cells arrested in G(1)/S phase showed colocalization of LANA with ORCs. Furthermore, replication of The TR-containing plasmid required both the N- and C termini of LANA in 293 and DG75 cells. Interestingly, our studies did not detect cellular ORCs associated with packaged viral DNA as an analysis of purified virions did not reveal the presence of ORCs, minichromosome maintenance proteins, or LANA. PMID:16474132

  11. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 3 Inhibits Gamma Interferon and Major Histocompatibility Complex Class II Expression▿†

    PubMed Central

    Schmidt, Katharina; Wies, Effi; Neipel, Frank

    2011-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) carries four genes with homology to human interferon regulatory factors (IRFs). One of these IRFs, the viral interferon regulatory factor 3 (vIRF-3), is expressed in latently infected primary effusion lymphoma (PEL) cells and required for their continuous proliferation. Moreover, vIRF-3 is known to be involved in modulation of the type I interferon (IFN) response. We now show that vIRF-3 also interferes with the type II interferon system and antigen presentation to the adaptive immune system. Starting with an analysis of the transcriptome, we show that vIRF-3 inhibits expression of major histocompatibility complex class II (MHC II) molecules: small interfering RNA (siRNA)-mediated knockdown of vIRF-3 in KSHV-infected PEL cell lines resulted in increased MHC II levels; overexpression of vIRF-3 in KSHV-negative B cells leads to downmodulation of MHC II. This regulation could be traced back to inhibition of class II transactivator (CIITA) transcription by vIRF-3. Reporter assays revealed that the gamma interferon (IFN-γ)-sensitive CIITA promoters PIV and PIII were inhibited by vIRF-3. Consistently, IFN-γ levels increased upon vIRF-3 knockdown in PEL cells. IFN-γ regulation by vIRF-3 was confirmed in reporter assays as well as by upregulation of typical IFN-γ target genes upon knockdown of vIRF-3 in PEL cells. In summary, we conclude that vIRF-3 contributes to the viral immunoevasion by downregulation of IFN-γ and CIITA and thus MHC II expression. PMID:21345951

  12. Genomewide mapping and screening of Kaposi's sarcoma-associated herpesvirus (KSHV) 3' untranslated regions identify bicistronic and polycistronic viral transcripts as frequent targets of KSHV microRNAs.

    PubMed

    Bai, Zhiqiang; Huang, Yufei; Li, Wan; Zhu, Ying; Jung, Jae U; Lu, Chun; Gao, Shou-Jiang

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) encodes over 90 genes and 25 microRNAs (miRNAs). The KSHV life cycle is tightly regulated to ensure persistent infection in the host. In particular, miRNAs, which primarily exert their effects by binding to the 3' untranslated regions (3'UTRs) of target transcripts, have recently emerged as key regulators of KSHV life cycle. Although studies with RNA cross-linking immunoprecipitation approach have identified numerous targets of KSHV miRNAs, few of these targets are of viral origin because most KSHV 3'UTRs have not been characterized. Thus, the extents of viral genes targeted by KSHV miRNAs remain elusive. Here, we report the mapping of the 3'UTRs of 74 KSHV genes and the effects of KSHV miRNAs on the control of these 3'UTR-mediated gene expressions. This analysis reveals new bicistronic and polycistronic transcripts of KSHV genes. Due to the 5'-distal open reading frames (ORFs), KSHV bicistronic or polycistronic transcripts have significantly longer 3'UTRs than do KSHV monocistronic transcripts. Furthermore, screening of the 3'UTR reporters has identified 28 potential new targets of KSHV miRNAs, of which 11 (39%) are bicistronic or polycistronic transcripts. Reporter mutagenesis demonstrates that miR-K3 specifically targets ORF31-33 transcripts at the lytic locus via two binding sites in the ORF33 coding region, whereas miR-K10a-3p and miR-K10b-3p and their variants target ORF71-73 transcripts at the latent locus through distinct binding sites in both 5'-distal ORFs and intergenic regions. Our results indicate that KSHV miRNAs frequently target the 5'-distal coding regions of bicistronic or polycistronic transcripts and highlight the unique features of KSHV miRNAs in regulating gene expression and life cycle. PMID:24155407

  13. Kaposi's sarcoma-associated herpesvirus noncoding polyadenylated nuclear RNA interacts with virus- and host cell-encoded proteins and suppresses expression of genes involved in immune modulation.

    PubMed

    Rossetto, Cyprian C; Pari, Gregory S

    2011-12-01

    During lytic infection, Kaposi's sarcoma-associated herpesvirus (KSHV) expresses a polyadenylated nuclear RNA (PAN RNA). This noncoding RNA (ncRNA) is localized to the nucleus and is the most abundant viral RNA during lytic infection; however, to date, the role of PAN RNA in the virus life cycle is unknown. Many examples exist where ncRNAs have a defined key regulatory function controlling gene expression by various mechanisms. Our goal for this study was to identify putative binding partners for PAN RNA in an effort to elucidate a possible function for the transcript in KSHV infection. We employed an in vitro affinity protocol where PAN RNA was used as bait for factors present in BCBL-1 cell nuclear extract to show that PAN RNA interacts with several virus- and host cell-encoded factors, including histones H1 and H2A, mitochondrial and cellular single-stranded binding proteins (SSBPs), and interferon regulatory factor 4 (IRF4). RNA chromatin immunoprecipitation (ChIP) assays confirmed that PAN RNA interacted with these factors in the infected cell environment. A luciferase reporter assay showed that PAN RNA expression interfered with the ability of IRF4/PU.1 to activate the interleukin-4 (IL-4) promoter, strongly suggesting a role for PAN RNA in immune modulation. Since the proteomic screen and functional data suggested a role in immune responses, we investigated if constitutive PAN RNA expression could affect other genes involved in immune responses. PAN RNA expression decreased expression of gamma interferon, interleukin-18, alpha interferon 16, and RNase L. These data strongly suggest that PAN RNA interacts with viral and cellular proteins and can function as an immune modulator. PMID:21957289

  14. Functional Characterization of Kaposi's Sarcoma-Associated Herpesvirus Open Reading Frame K8 by Bacterial Artificial Chromosome-Based Mutagenesis▿ †

    PubMed Central

    Wang, Yan; Sathish, Narayanan; Hollow, Charles; Yuan, Yan

    2011-01-01

    The open reading frame K8 of Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a basic leucine zipper (bZip) protein that binds to the origin of viral DNA replication and is an integral component of viral lytic DNA replication complex. Moreover, K8 physically interacts with replication and transcription activator (RTA) and represses its transactivation activity on several viral promoters. To investigate the role of this protein in viral life cycle, we constructed two K8-null recombinant mutant viruses (BAC-ΔK8 and BAC-stopK8) by using a bacterial artificial chromosome (BAC) system. Latent viral infection can be reconstituted in 293T and BJAB cells with wild-type and the K8-null recombinant viruses by introducing the cloned viral genomes into the cells. When the cells carrying these viruses were induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) and sodium butyrate, no significant difference was seen in overall viral gene expression between wild-type and K8-null viruses, with lytic DNA replication still active in the latter. However, 293T cells harboring K8-null mutant viruses, either BAC-ΔK8 or BAC-stopK8, displayed lower copy numbers of latent KSHV genome in comparison with wild-type viruses. Furthermore, although K8 deficiency appeared to not affect infectivity when K8-null viruses were used to infect 293T, primary human microvascular dermal endothelial and human foreskin fibroblast cells, they exhibited much lower viral genome copy numbers in all types of cell compared to wild-type viruses. Taken together, these data suggest a possible role of K8 in abortive lytic DNA replication occurring in early stages of de novo infection or in the maintenance of latent viral genomes. PMID:21159864

  15. The CD8 and CD4 T-Cell Response against Kaposi's Sarcoma-Associated Herpesvirus Is Skewed Towards Early and Late Lytic Antigens

    PubMed Central

    Robey, Rebecca C.; Lagos, Dimitrios; Gratrix, Fiona; Henderson, Stephen; Matthews, Nick C.; Vart, Richard J.; Bower, Mark; Boshoff, Chris; Gotch, Frances M.

    2009-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is causally related to Kaposi's sarcoma (KS), the most common malignancy in untreated individuals with HIV/AIDS. The adaptive T-cell immune response against KSHV has not been fully characterized. To achieve a better understanding of the antigenic repertoire of the CD8 and CD4 T-cell responses against KSHV, we constructed a library of lentiviral expression vectors each coding for one of 31 individual KSHV open reading frames (ORFs). We used these to transduce monocyte-derived dendritic cells (moDCs) isolated from 14 KSHV-seropositive (12 HIV-positive) and 7 KSHV-seronegative (4 HIV-positive) individuals. moDCs were transduced with up to 3 KSHV ORFs simultaneously (ORFs grouped according to their expression during the viral life cycle). Transduced moDCs naturally process the KSHV genes and present the resulting antigens in the context of MHC class I and II. Transduced moDCs were cultured with purified autologous T cells and the CD8 and CD4 T-cell proliferative responses to each KSHV ORF (or group) was assessed using a CFSE dye-based assay. Two pools of early lytic KSHV genes ([ORF8/ORF49/ORF61] and [ORF59/ORF65/K4.1]) were frequently-recognized targets of both CD8 and CD4 T cells from KSHV seropositive individuals. One pool of late lytic KSHV genes ([ORF28/ORF36/ORF37]) was a frequently-recognized CD8 target and another pool of late genes ([ORF33/K1/K8.1]) was a frequently-recognized CD4 target. We report that both the CD8 and CD4 T-cell responses against KSHV are skewed towards genes expressed in the early and late phases of the viral lytic cycle, and identify some previously unknown targets of these responses. This knowledge will be important to future immunological investigations into KSHV and may eventually lead to the development of better immunotherapies for KSHV-related diseases. PMID:19536280

  16. Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 during De Novo Infection of Endothelial Cells to Create a Microenvironment Conducive to Infection

    PubMed Central

    Gjyshi, Olsi; Bottero, Virginie; Veettil, Mohanan Valliya; Dutta, Sujoy; Singh, Vivek Vikram; Chikoti, Leela; Chandran, Bala

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS) and primary effusion B-cell lymphoma. KSHV induces reactive oxygen species (ROS) early during infection of human dermal microvascular endothelial (HMVEC-d) cells that are critical for virus entry. One of the downstream targets of ROS is nuclear factor E2-related factor 2 (Nrf2), a transcription factor with important anti-oxidative functions. Here, we show that KS skin lesions have high Nrf2 activity compared to healthy skin tissue. Within 30 minutes of de novo KSHV infection of HMVEC-d cells, we observed Nrf2 activation through ROS-mediated dissociation from its inhibitor Keap1, Ser-40 phosphorylation, and subsequent nuclear translocation. KSHV binding and consequent signaling through Src, PI3-K and PKC-ζ were also important for Nrf2 stability, phosphorylation and transcriptional activity. Although Nrf2 was dispensable for ROS homeostasis, it was essential for the induction of COX-2, VEGF-A, VEGF-D, Bcl-2, NQO1, GCS, HO1, TKT, TALDO and G6PD gene expression in KSHV-infected HMVEC-d cells. The COX-2 product PGE2 induced Nrf2 activity through paracrine and autocrine signaling, creating a feed-forward loop between COX-2 and Nrf2. vFLIP, a product of KSHV latent gene ORF71, induced Nrf2 and its target genes NQO1 and HO1. Activated Nrf2 colocalized with the KSHV genome as well as with the latency protein LANA-1. Nrf2 knockdown enhanced ORF73 expression while reducing ORF50 and other lytic gene expression without affecting KSHV entry or genome nuclear delivery. Collectively, these studies for the first time demonstrate that during de novo infection, KSHV induces Nrf2 through intricate mechanisms involving multiple signal molecules, which is important for its ability to manipulate host and viral genes, creating a microenvironment conducive to KSHV infection. Thus, Nrf2 is a potential attractive target to intervene in KSHV infection and the associated maladies. PMID:25340789

  17. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G1-S Cell Cycle Progression via Deregulation of the cyclin D1 Gene.

    PubMed

    Lee, Hye-Ra; Mitra, Jaba; Lee, Stacy; Gao, Shou-Jiang; Oh, Tae-Kwang; Kim, Myung Hee; Ha, Taekjip; Jung, Jae U

    2016-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates the host cell cycle to create an environment optimal for its viral-DNA replication during the lytic life cycle. We report here that KSHV vIRF4 targets the β-catenin/CBP cofactor and blocks its occupancy on the cyclin D1 promoter, suppressing the G1-S cell cycle progression and enhancing KSHV replication. This shows that KSHV vIRF4 suppresses host G1-S transition, possibly providing an intracellular milieu favorable for its replication. PMID:26491150

  18. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 1 Interacts with a Member of the Interferon-Stimulated Gene 15 Pathway

    PubMed Central

    Jacobs, Sarah R.; Stopford, Charles M.; West, John A.; Bennett, Christopher L.; Giffin, Louise

    2015-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus known to establish lifelong latency in the human host. We and others have previously shown that three KSHV homologs of cellular interferon regulatory factors (IRFs), known as viral IRFs (vIRFs), participate in evasion of the host interferon (IFN) response. We report that vIRF1 interacts with the cellular interferon-stimulated gene 15 (ISG15) E3 ligase, HERC5, in the context of Toll-like receptor 3 (TLR3) activation and IFN induction. The ISG15 protein is covalently conjugated to target proteins upon activation of the interferon response. Interaction between vIRF1 and HERC5 was confirmed by immunoprecipitation, and the region between amino acids 224 and 349 of vIRF1 was required for interaction with HERC5. We further report that expression of vIRF1 in the context of TLR3 activation results in decreased ISG15 conjugation of proteins. Specifically, TLR3-induced ISG15 conjugation and protein levels of cellular IRF3, a known ISG15 target, were decreased in the presence of vIRF1 compared to the control. vIRF1 itself was also identified as a target of ISG15 conjugation. KSHV-infected cells exhibited increased ISG15 conjugation upon reactivation from latency in coordination with increased IFN. Furthermore, knockdown of ISG15 in latently infected cells resulted in a higher level of KSHV reactivation and an increase in infectious virus. These data suggest that the KSHV vIRF1 protein affects ISG15 conjugation and interferon responses and may contribute to effective KSHV replication. IMPORTANCE The KSHV vIRF1 protein can inhibit interferon activation in response to viral infection. We identified a cellular protein named HERC5, which is the major ligase for ISG15, as a vIRF1 binding partner. vIRF1 association with HERC5 altered ISG15 modification of cellular proteins, and knockdown of ISG15 augmented reactivation of KSHV from latency. PMID:26355087

  19. Identification of Properties of the Kaposi's Sarcoma-Associated Herpesvirus Latent Origin of Replication That Are Essential for the Efficient Establishment and Maintenance of Intact Plasmids

    PubMed Central

    Shrestha, Prabha

    2014-01-01

    ABSTRACT The maintenance of latent Kaposi's sarcoma-associated herpesvirus (KSHV) genomes is mediated in cis by their terminal repeats (TR). A KSHV genome can have 16 to 50 copies of the 801-bp TR, each of which harbors a 71-bp-long minimal replicator element (MRE). A single MRE can support replication in transient assays, and the presence of as few as two TRs appears to support establishment of KSHV-derived plasmids. Why then does KSHV have such redundancy and heterogeneity in the number of TRs? By determining the abilities of KSHV-derived plasmids containing various numbers of the TRs and MREs to be established and maintained in the long term, we have found that plasmids with fewer than 16 TRs or those with tandem repeats of the MREs are maintained inefficiently, as shown by both their decreased abilities to support formation of colonies and their instability, resulting in frequent rearrangements yielding larger plasmids during and after establishment. These defects often can be overcome by adding the Epstein-Barr virus (EBV) partitioning element, FR (i.e., family of repeats), in cis to these plasmids. In addition we have found that the spacing between MREs is important for their functions, too. Thus, two properties of KSHV's origin of latent replication essential for the efficient establishment and maintenance of viral plasmids stably are (i) the presence of approximately 16 copies of the TR, which are needed for efficient partitioning, and (ii) the presence of at least 2 MRE units separated by 801 bp of center-to-center spacing, which are required for efficient synthesis. IMPORTANCE KSHV is a human tumor virus that maintains its genome as a plasmid in lymphoid tumor cells. Each plasmid DNA molecule encodes many origins of synthesis. Here we show that these many origins provide an essential advantage to KSHV, allowing the DNAs to be maintained without rearrangement. We find also that the correct spacing between KSHV's origins of DNA synthesis is required for

  20. Kaposi sarcoma associated herpesvirus (KSHV) induces AKT hyperphosphorylation, bortezomib-resistance and GLUT-1 plasma membrane exposure in THP-1 monocytic cell line

    PubMed Central

    2013-01-01

    Background Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway regulates multiple cellular processes such as cell proliferation, evasion from apoptosis, migration, glucose metabolism, protein synthesis and proper differentiation in immune cells. Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several human malignancies, expresses a variety of latent and lytic proteins able to activate PI3K/AKT pathway, promoting the growth of infected cells and a successful viral infection. Results We found that KSHV latent infection of THP-1 cells, a human monocytic cell line derived from an acute monocytic leukemia patient, resulted in an increase of AKT phoshorylation, not susceptible to bortezomib-induced dephosphorylation, compared to the mock-infected THP-1. Accordingly, THP-1-infected cells displayed increased resistance to the bortezomib cytotoxic effect in comparison to the uninfected cells, which was counteracted by pre-treatment with AKT-specific inhibitors. Finally, AKT hyperactivation by KSHV infection correlated with plasma membrane exposure of glucose transporter GLUT1, particularly evident during bortezomib treatment. GLUT1 membrane trafficking is a characteristic of malignant cells and underlies a change of glucose metabolism that ensures the survival to highly proliferating cells and render these cells highly dependent on glycolysis. GLUT1 membrane trafficking in KSHV-infected THP-1 cells indeed led to increased sensitivity to cell death induced by the glycolysis inhibitor 2-Deoxy-D-glucose (2DG), further potentiated by its combination with bortezomib. Conclusions KSHV confers to the THP-1 infected cells an oncogenic potential by altering the phosphorylation, expression and localization of key molecules that control cell survival and metabolism such as AKT and GLUT1. Such modifications in one hand lead to resistance to cell death induced by some chemotherapeutic drugs such as bortezomib

  1. Primary B Lymphocytes Infected with Kaposi's Sarcoma-Associated Herpesvirus Can Be Expanded In Vitro and Are Recognized by LANA-Specific CD4+ T Cells

    PubMed Central

    Nicol, Samantha M.; Sabbah, Shereen; Brulois, Kevin F.; Jung, Jae U.; Bell, Andrew I.

    2016-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) has tropism for B lymphocytes, in which it establishes latency, and can also cause lymphoproliferative disorders of these cells manifesting as primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). T cell immunity is vital for the control of KSHV infection and disease; however, few models of B lymphocyte infection exist to study immune recognition of such cells. Here, we developed a model of B lymphocyte infection with KSHV in which infected tonsillar B lymphocytes were expanded by providing mitogenic stimuli and then challenged with KSHV-specific CD4+ T cells. The infected cells expressed viral proteins found in PELs, namely, LANA and viral IRF3 (vIRF3), albeit at lower levels, with similar patterns of gene expression for the major latency, viral interleukin 6 (vIL-6), and vIRF3 transcripts. Despite low-level expression of open reading frame 50 (ORF50), transcripts for the immune evasion genes K3 and K5 were detected, with some downregulation of cell surface-expressed CD86 and ICAM. The vast majority of infected lymphocytes expressed IgM heavy chains with Igλ light chains, recapitulating the features seen in infected cells in MCD. We assessed the ability of the infected lymphocytes to be targeted by a panel of major histocompatibility complex (MHC) class II-matched CD4+ T cells and found that LANA-specific T cells restricted to different epitopes recognized these infected cells. Given that at least some KSHV latent antigens are thought to be poor targets for CD8+ T cells, we suggest that CD4+ T cells are potentially important effectors for the in vivo control of KSHV-infected B lymphocytes. IMPORTANCE KSHV establishes a latent reservoir within B lymphocytes, but few models exist to study KSHV-infected B cells other than the transformed PEL cell lines, which have likely accrued mutations during the transformation process. We developed a model of KSHV-infected primary B lymphocytes that

  2. Cooperation between Viral Interferon Regulatory Factor 4 and RTA To Activate a Subset of Kaposi's Sarcoma-Associated Herpesvirus Lytic Promoters

    PubMed Central

    Xi, Xiangmei; Persson, Linda M.; O'Brien, Michael W.; Mohr, Ian

    2012-01-01

    The four Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded interferon (IFN) regulatory factor homologues (vIRF1 to vIRF4) are used to counter innate immune defenses and suppress p53. The vIRF genes are arranged in tandem but differ in function and expression. In KSHV-infected effusion lymphoma lines, K10.5/vIRF3 and K11/vIRF2 mRNAs are readily detected during latency, whereas K9/vIRF1 and K10/vIRF4 mRNAs are upregulated during reactivation. Here we show that the K10/vIRF4 promoter responds to the lytic switch protein RTA in KSHV-infected cells but is essentially unresponsive in uninfected cells. Coexpression of RTA with vIRF4 is sufficient to restore regulation, a property not shared by other vIRFs. The K9/vIRF1 promoter behaves similarly, and production of infectious virus is enhanced by the presence of vIRF4. Synergy requires the DNA-binding domain (DBD) and C-terminal IRF homology regions of vIRF4. Mutations of arginine residues within the putative DNA recognition helix of vIRF4 or the invariant cysteines of the adjacent CxxC motif abolish cooperation with RTA, in the latter case by preventing self-association. The oligomerization and transactivation functions of RTA are also essential for synergy. The K10/vIRF4 promoter contains two transcription start sites (TSSs), and a 105-bp fragment containing the proximal promoter is responsive to vIRF4/RTA. Binding of a cellular factor(s) to this fragment is altered when both viral proteins are present, suggesting a possible mechanism for transcriptional synergy. Reliance on coregulators encoded by either the host or viral genome provides an elegant strategy for expanding the regulatory potential of a master regulator, such as RTA. PMID:22090118

  3. Activated Nrf2 Interacts with Kaposi's Sarcoma-Associated Herpesvirus Latency Protein LANA-1 and Host Protein KAP1 To Mediate Global Lytic Gene Repression

    PubMed Central

    Gjyshi, Olsi; Roy, Arunava; Dutta, Sujoy; Veettil, Mohanan Valiya; Dutta, Dipanjan

    2015-01-01

    ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. We have previously shown that KSHV utilizes the host transcription factor Nrf2 to aid in infection of endothelial cells and oncogenesis. Here, we investigate the role of Nrf2 in PEL and PEL-derived cell lines and show that KSHV latency induces Nrf2 protein levels and transcriptional activity through the COX-2/PGE2/EP4/PKCζ axis. Next-generation sequencing of KSHV transcripts in the PEL-derived BCBL-1 cell line revealed that knockdown of this activated Nrf2 results in global elevation of lytic genes. Nrf2 inhibition by the chemical brusatol also induces lytic gene expression. Both Nrf2 knockdown and brusatol-mediated inhibition induced KSHV lytic reactivation in BCBL-1 cells. In a series of follow-up experiments, we characterized the mechanism of Nrf2-mediated regulation of KSHV lytic repression during latency. Biochemical assays showed that Nrf2 interacted with KSHV latency-associated nuclear antigen 1 (LANA-1) and the host transcriptional repressor KAP1, which together have been shown to repress lytic gene expression. Promoter studies showed that although Nrf2 alone induces the open reading frame 50 (ORF50) promoter, its association with LANA-1 and KAP1 abrogates this effect. Interestingly, LANA-1 is crucial for efficient KAP1/Nrf2 association, while Nrf2 is essential for LANA-1 and KAP1 recruitment to the ORF50 promoter and its repression. Overall, these results suggest that activated Nrf2, LANA-1, and KAP1 assemble on the ORF50 promoter in a temporal fashion. Initially, Nrf2 binds to and activates the ORF50 promoter during early de novo infection, an effect that is exploited during latency by LANA-1-mediated recruitment of the host transcriptional repressor KAP1 on Nrf2. Cell death assays further showed that Nrf2 and KAP1 knockdown induce significant cell death in PEL cell lines

  4. Kaposi sarcoma

    MedlinePlus

    ... HIV, a weakened immune system, and the human herpesvirus-8 (HHV-8). Kaposi sarcoma has been linked ... on foot References Kaye KM. Kaposi's sarcoma-associated herpesvirus (human herpesvirus type 8). In: Mandell GL, Bennett ...

  5. Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus Results in the Formation of Multiple Capsid Species: Isolation and Molecular Characterization of A, B, and C Capsids from a Gammaherpesvirus

    PubMed Central

    Nealon, K.; Newcomb, W. W.; Pray, T. R.; Craik, C. S.; Brown, J. C.; Kedes, D. H.

    2001-01-01

    Despite the discovery of Epstein-Barr virus more than 35 years ago, a thorough understanding of gammaherpesvirus capsid composition and structure has remained elusive. We approached this problem by purifying capsids from Kaposi's sarcoma-associated herpesvirus (KSHV), the only other known human gammaherpesvirus. The results from our biochemical and imaging analyses demonstrate that KSHV capsids possess a typical herpesvirus icosahedral capsid shell composed of four structural proteins. The hexameric and pentameric capsomers are composed of the major capsid protein (MCP) encoded by open reading frame 25. The heterotrimeric complexes, forming the capsid floor between the hexons and pentons, are each composed of one molecule of ORF62 and two molecules of ORF26. Each of these proteins has significant amino acid sequence homology to capsid proteins in alpha- and betaherpesviruses. In contrast, the fourth protein, ORF65, lacks significant sequence homology to its structural counterparts from the other subfamilies. Nevertheless, this small, basic, and highly antigenic protein decorates the surface of the capsids, as does, for example, the even smaller basic capsid protein VP26 of herpes simplex virus type 1. We have also found that, as with the alpha- and betaherpesviruses, lytic replication of KSHV leads to the formation of at least three capsid species, A, B, and C, with masses of approximately 200, 230, and 300 MDa, respectively. A capsids are empty, B capsids contain an inner array of a fifth structural protein, ORF17.5, and C capsids contain the viral genome. PMID:11222712

  6. Kaposi's sarcoma-associated herpesvirus Rta tetramers make high-affinity interactions with repetitive DNA elements in the Mta promoter to stimulate DNA binding of RBP-Jk/CSL.

    PubMed

    Palmeri, Diana; Carroll, Kyla Driscoll; Gonzalez-Lopez, Olga; Lukac, David M

    2011-11-01

    Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 [HHV-8]) is the etiologic agent of Kaposi's sarcoma (KS) and lymphoproliferative diseases. We previously demonstrated that the KSHV lytic switch protein Rta stimulates DNA binding of the cellular RBP-Jk/CSL protein, the nuclear component of the Notch pathway, on Rta target promoters. In the current study, we define the promoter requirements for formation of transcriptionally productive Rta/RBP-Jk/DNA complexes. We show that highly pure Rta footprints 7 copies of a previously undescribed repetitive element in the promoter of the essential KSHV Mta gene. We have termed this element the "CANT repeat." CANT repeats are found on both strands of DNA and have a consensus sequence of ANTGTAACANT(A/T)(A/T)T. We demonstrate that Rta tetramers make high-affinity interactions (i.e., nM) with 64 bp of the Mta promoter but not single CANT units. The number of CANT repeats, their presence in palindromes, and their positions relative to the RBP-Jk binding site determine the optimal target for Rta stimulation of RBP-Jk DNA binding and formation of ternary Rta/RBP-Jk/DNA complexes. DNA binding and tetramerization mutants of Rta fail to stimulate RBP-Jk DNA binding. Our chromatin immunoprecipitation assays show that RBP-Jk DNA binding is broadly, but selectively, stimulated across the entire KSHV genome during reactivation. We propose a model in which tetramerization of Rta allows it to straddle RBP-Jk and contact repeat units on both sides of RBP-Jk. Our study integrates high-affinity Rta DNA binding with the requirement for a cellular transcription factor in Rta transactivation. PMID:21880753

  7. The product of Kaposi's sarcoma-associated herpesvirus immediate early gene K4.2 regulates immunoglobulin secretion and calcium homeostasis by interacting with and inhibiting pERP1.

    PubMed

    Wong, Lai-Yee; Brulois, Kevin; Toth, Zsolt; Inn, Kyung-Soo; Lee, Sun-Hwa; O'Brien, Kathryn; Lee, Hyera; Gao, Shou-Jiang; Cesarman, Ethel; Ensser, Armin; Jung, Jae U

    2013-11-01

    Chaperones are proteins that assist the noncovalent folding and assembly of macromolecular polypeptide chains, ultimately preventing the formation of nonfunctional or potentially toxic protein aggregates. Plasma cell-induced-endoplasmic reticulum (ER)-resident protein 1 (pERP1) is a cellular chaperone that is preferentially expressed in marginal-zone B cells and is highly upregulated during plasma cell differentiation. While initially identified as a dedicated factor for the assembly of secreted IgM, pERP1 has since been implicated in suppressing calcium mobilization, and its expression is misregulated in multiple tumors. A number of herpesvirus immediate early gene products play important roles in the regulation of viral gene expression and/or evasion of host immune responses. Here, we report that the Kaposi's sarcoma-associated herpesvirus (KSHV) immediate early viral gene K4.2 encodes an endoplasmic reticulum-localized protein that interacts with and inhibits pERP1. Consequently, K4.2 expression interfered with immunoglobulin secretion by delaying the kinetics of immunoglobulin assembly and also led to increased responsiveness of B-cell receptor signal transduction by enhancing phosphotyrosine signals and intracellular calcium fluxes. Furthermore, K4.2 expression also appeared to contribute to maximal lytic replication by enhancing viral glycoprotein expression levels and ultimately promoting infectious-virus production. Finally, immunohistochemistry analysis showed that pERP1 expression was readily detected in KSHV-positive cells from multicentric Castleman's disease (MCD) and Kaposi's sarcoma (KS) lesions, suggesting that pERP1 may have potential roles in the KSHV life cycle and malignancy. In conclusion, our data suggest that K4.2 participates in lytic replication by enhancing calcium flux and viral glycoprotein expression, but also by interfering with immunoglobulin assembly to potentially dampen the adaptive immune response. PMID:23986581

  8. Kaposi's sarcoma associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 suppresses CXCR4 expression by upregulating miR-146a

    PubMed Central

    Punj, Vasu; Matta, Hittu; Schamus, Sandra; Tamewitz, Aletheia; Anyang, Bean; Chaudhary, Preet M.

    2009-01-01

    Kaposi's sarcoma (KS) associated herpesvirus (KSHV)-encoded viral FLICE inhibitory protein (vFLIP) K13 is a potent activator of the NF-κB pathway. Here we demonstrate that infection with KHSV and ectopic expression of K13, but not its NF-κB-defective mutant, suppressed the expression of CXCR4. Suppression of CXCR4 by KSHV and K13 was associated with upregulated expression of miR-146a, a microRNA that is known to bind to the 3′ untranslated region of CXCR4 mRNA. Reporter studies identified two NF-κB sites in the promoter of miR-146a that were essential for its activation by K13. Accordingly, ectopic expression of K13, but not its NF-κB-defective mutant or other vFLIPs, strongly stimulated the miR-146a promoter activity, which could be blocked by specific genetic and pharmacological inhibitors of the NF-κB pathway. Finally, expression of CXCR4 was downregulated in clinical samples of KS and this was accompanied by increased expression of miR-146a. Our results demonstrate that K13-induced NF-κB activity suppresses CXCR4 via upregulation of miR-146a. Downregulation of CXCR4 expression by K13 may contribute to KS development by promoting premature release of KSHV-infected endothelial progenitors into the circulation. PMID:20023696

  9. High seroprevalence of antibodies against Kaposi's sarcoma-associated herpesvirus (KSHV) among HIV-1-infected children and adolescents in a non-endemic population.

    PubMed

    Feiterna-Sperling, Cornelia; Königs, Christoph; Notheis, Gundula; Buchholz, Bernd; Krüger, Renate; Weizsäcker, Katharina; Eberle, Josef; Hanhoff, Nikola; Gärtner, Barbara; Heider, Harald; Krüger, Detlev H; Hofmann, Jörg

    2016-10-01

    Human herpesvirus-8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS), which primarily affects human immunodeficiency virus (HIV)-infected adults with advanced immunodeficiency. Currently, only limited prevalence data for HHV-8 infection in HIV-infected children living in non-endemic areas are available. This multicenter cross-sectional study was conducted in four university hospitals in Germany specializing in pediatric HIV care. Stored serum specimens obtained from 207 vertically HIV-1-infected children and adolescents were tested for antibodies against lytic and latent HHV-8 antigens. Logistic regression was used to assess independent risk factors associated with HHV-8 seropositivity. The overall HHV-8 seroprevalence was 24.6 % (n = 51/207) without significant differences related to sex, age, or ethnicity. In univariate analysis, HHV-8 seropositivity was significantly associated with a child having being born outside Germany, maternal origin from sub-Saharan Africa, a history of breastfeeding, CDC immunologic category 3, and deferred initiation of antiretroviral therapy (>24 months of age). In multivariate analysis, a child's birth outside Germany was the only significant risk factor for HHV-8 seropositivity (odds ratio 3.98; 95 % confidence interval 1.27-12.42). HHV-8-associated malignancies were uncommon; only one patient had a history of KS. Serum specimen of vertically HIV-infected children and adolescents living in Germany showed a high HHV-8 seroprevalence. These findings suggest that primary HHV-8 infection-a risk factor for KS and other HHV-8-associated malignancies-occurs early in life. Thus, management of perinatally HIV-infected children should include testing for HHV-8 coinfection and should consider future risks of HHV-8-associated malignancies. PMID:27240652

  10. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4/K10) Is a Novel Interaction Partner of CSL/CBF1, the Major Downstream Effector of Notch Signaling▿

    PubMed Central

    Heinzelmann, Katharina; Scholz, Barbara A.; Nowak, Agnes; Fossum, Even; Kremmer, Elisabeth; Haas, Juergen; Frank, Ronald; Kempkes, Bettina

    2010-01-01

    In cells infected with the Kaposi's sarcoma-associated herpesvirus (KSHV), CSL/CBF1 signaling is essential for viral replication and promotes the survival of KSHV-infected cells. CSL/CBF1 is a DNA adaptor molecule which recruits coactivator and corepressor complexes to regulate viral and cellular gene transcription and which is a major downstream effector molecule of activated Notch. The interaction of KSHV RTA and LANA with CSL/CBF1 has been shown to balance the lytic and latent viral life cycle. Here we report that a third KSHV protein, viral interferon regulatory factor 4 (vIRF4/K10), but none of the three other KSHV-encoded vIRFs, interacts with CSL/CBF1. Two regions of vIRF4 with dissimilar affinities contribute to CSL/CBF1 binding. Similar to Notch, vIRF4 targets the hydrophobic pocket in the beta trefoil domain of CSL/CBF1 through a short peptide motif which closely resembles a motif found in Notch but does not strictly follow the ΦWΦP consensus conserved in human and mouse Notch proteins. Our results suggest that vIRF4 might compete with Notch for CSL/CBF1 binding and signaling. PMID:20861242

  11. Functional dissection of latency-associated nuclear antigen 1 of Kaposi's sarcoma-associated herpesvirus involved in latent DNA replication and transcription of terminal repeats of the viral genome.

    PubMed

    Lim, Chunghun; Sohn, Hekwang; Lee, Daeyoup; Gwack, Yousang; Choe, Joonho

    2002-10-01

    Latency-associated nuclear antigen 1 (LANA1) of Kaposi's sarcoma-associated herpesvirus (KSHV) is implicated in the maintenance of the viral genome during latent infection. LANA1 colocalizes with KSHV episomes on the host chromosome and mediates their maintenance by attaching these viral structures to host chromosomes. Data from long-term selection of drug resistance in cells conferred by plasmids containing the terminal repeat (TR) sequence of KSHV revealed that KSHV TRs and LANA1 act as cis and trans elements of viral latent replication, respectively. In this study, we further characterized the cis- and trans-acting elements of KSHV latent replication by using a transient replication assay with a methylation-sensitive restriction enzyme, DpnI. Transient reporter and replication assays disclosed that the orientation and basal transcriptional activity of TR constructs did not significantly affect the efficiency of replication. However, at least two TR units were necessary for efficient replication. The N-terminal 90 amino acids comprising the chromosome-binding domain of LANA1 were required for the mediation of LANA1 C-terminal DNA-binding and dimerization domains to support the transient replication of KSHV TRs. LANA1 interacted with components of the origin recognition complexes (ORCs), similar to Epstein-Barr virus nuclear antigen 1. Our data suggest that LANA1 recruits ORCs to KSHV TRs for latent replication of the viral genome. PMID:12239308

  12. Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 (vIRF4/K10) is a novel interaction partner of CSL/CBF1, the major downstream effector of Notch signaling.

    PubMed

    Heinzelmann, Katharina; Scholz, Barbara A; Nowak, Agnes; Fossum, Even; Kremmer, Elisabeth; Haas, Juergen; Frank, Ronald; Kempkes, Bettina

    2010-12-01

    In cells infected with the Kaposi's sarcoma-associated herpesvirus (KSHV), CSL/CBF1 signaling is essential for viral replication and promotes the survival of KSHV-infected cells. CSL/CBF1 is a DNA adaptor molecule which recruits coactivator and corepressor complexes to regulate viral and cellular gene transcription and which is a major downstream effector molecule of activated Notch. The interaction of KSHV RTA and LANA with CSL/CBF1 has been shown to balance the lytic and latent viral life cycle. Here we report that a third KSHV protein, viral interferon regulatory factor 4 (vIRF4/K10), but none of the three other KSHV-encoded vIRFs, interacts with CSL/CBF1. Two regions of vIRF4 with dissimilar affinities contribute to CSL/CBF1 binding. Similar to Notch, vIRF4 targets the hydrophobic pocket in the beta trefoil domain of CSL/CBF1 through a short peptide motif which closely resembles a motif found in Notch but does not strictly follow the ΦWΦP consensus conserved in human and mouse Notch proteins. Our results suggest that vIRF4 might compete with Notch for CSL/CBF1 binding and signaling. PMID:20861242

  13. Kaposi's Sarcoma-Associated Herpesvirus Latent Gene vFLIP Inhibits Viral Lytic Replication through NF-κB-Mediated Suppression of the AP-1 Pathway: a Novel Mechanism of Virus Control of Latency▿

    PubMed Central

    Ye, Feng-Chun; Zhou, Fu-Chun; Xie, Jian-Ping; Kang, Tao; Greene, Whitney; Kuhne, Kurt; Lei, Xiu-Fen; Li, Qui-Hua; Gao, Shou-Jiang

    2008-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) latency is central to the evasion of host immune surveillances and induction of KSHV-related malignancies. The mechanism of KSHV latency remains unclear. Here, we show that the KSHV latent gene vFLIP promotes viral latency by inhibiting viral lytic replication. vFLIP suppresses the AP-1 pathway, which is essential for KSHV lytic replication, by activating the NF-κB pathway. Thus, by manipulating two convergent cellular pathways, vFLIP regulates both cell survival and KSHV lytic replication to promote viral latency. These results also indicate that the effect of the NF-κB pathway on KSHV replication is determined by the status of the AP-1 pathway and hence provide a mechanistic explanation for the contradictory role of the NF-κB pathway in KSHV replication. Since the NF-κB pathway is commonly activated during infection of gammaherpesviruses, these findings might have general implications for the control of gammaherpesviral latency. PMID:18305042

  14. Genome-Wide Mapping of the Binding Sites and Structural Analysis of Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 2 Reveal that It Is a DNA-Binding Transcription Factor

    PubMed Central

    Hu, Haidai; Dong, Jiazhen; Liang, Deguang; Gao, Zengqiang; Bai, Lei; Sun, Rui; Hu, Hao; Zhang, Heng

    2015-01-01

    ABSTRACT The oncogenic herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is known to encode four viral interferon regulatory factors (vIRF1 to -4) to subvert the host antiviral immune response, but their detailed DNA-binding profiles as transcription factors in the host remain uncharacterized. Here, we first performed genome-wide vIRF2-binding site mapping in the human genome using chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq). vIRF2 was capable of binding to the promoter regions of 100 putative target genes. Importantly, we confirmed that vIRF2 can specifically interact with the promoters of the genes encoding PIK3C3, HMGCR, and HMGCL, which are associated with autophagosome formation or tumor progression and metastasis, and regulate their transcription in vivo. The crystal structure of the vIRF2 DNA-binding domain (DBD) (referred to here as vIRF2DBD) showed variable loop conformations and positive-charge distributions different from those of vIRF1 and cellular IRFs that are associated with DNA-binding specificities. Structure-based mutagenesis revealed that Arg82 and Arg85 are required for the in vitro DNA-binding activity of vIRF2DBD and can abolish the transcription regulation function of vIRF2 on the promoter reporter activity of PIK3C3, HMGCR, and HMGCL. Collectively, our study provided unique insights into the DNA-binding potency of vIRF2 and suggested that vIRF2 could act as a transcription factor of its target genes in the host antiviral immune response. IMPORTANCE The oncogenic herpesvirus KSHV is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV has developed a unique mechanism to subvert the host antiviral immune responses by encoding four homologues of cellular interferon regulatory factors (vIRF1 to -4). However, none of their DNA-binding profiles in the human genome have been characterized until now, and the structural basis for their diverse

  15. Kaposi's Sarcoma Herpesvirus Genome Persistence.

    PubMed

    Juillard, Franceline; Tan, Min; Li, Shijun; Kaye, Kenneth M

    2016-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) has an etiologic role in Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. These diseases are most common in immunocompromised individuals, especially those with AIDS. Similar to all herpesviruses, KSHV infection is lifelong. KSHV infection in tumor cells is primarily latent, with only a small subset of cells undergoing lytic infection. During latency, the KSHV genome persists as a multiple copy, extrachromosomal episome in the nucleus. In order to persist in proliferating tumor cells, the viral genome replicates once per cell cycle and then segregates to daughter cell nuclei. KSHV only expresses several genes during latent infection. Prominent among these genes, is the latency-associated nuclear antigen (LANA). LANA is responsible for KSHV genome persistence and also exerts transcriptional regulatory effects. LANA mediates KSHV DNA replication and in addition, is responsible for segregation of replicated genomes to daughter nuclei. LANA serves as a molecular tether, bridging the viral genome to mitotic chromosomes to ensure that KSHV DNA reaches progeny nuclei. N-terminal LANA attaches to mitotic chromosomes by binding histones H2A/H2B at the surface of the nucleosome. C-terminal LANA binds specific KSHV DNA sequence and also has a role in chromosome attachment. In addition to the essential roles of N- and C-terminal LANA in genome persistence, internal LANA sequence is also critical for efficient episome maintenance. LANA's role as an essential mediator of virus persistence makes it an attractive target for inhibition in order to prevent or treat KSHV infection and disease. PMID:27570517

  16. Kaposi's Sarcoma-associated Herpesvirus K3 and K5 Proteins Block Distinct Steps in Transendothelial Migration of Effector Memory CD4+ T cells by Targeting Different Endothelial Proteins

    PubMed Central

    Manes, Thomas D.; Hoer, Simon; Muller, William A.; Lehner, Paul J.; Pober, Jordan S.

    2010-01-01

    K3 and K5 are Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded E3 ubiquitin ligases that differentially reduce surface expression of various proteins in infected cells. Here we describe their effects on human dermal microvascular endothelial cells (HDMEC), a natural target of KSHV infection. TNF-treated HDMEC transduced to express K5 show reduced capacity to capture effector memory (EM) CD4+ T cells under conditions of venular shear stress. K5 but not K3 transduction significantly reduces ICAM-1 expression and the inhibition of T cell capture was phenocopied by siRNA knockdown of ICAM-1 and by anti-ICAM-1 Ab blocking. Co-transduction with an ICAM-1 truncated construct not subject to K5 ubiquitylation restored EM CD4+ T cell capture. K3 transductants effectively capture EM CD4+ T cells, but fail to support their transendothelial migration (TEM) in response to TCR engagement by superantigen presented by the EC, leaving intact chemokine-dependent TEM. K3 but not K5 transduction significantly reduces PECAM-1 expression and the effect on TCR-induced TEM is phenocopied by siRNA knockdown of PECAM-1 and by anti-PECAM-1 Ab blocking. TCR-dependent TEM was restored in K3 transductants co-transduced to express a mutant of PECAM-1 not subject to K3-induced ubiquitylation. EM CD4+ T cells lack any known PECAM-1 counter receptor, but heterophilic engagement of PECAM-1 may involve glycosaminoglycans, and TCR-induced TEM, but not chemokine-induced TEM, appears to involve a heparan- or chondroitin-like molecule on T cells. These results both identify specific roles of K5 and K3 in immune evasion and further differentiate the processes of inflammatory chemokine- versus TCR-dependent recruitment of human EM CD4+ T cells. PMID:20357254

  17. Concurrent targeting of eicosanoid receptor 1/eicosanoid receptor 4 receptors and COX-2 induces synergistic apoptosis in Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus associated non-Hodgkin lymphoma cell lines.

    PubMed

    Paul, Arun George; Chandran, Bala; Sharma-Walia, Neelam

    2013-06-01

    The effective antitumorigenic potential of nonsteroidal anti-inflammatory drugs (NSAIDs) and eicosonoid (EP; EP1-4) receptor antagonists prompted us to test their efficacy in Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) related lymphomas. Our study demonstrated that (1) EP1-4 receptor protein levels vary among the various non-Hodgkin's lymphoma (NHL) cell lines tested (BCBL-1:KSHV+/EBV-;BC-3: KSHV+/EBV-; Akata/EBV+: KSHV-/EBV+; and JSC-1 cells: KSHV+/EBV + cells); (2) 5.0 μM of EP1 antagonist (SC-51322) had a significant antiproliferative effect on BCBL-1, BC-3, Akata/EBV+, and JSC-1 cells; (3) 50.0 μM of EP2 antagonist (AH6809) was required to induce a significant antiproliferative effect on BCBL-1, Akata/EBV+, and JSC-1 cells; (4) 5.0 μM of EP4 antagonist (GW 627368X) had a significant antiproliferative effect on BC-3, Akata/EBV+, and JSC-1 cells; (5) COX-2 selective inhibitor celecoxib (5.0 μM) had significant antiproliferative effects on BCBL-1, BC-3, Akata/EBV+, and JSC-1 cells; and (6) a combination of 1.0 μM each of celecoxib, SC-51322 and GW 627368X could potentiate the proapoptotic properties of celecoxib or vice-versa. Overall, our studies identified the synergistic antiproliferative effect of NSAIDs and EP receptor blockers on KSHV and EBV related B cell malignancies. PMID:23523954

  18. The central repeat domain 1 of Kaposi's sarcoma-associated herpesvirus (KSHV) latency associated-nuclear antigen 1 (LANA1) prevents cis MHC class I peptide presentation

    SciTech Connect

    Kwun, Hyun Jin; Ramos da Silva, Suzane; Qin Huilian; Ferris, Robert L.; Tan Rusung; Chang Yuan; Moore, Patrick S.

    2011-04-10

    KSHV LANA1, a latent protein expressed during chronic infection to maintain a viral genome, inhibits major histocompatibility complex class I (MHC I) peptide presentation in cis as a means of immune evasion. Through deletional cloning, we localized this function to the LANA1 central repeat 1 (CR1) subregion. Other CR subregions retard LANA1 translation and proteasomal processing but do not markedly inhibit LANA1 peptide processing by MHC I. Inhibition of proteasomal processing ablates LANA1 peptide presentation. Direct expression of LANA1 within the endoplasmic reticulum (ER) overcomes CR1 inhibition suggesting that CR1 acts prior to translocation of cytoplasmic peptides into the ER. By physically separating CR1 from other subdomains, we show that LANA1 evades MHC I peptide processing by a mechanism distinct from other herpesviruses including Epstein-Barr virus (EBV). Although LANA1 and EBV EBNA1 are functionally similar, they appear to use different mechanisms to evade host cytotoxic T lymphocyte surveillance.

  19. A single 13-kilobase divergent locus in the Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genome contains nine open reading frames that are homologous to or related to cellular proteins.

    PubMed Central

    Nicholas, J; Ruvolo, V; Zong, J; Ciufo, D; Guo, H G; Reitz, M S; Hayward, G S

    1997-01-01

    Two small fragments of a novel human gammaherpesvirus genome known as Kaposi's sarcoma (KS)-associated herpesvirus or human herpesvirus 8 (HHV-8) have been shown to be present in virtually all AIDS and non-AIDS KS lesions, as well as in body cavity-based lymphomas (BCBL) and in multicentric Castleman's disease. We have extended those studies by identifying and sequencing a third fragment of HHV-8 DNA encoding a viral thymidylate synthetase (TS) gene. Use of this viral TS fragment as a probe led to the identification and mapping of a cluster of overlapping phage lambda clones from a BCBL tumor DNA genomic library that spanned 48 kb on the left-hand side of the HHV-8 genome between the equivalents of open reading frame 6 (ORF6) and ORF31 of herpesvirus saimiri (HVS). DNA sequencing of a 17-kb segment encompassing a gammaherpesvirus divergent locus (DL-B) between ORF11 and ORF17 revealed the presence of nine viral ORFs with predicted gene products related to cellular proteins. These include the complete TS gene and a dihydrofolate reductase (DHFR) gene, four novel cytokine genes (encoding viral interleukin-6, viral MIP-1A, viral MIP-1B, and BCK) that have not previously been found to be encoded by a virus, and a bcl-2 homolog. This region in HHV-8 also contains the T1.1 abundant lytic cycle nuclear RNA gene and encompasses two genes (or exons) encoding proteins with C4HC3 zinc finger domains of the PHD/leukemia-associated protein subtype. The latter are related to the spliced immediate-early IE1 protein of the gamma-2 class herpesvirus bovine herpesvirus type 4 and a similar motif found in HVS ORF12. Although genes for TS and DHFR enzymes are also encoded by HVS (ORF70 and ORF2), both occur at different genomic loci than in HHV-8, and the HHV-8 DHFR protein is much farther diverged from human DHFR than is the HVS version, implying that they were probably acquired as host cell cDNAs by independent evolutionary events. Transcripts from the IE1-A, IE1-B, DHFR, and MIP-1B

  20. Can Kaposi Sarcoma Be Prevented?

    MedlinePlus

    ... early? Can Kaposi sarcoma be prevented? Kaposi sarcoma (KS) is caused by the Kaposi sarcoma associated herpesvirus ( ... to protect people against KSHV. For now, preventing KS depends on reducing the chance of becoming infected ...

  1. Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen and Angiogenin Interact with Common Host Proteins, Including Annexin A2, Which Is Essential for Survival of Latently Infected Cells

    PubMed Central

    Paudel, Nitika; Sadagopan, Sathish; Balasubramanian, Sandhya

    2012-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) infection and latency-associated nuclear antigen (LANA-1) upregulate the multifunctional protein angiogenin (ANG). Our studies demonstrate that silencing ANG or inhibiting its nuclear translocation downregulates KSHV LANA-1 expression and ANG is necessary for KSHV latency, anti-apoptosis and angiogenesis (Sadagopan et al., J. Virol. 83:3342–3364, 2009; Sadagopan et al., J Virol. 85:2666–2685, 2011). Here we show that LANA-1 interacts with ANG and colocalizes in latently infected endothelial telomerase-immortalized human umbilical vein endothelial (TIVE-LTC) cells. Mass spectrometric analyses of TIVE-LTC proteins immunoprecipitated by anti-LANA-1 and ANG antibodies identified 28 common cellular proteins such as ribosomal proteins, structural proteins, tRNA synthetases, metabolic pathway enzymes, chaperons, transcription factors, antioxidants, and ubiquitin proteosome proteins. LANA-1 and ANG interaction with one of the proteins, annexin A2, was validated. Annexin A2 has been shown to play roles in cell proliferation, apoptosis, plasmin generation, exocytosis, endocytosis, and cytoskeleton reorganization. It is also known to associate with glycolytic enzyme 3-phosphoglyceratekinase in the primer recognition protein (PRP) complex that interacts with DNA polymerase α in the lagging strand of DNA during replication. A higher level of annexin A2 is expressed in KSHV+ but not in Epstein-Barr virus (EBV)+ B-lymphoma cell lines. Annexin A2 colocalized with several LANA-1 punctate spots in KSHV+ body cavity B-cell lymphoma (BCBL-1) cells. In triple-staining analyses, we observed annexin A2-ANG-LANA-1, annexin A2-ANG, and ANG-LANA-1 colocalizations. Annexin A2 appeared as punctate nuclear dots in LANA-1-positive TIVE-LTC cells. In LANA-1-negative TIVE-LTC cells, annexin A2 was detected predominately in the cytoplasm, with some nuclear spots, and colocalization with ANG was observed mostly in the cytoplasm. Annexin A2

  2. Immune evasion by Kaposi’s sarcoma-associated herpesvirus

    PubMed Central

    Lee, Hye-Ra; Lee, Stacy; Chaudhary, Preet M; Gill, Parkash; Jung, Jae U

    2011-01-01

    Persistent viral infections are often associated with serious diseases, primarily by altering functions of the host immune system. The hallmark of Kaposi’s sarcoma-associated herpesvirus (KSHV) infection is the establishment of a life-long persistent infection, which leads to several clinical, epidemiological and infectious diseases, such as Kaposi’s sarcoma, a plasmablastic variant of multicentric Castleman’s disease, and primary effusion lymphoma. To sustain an efficient life-long persistency, KSHV dedicates a large portion of its genome to encoding immunomodulatory proteins that antagonize the immune system of its host. In this article, we highlight the strategies KSHV uses to evade, escape and survive its battle against the host’s immune system. PMID:20860481

  3. Kaposi's sarcoma-associated herpesvirus K8beta is derived from a spliced intermediate of K8 pre-mRNA and antagonizes K8alpha (K-bZIP) to induce p21 and p53 and blocks K8alpha-CDK2 interaction.

    PubMed

    Yamanegi, Koji; Tang, Shuang; Zheng, Zhi-Ming

    2005-11-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a lymphotropic DNA tumor virus that induces Kaposi's sarcoma and AIDS-related primary effusion lymphoma. KSHV open reading frame 50 and K8 genes in early viral lytic infection express, respectively, a tricistronic and a bicistronic pre-mRNA, which undergo alternative splicing to create two major spliced mRNA isoforms, alpha and beta, by inclusion (beta) or exclusion (alpha) of an intron at nucleotides 75563 to 75645. This intron contains some suboptimal features, which cause the intron 5' splice site (ss) to interact weakly with U1 snRNA and the 3' ss to bind a U2 auxiliary factor, U2AF, with low affinity. Optimization of this intron in K8 (K8 intron 2) promoted the interaction of the 5' ss with U1 and the 3' ss with U2AF, resulting in a substantial increase in intron splicing. Splicing of K8 intron 2 has also been shown to be stimulated by the splicing of a downstream intron. This was confirmed by the insertion of a human beta-globin intron into the K8beta exon 3-exon 4 splice junction, which promoted splicing of K8beta intron 2 and conversion of the K8beta mRNA to the K8alpha mRNA that encodes a K-bZIP protein. Intron 2 contains a premature termination codon, yet the K8beta mRNA is insensitive to nonsense-mediated mRNA decay, suggesting that the truncated K8beta protein may have a biological function. Indeed, although the truncated K8beta protein is missing only a C-terminal leucine zipper domain from the K-bZIP, its expression antagonizes the ability of the K-bZIP to induce p53 and p21 and blocks K-bZIP-CDK2 interaction through interfering K8alpha mRNA production. PMID:16254356

  4. Human herpesvirus-8: beyond Kaposi's .

    PubMed

    Rimar, Doron; Rimar, Yossi; Keynan, Yoav

    2006-07-01

    Today, more than 10 years and 2000 articles since human herpesvirus 8 was first described by Chang et al., novel insights into the transmission and molecular biology of HHV-8 have unveiled a new spectrum of diseases attributed to the virus. The association of HHV-8 with proliferative disorders--including Kaposi's sarcoma, multicentric Castleman disease and primary effusion lymphoma--is well established. Other aspects of HHV-8 infection are currently the subject of accelerated research. Primary HHV-8 infection may manifest as a mononucleosis-like syndrome in the immunocompetent host, or in various forms in the immunocompromised host. The association of HHV-8 with primary pulmonary hypertension was observed by Cool et al. in 2003, but six clinical trials evaluating the role of HHV-8 in pulmonary hypertension have not been able to replicate this intriguing observation. It has been speculated that HHV-8 may secondarily infect proliferating endothelium in patients with pulmonary hypertension. HHV-8 epidemiology, modes of transmission, new spectrum of disease and treatment are presented and discussed. PMID:16889165

  5. Array-Based Transcript Profiling and Limiting-Dilution Reverse Transcription-PCR Analysis Identify Additional Latent Genes in Kaposi's Sarcoma-Associated Herpesvirus▿ †

    PubMed Central

    Chandriani, Sanjay; Ganem, Don

    2010-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is a B-lymphotropic herpesvirus strongly linked to both lymphoproliferative diseases and Kaposi's sarcoma. The viral latency program of KSHV is central to persistent infection and plays important roles in the pathogenesis of KSHV-related tumors. Up to six polypeptides and 18 microRNAs are known to be expressed in latency, but it is unclear if all major latency genes have been identified. Here, we have employed array-based transcript profiling and limiting-dilution reverse transcription-PCR (RT-PCR) methodologies to explore this issue in several KSHV-infected cell lines. Our results show that RNAs encoding the K1 protein are found at low levels in most latently infected cell lines. The gene encoding v-IL-6 is also expressed as a latent transcript in some contexts. Both genes encode powerful signaling molecules with particular relevance to B cell biology: K1 mimics signaling through the B cell receptor, and v-IL-6 promotes B cell survival. These data resolve earlier controversies about K1 and v-IL-6 expression and indicate that, in addition to core latency genes, some transcripts can be expressed in KSHV latency in a context-dependent manner. PMID:20219929

  6. Human herpes virus 8 (Kaposi's sarcoma herpesvirus).

    PubMed

    Porter, S R; Di Alberti, L; Kumar, N

    1998-01-01

    Human herpes virus 8 (HHV-8) is a recently discovered herpesvirus related to Herpesvirus saimiri and Epstein-Barr virus (EBV). It has been assigned to the Rhadinovirus genus (gamma-2 herpesvirus) on the basis of its genomic sequence and structure. HHV-8 is the first member of this genus known to infect humans and it is now evident that it is the likely cause of Kaposi's sarcoma (KS). The virus is present in endothelial and spindle cells of KS, and in HIV disease the presence of HHV-8 in peripheral blood, and/or serum IgG antibodies to HHV-8, predicts the development of AIDS-related KS. HHV-8 can also infect CD19 + B cells and is of aetiological significance in the development of body cavity B cell lymphomas of AIDS. Of note, the translation products of viral open reading frames (ORFs) reveal HHV-8 to be a molecular pirate, capable of producing homologues of several human gene products that may result in alterations in cell cycle arrest, inhibit apoptosis and cell-mediated immune responses, and thus provide the potential for tumour production. PMID:9659514

  7. Electrical response of a B lymphoma cell line latently infected with Kaposi's sarcoma herpesvirus.

    PubMed

    Safavieh, Mohammadali; Khetani, Sultan; Juillard, Franceline; Kaul, Vivasvat; Kanakasabapathy, Manoj Kumar; Kaye, Kenneth M; Shafiee, Hadi

    2016-06-15

    Certain viruses, such as herpesviruses, are capable of persistent and latent infection of host cells. Distinguishing and separating live, latently infected cells from uninfected cells is not easily attainable using current approaches. The ability to perform such separation would greatly enhance the ability to study primary, infected cells and potentially enable elimination of latently infected cells from the host. Here, the dielectrophoretic response of B cells infected with Kaposi's sarcoma-associated herpesvirus (KSHV) were investigated and compared to uninfected B cells. We evaluated the effect of applied voltage, signal frequency, and flow rate of the sample on the cell capture efficiency. We achieved 37.1%±8.5% difference in capture efficiencies between latently KSHV-infected and uninfected BJAB B lymphoma cells at the chip operational conditions of 1V, 50kHz and 0.02μl/min sample flow rate. Our results show that latently infected B lymphoma cells demonstrated significantly different electrical response compared to uninfected B cells and DEP-based microchips can be potentially used for sorting latently infected cells based on their electrical properties. PMID:26851580

  8. Modulation of Immune System by Kaposi’s Sarcoma-Associated Herpesvirus: Lessons from Viral Evasion Strategies

    PubMed Central

    Lee, Hye-Ra; Brulois, Kevin; Wong, LaiYee; Jung, Jae U.

    2012-01-01

    Kaposi’s sarcoma-associated herpesvirus (KSHV), a member of the herpesvirus family, has evolved to establish a long-term, latent infection of cells such that while they carry the viral genome gene expression is highly restricted. Latency is a state of cryptic viral infection associated with genomic persistence in their host and this hallmark of KSHV infection leads to several clinical–epidemiological diseases such as KS, a plasmablastic variant of multicentric Castleman’s disease, and primary effusion lymphoma upon immune suppression of infected hosts. In order to sustain efficient life-long persistency as well as their life cycle, KSHV dedicates a large portion of its genome to encode immunomodulatory proteins that antagonize its host’s immune system. In this review, we will describe our current knowledge of the immune evasion strategies employed by KSHV at distinct stages of its viral life cycle to control the host’s immune system. PMID:22403573

  9. Cellular and Kaposi's sarcoma-associated herpes virus microRNAs in sepsis and surgical trauma.

    PubMed

    Tudor, S; Giza, D E; Lin, H Y; Fabris, L; Yoshiaki, K; D'Abundo, L; Toale, K M; Shimizu, M; Ferracin, M; Challagundla, K B; Cortez, M Angelica; Fuentes-Mattei, E; Tulbure, D; Gonzalez, C; Henderson, J; Row, M; Rice, T W; Ivan, C; Negrini, M; Fabbri, M; Morris, J S; Yeung, S-C J; Vasilescu, C; Calin, G A

    2014-01-01

    Once a patient is in septic shock, survival rates drop by 7.6% for every hour of delay in antibiotic therapy. Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and triage. Here, we study the potential roles of a panel of cellular and viral miRNAs as sepsis biomarkers. We performed genome-wide microRNA (miRNA) expression profiling in leukocytes from septic patients and nonseptic controls, combined with quantitative RT-PCR in plasmas from two cohorts of septic patients, two cohorts of nonseptic surgical patients and healthy volunteers. Enzyme-linked immunosorbent assay, miRNA transfection and chromatin immunoprecipitation were used to study the effects of Kaposi sarcoma herpes virus (KSHV) miRNAs on interleukin's secretion. Differences related to sepsis etiology were noted for plasma levels of 10 cellular and 2 KSHV miRNAs (miR-K-10b and miR-K-12-12*) between septic and nonseptic patients. All the sepsis groups had high KSHV miRNAs levels compared with controls; Afro-American patients had higher levels of KSHV-miR-K12-12* than non-Afro-American patients. Both KSHV miRNAs were increased on postoperative day 1, but returned to baseline on day 7; they acted as direct agonists of Toll-like receptor 8 (TLR8), which might explain the increased secretion of the IL-6 and IL-10. Cellular and KSHV miRNAs are differentially expressed in sepsis and early postsurgical patients and may be exploited for diagnostic and therapeutic purposes. Increased miR-K-10b and miR-K12-12* are functionally involved in sepsis as agonists of TLR8, forming a positive feedback that may lead to cytokine dysregulation. PMID:25476907

  10. Recent advances in understanding Kaposi’s sarcoma-associated herpesvirus

    PubMed Central

    Dissinger, Nathan J.; Damania, Blossom

    2016-01-01

    Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV) is an oncogenic human herpesvirus. KSHV is associated with three cancers in the human population: KS, primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). KS is the leading cause of cancer in HIV-infected individuals. In this review, we discuss the most recent discoveries behind the mechanisms of KSHV latency maintenance and lytic replication. We also review current therapies for KSHV-associated cancers. PMID:27158465

  11. Next-Generation Sequencing in the Understanding of Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) Biology

    PubMed Central

    Strahan, Roxanne; Uppal, Timsy; Verma, Subhash C.

    2016-01-01

    Non-Sanger-based novel nucleic acid sequencing techniques, referred to as Next-Generation Sequencing (NGS), provide a rapid, reliable, high-throughput, and massively parallel sequencing methodology that has improved our understanding of human cancers and cancer-related viruses. NGS has become a quintessential research tool for more effective characterization of complex viral and host genomes through its ever-expanding repertoire, which consists of whole-genome sequencing, whole-transcriptome sequencing, and whole-epigenome sequencing. These new NGS platforms provide a comprehensive and systematic genome-wide analysis of genomic sequences and a full transcriptional profile at a single nucleotide resolution. When combined, these techniques help unlock the function of novel genes and the related pathways that contribute to the overall viral pathogenesis. Ongoing research in the field of virology endeavors to identify the role of various underlying mechanisms that control the regulation of the herpesvirus biphasic lifecycle in order to discover potential therapeutic targets and treatment strategies. In this review, we have complied the most recent findings about the application of NGS in Kaposi’s sarcoma-associated herpesvirus (KSHV) biology, including identification of novel genomic features and whole-genome KSHV diversities, global gene regulatory network profiling for intricate transcriptome analyses, and surveying of epigenetic marks (DNA methylation, modified histones, and chromatin remodelers) during de novo, latent, and productive KSHV infections. PMID:27043613

  12. Sequence and Genomic Analysis of a Rhesus Macaque Rhadinovirus with Similarity to Kaposi’s Sarcoma-Associated Herpesvirus/Human Herpesvirus 8

    PubMed Central

    Searles, Robert P.; Bergquam, Eric P.; Axthelm, Michael K.; Wong, Scott W.

    1999-01-01

    We have sequenced the long unique region (LUR) and characterized the terminal repeats of the genome of a rhesus rhadinovirus (RRV), strain 17577. The LUR as sequenced is 131,364 bp in length, with a G+C content of 52.2% and a CpG ratio of 1.11. The genome codes for 79 open reading frames (ORFs), with 67 of these ORFs similar to genes found in both Kaposi’s sarcoma-associated herpesvirus (KSHV) (formal name, human herpesvirus 8) and herpesvirus saimiri. Eight of the 12 unique genes show similarity to genes found in KSHV, including genes for viral interleukin-6, viral macrophage inflammatory protein, and a family of viral interferon regulatory factors (vIRFs). Genomic organization is essentially colinear with KSHV, the primary differences being the number of cytokine and IRF genes and the location of the gene for dihydrofolate reductase. Highly repetitive sequences are located in positions corresponding to repetitive sequences found in KSHV. Phylogenetic analysis of several ORFs supports the similarity between RRV and KSHV. Overall, the sequence, structural, and phylogenetic data combine to provide strong evidence that RRV 17577 is the rhesus macaque homolog of KSHV. PMID:10074154

  13. Hsp70 Isoforms Are Essential for the Formation of Kaposi’s Sarcoma-Associated Herpesvirus Replication and Transcription Compartments

    PubMed Central

    Baquero-Pérez, Belinda; Whitehouse, Adrian

    2015-01-01

    Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with various AIDS-related malignancies. Like other herpesviruses, multiple processes required for KSHV lytic replication, including viral transcription, viral DNA synthesis and capsid assembly occur in virus-induced intranuclear structures, termed replication and transcription compartments (RTCs). Here we utilised a novel methodology, combining subcellular fractionation and quantitative proteomics, to identify cellular proteins which are recruited to KSHV-induced RTCs and thus play a key role in KSHV lytic replication. We show that several isoforms of the HSP70 chaperone family, Hsc70 and iHsp70, are redistributed from the cytoplasm into the nucleus coinciding with the initial formation of KSHV-induced RTCs. We demonstrate that nuclear chaperone foci are dynamic, initially forming adjacent to newly formed KSHV RTCs, however during later time points the chaperones move within KSHV RTCs and completely co-localise with actively replicating viral DNA. The functional significance of Hsp70 isoforms recruitment into KSHV RTCs was also examined using the specific Hsp70 isoform small molecule inhibitor, VER-155008. Intriguingly, results highlight an essential role of Hsp70 isoforms in the KSHV replication cycle independent of protein stability and maturation. Notably, inhibition of Hsp70 isoforms precluded KSHV RTC formation and RNA polymerase II (RNAPII) relocalisation to the viral genome leading to the abolishment of global KSHV transcription and subsequent viral protein synthesis and DNA replication. These new findings have revealed novel mechanisms that regulate KSHV lytic replication and highlight the potential of HSP70 inhibitors as novel antiviral agents. PMID:26587836

  14. COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP

    PubMed Central

    Sharma-Walia, N; Patel, K; Chandran, K; Marginean, A; Bottero, V; Kerur, N; Paul, A G

    2012-01-01

    Kaposi's sarcoma herpesvirus (KSHV) latent oncoprotein viral FLICE (FADD-like interferon converting enzyme)-like inhibitory protein (v-FLIP) or K13, a potent activator of NF-κB, has well-established roles in KSHV latency and oncogenesis. KSHV-induced COX-2 represents a novel strategy employed by KSHV to promote latency and inflammation/angiogenesis/invasion. Here, we demonstrate that v-FLIP/K13 promotes tumorigenic effects via the induction of host protein COX-2 and its inflammatory metabolite PGE2 in an NF-κB-dependent manner. In addition to our previous studies demonstrating COX-2/PGE2's role in transcriptional regulation of KSHV latency promoter and latent gene expression, the current study adds to the complexity that though LANA-1 (latency associated nuclear antigen) is utilizing COX-2/PGE2 as critical factors for its transcriptional regulation, it is the v-FLIP/K13 gene in the KSHV latency cluster that maintains continuous COX-2/PGE2 levels in the infected cells. We demonstrate that COX-2 inhibition, via its chemical inhibitors (NS-398 or celecoxib), reduced v-FLIP/K13-mediated NF-κB induction, and extracellular matrix (ECM) interaction-mediated signaling, mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) levels, and subsequently downregulated detachment-induced apoptosis (anoikis) resistance. vFLIP expression mediated the secretion of cytokines, and spindle cell differentiation activated the phosphorylation of p38, RSK, FAK, Src, Akt and Rac1-GTPase. The COX-2 inhibition in v-FLIP/K13-HMVECs reduced inflammation and invasion/metastasis-related genes, along with reduced anchorage-independent colony formation via modulating ‘extrinsic' as well as ‘intrinsic' cell death pathways. COX-2 blockade in v-FLIP/K13-HMVEC cells drastically augmented cell death induced by removal of essential growth/survival factors secreted in the microenvironment. Transformed cells obtained from anchorage-independent colonies of COX-2 inhibitor-treated v

  15. The Ephrin Receptor Tyrosine Kinase A2 is a Cellular Receptor for Kaposi’s Sarcoma-Associated Herpesvirus

    PubMed Central

    Hahn, Alexander; Kaufmann, Johanna; Wies, Effi; Naschberger, Elisabeth; Panteleev-Ivlev, Julia; Schmidt, Katharina; Holzer, Angela; Schmidt, Martin; Chen, Jin; König, Simone; Ensser, Armin; Myoung, Jinjong; Brockmeyer, Norbert H.; Stürzl, Michael; Fleckenstein, Bernhard; Neipel, Frank

    2013-01-01

    Kaposi’s sarcoma associated herpesvirus (KSHV) is the human oncovirus which causes Kaposi’s sarcoma (KS), a highly vascularised tumour originating from lymphatic endothelial cells. Amongst others, the dimeric complex formed by the KSHV virion envelope glycoproteins H and L (gH/gL) is required for entry of herpesviruses into the host cell. We show that the Ephrin receptor tyrosine kinase A2 (EphA2) is a cellular receptor for KSHV gH/gL. EphA2 co-precipitated with both gH/gL and KSHV virions. KSHV infection rates were increased upon over-expression of EphA2. In contrast, antibodies against EphA2 and siRNAs directed against EphA2 inhibited KSHV infection of lymphatic endothelial cells. Pretreatment of KSHV virions with soluble EphA2 resulted in a dose-dependent inhibition of KSHV infection by up to 90%. Similarly, pretreating cells with the soluble EphA2 ligand EphrinA4 but not with EphA2 itself impaired KSHV infection. Notably, deletion of the EphA2 gene essentially abolished KSHV infection of murine vascular endothelial cells. Binding of gH/gL to EphA2 triggered EphA2 phosphorylation and endocytosis, a major pathway of KSHV entry. Quantitative RT-PCR and situ histochemistry revealed a close correlation between KSHV infection and EphA2 expression both in cultured cells derived from KS or lymphatic endothelium and in KS specimens, respectively. Taken together, these results identify EphA2, a tyrosine kinase with known functions in neo-vascularisation and oncogenesis, as receptor for KSHV gH/gL and implicate an important role for EphA2 in KSHV infection especially of endothelial cells and in KS. PMID:22635007

  16. A hydrophobic domain within the small capsid protein of Kaposi’s sarcoma-associated herpesvirus is required for assembly

    PubMed Central

    Capuano, Christopher M.; Grzesik, Peter; Kreitler, Dale; Pryce, Erin N.; Desai, Keshal V.; Coombs, Gavin; McCaffery, J. Michael

    2014-01-01

    Kaposi’s sarcoma-associated herpesvirus (KSHV) capsids can be produced in insect cells using recombinant baculoviruses for protein expression. All six capsid proteins are required for this process to occur and, unlike for alphaherpesviruses, the small capsid protein (SCP) ORF65 is essential for this process. This protein decorates the capsid shell by virtue of its interaction with the capsomeres. In this study, we have explored the SCP interaction with the major capsid protein (MCP) using GFP fusions. The assembly site within the nucleus of infected cells was visualized by light microscopy using fluorescence produced by the SCP–GFP polypeptide, and the relocalization of the SCP to these sites was evident only when the MCP and the scaffold protein were also present – indicative of an interaction between these proteins that ensures delivery of the SCP to assembly sites. Biochemical assays demonstrated a physical interaction between the SCP and MCP, and also between this complex and the scaffold protein. Self-assembly of capsids with the SCP–GFP polypeptide was evident. Potentially, this result can be used to engineer fluorescent KSHV particles. A similar SCP–His6 polypeptide was used to purify capsids from infected cell lysates using immobilized affinity chromatography and to directly label this protein in capsids using chemically derivatized gold particles. Additional studies with SCP–GFP polypeptide truncation mutants identified a domain residing between aa 50 and 60 of ORF65 that was required for the relocalization of SCP–GFP to nuclear assembly sites. Substitution of residues in this region and specifically at residue 54 with a polar amino acid (lysine) disrupted or abolished this localization as well as capsid assembly, whereas substitution with non-polar residues did not affect the interaction. Thus, this study identified a small conserved hydrophobic domain that is important for the SCP–MCP interaction. PMID:24824860

  17. Kaposi's sarcoma herpesvirus C-terminal LANA concentrates at pericentromeric and peri-telomeric regions of a subset of mitotic chromosomes

    SciTech Connect

    Kelley-Clarke, Brenna; Ballestas, Mary E.; Komatsu, Takashi; Kaye, Kenneth M. . E-mail: kkaye@rics.bwh.harvard.edu

    2007-01-20

    The Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) tethers KSHV terminal repeat (TR) DNA to mitotic chromosomes to efficiently segregate episomes to progeny nuclei. LANA contains N- and C-terminal chromosome binding regions. We now show that C-terminal LANA preferentially concentrates to paired dots at pericentromeric and peri-telomeric regions of a subset of mitotic chromosomes through residues 996-1139. Deletions within C-terminal LANA abolished both self-association and chromosome binding, consistent with a requirement for self-association to bind chromosomes. A deletion abolishing TR DNA binding did not affect chromosome targeting, indicating LANA's localization is not due to binding its recognition sequence in chromosomal DNA. LANA distributed similarly on human and non-human mitotic chromosomes. These results are consistent with C-terminal LANA interacting with a cell factor that concentrates at pericentromeric and peri-telomeric regions of mitotic chromosomes.

  18. Seroprevalence of Kaposi Sarcoma–associated Herpesvirus and Other Serologic Markers in the Brazilian Amazon

    PubMed Central

    Sumita, Laura M.; Souza, Vanda U.; Weiss, Helen A.; Oliveira, Juliane; Mascheretti, Melissa; Quiroga, Mariana; Vela, Rodrigo A.R.; Sabino, Ester; Pannuti, Claudio S.; Mayaud, Philippe

    2009-01-01

    To determine the presence of Kaposi sarcoma–associated herpesvirus (KSHV) and other serologic markers, we tested serum specimens of 339 Amerindians, 181 rural non-Amerindians, and 1,133 urban blood donors (13 Amerindians) in the Brazilian Amazon. High KSHV seroprevalence in children and inverse association with herpes simplex virus type 2 indicates predominant nonsexual transmission among Amerindians. PMID:19331768

  19. Human Herpesvirus 8 Genotype E in Patients with Kaposi Sarcoma, Peru

    PubMed Central

    Cassar, Olivier; Blondot, Marie-Lise; Mohanna, Salim; Jouvion, Gregory; Bravo, Francisco; Maco, Vicente; Duprez, Renan; Huerre, Michel; Gotuzzo, Eduardo

    2010-01-01

    To determine human herpesvirus 8 (HHV-8) K1 genotypes in patients with Kaposi sarcoma (KS) from Peru, we characterized HHV-8 in 25 KS biopsy samples. Our findings of 8 A, 1 B, 14 C, and 2 E subtypes showed high HHV-8 diversity in these patients and association between E genotype and KS development. PMID:20735933

  20. Piracy of prostaglandin E2/EP receptor-mediated signaling by Kaposi's sarcoma-associated herpes virus (HHV-8) for latency gene expression: strategy of a successful pathogen.

    PubMed

    George Paul, Arun; Sharma-Walia, Neelam; Kerur, Nagaraj; White, Carl; Chandran, Bala

    2010-05-01

    Kaposi's sarcoma-associated herpes virus (KSHV) is implicated in the pathogenesis of KS, a chronic inflammation-associated malignancy. Cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2), two pivotal proinflammatory/oncogeneic molecules, are proposed to play roles in the expression of major KSHV latency-associated nuclear antigen-1 (LANA-1). Microsomal PGE2 synthase, PGE2, and its receptors (EP1, EP2, EP3, and EP4) were detected in KS lesions with the distinct staining of EP2/EP4 in KS lesions. In latently infected endothelial TIVE-LTC cells, EP receptor antagonists downregulated LANA-1 expression as well as Ca(2+), p-Src, p-PI3K, p-PKCzeta/lambda, and p-NF-kappaB, which are also some of the signal molecules proposed to be important in KS pathogenesis. Exogenous PGE2 and EP receptor agonists induced the LANA-1 promoter in 293 cells, and YY1, Sp1, Oct-1, Oct-6, C/EBP, and c-Jun transcription factors seem to be involved in this induction. PGE2/EP receptor-induced LANA-1 promoter activity was downregulated significantly by the inhibition of Ca(2+), p-Src, p-PI3K, p-PKCzeta/lambda, and p-NF-kappaB. These findings implicate the inflammatory PGE2/EP receptors and the associated signal molecules in herpes virus latency and uncover a novel paradigm that shows the evolution of KSHV genome plasticity to use inflammatory response for its survival advantage of maintaining latent gene expression. These data also suggest that potential use of anti-COX-2 and anti-EP receptor therapy may not only ameliorate the chronic inflammation associated with KS but could also lead to elimination of the KSHV latent infection and the associated KS lesions. PMID:20388794

  1. Immune evasion strategies of the human gamma-herpesviruses: implications for viral tumorigenesis.

    PubMed

    Zhang, Xiangning; Dawson, Christopher W; He, Zhiwei; Huang, Peichun

    2012-02-01

    Two human gamma-herpesviruses, Epstein-Barr virus and Kaposi's sarcoma associated herpesvirus/human herpesvirus 8 display oncogenic potential, causing benign and malignant lymphoproliferative disorders in genetically susceptible or immunosuppressed individuals. As a family of viruses that establish persistent life-long infections, herpesviruses have evolved strategies to limit innate antiviral responses and evade host immune surveillance. Herpesviruses have developed mechanisms to disrupt antigen presentation, pirate the production of immune regulating cytokines, and inhibit pro-apoptotic signaling pathways. Although these strategies are designed to facilitate the long-term persistence of herpesviruses, in certain circumstances they can contribute to viral-driven carcinogenesis. PMID:22170548

  2. Human herpesvirus 8.

    PubMed

    Martinelli, Paul T; Tyring, Stephen K

    2002-04-01

    Human herpesvirus 8 (HHV 8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV) is a g2 herpesvirus and the most recently identified human tumor virus. HHV 8 has been consistently implicated in the pathogenesis of all clinical variants of Kaposi's sarcoma, as well as in the plasma cell variant of multicentric Castleman's disease and primary effusion lymphomas. Pathogenicity of the virus is increased in the host who is immunosuppressed, either iatrogenically or through H1V-1 infection. The HHV 8 genome contains several homologues of cellular genes that regulate cell growth and differentiation, and the exact mechanisms of the virus' oncogenicity using molecular piracy are still being investigated and elucidated. In this article, the authors review the epidemiology, transmission, clinical manifestations, and molecular genetics of HHV 8 infection and provide a summary of the current treatment modalities available to the clinician. PMID:12120444

  3. CpG Methylation as a Tool to Characterize Cell-Free Kaposi Sarcoma Herpesvirus DNA

    PubMed Central

    Shamay, Meir; Hand, Nicholas; Lemas, M. Victor; Koon, Henry B.; Krown, Susan E.; Wrangle, John; Desai, Prashant; Ramos, Juan Carlos

    2012-01-01

    (See the editorial commentary by Stebbing and Bower, on pages 1032–4.) We studied the presence of Kaposi sarcoma herpesvirus sequences in cell-free DNA (cfDNA) isolated from the blood of patients with AIDS-related Kaposi sarcoma (KS) and primary effusion lymphoma (PEL). The use of paramagnetic beads linked to methyl-CpG binding domain protein allowed separation of virion and cell-derived DNA. Only virion DNA was detected in the blood of KS patients, whereas cell-derived DNA was detected in a patient with AIDS-related PEL. The difference in the origins of cfDNA in these settings may in part reflect very different proliferative indices in KS and PEL tumor tissue. PMID:22357696

  4. Animal models of tumorigenic herpesviruses--an update.

    PubMed

    Dittmer, Dirk P; Damania, Blossom; Sin, Sang-Hoon

    2015-10-01

    Any one model system, be it culture or animal, only recapitulates one aspect of the viral life cycle in the human host. By providing recent examples of animal models for Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus, we would argue that multiple animal models are needed to gain a comprehensive understanding of the pathogenesis associated with human oncogenic herpesviruses. Transgenic mice, homologous animal herpesviruses, and tumorgraft and humanized mouse models all complement each other in the study of viral pathogenesis. The use of animal model systems facilitates the exploration of novel anti-viral and anti-cancer treatment modalities for diseases associated with oncogenic herpesviruses. PMID:26476352

  5. Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi’s Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes

    PubMed Central

    Lee, Myung-Shin; Yuan, Hongfeng; Jeon, Hyungtaek; Zhu, Ying; Yoo, Seungmin; Shi, Songtao; Krueger, Brian; Renne, Rolf; Lu, Chun; Jung, Jae U.

    2016-01-01

    ABSTRACT Kaposi’s sarcoma (KS), a highly angiogenic and invasive tumor often involving different organ sites, including the oral cavity, is caused by infection with Kaposi’s sarcoma-associated herpesvirus (KSHV). Diverse cell markers have been identified on KS tumor cells, but their origin remains an enigma. We previously showed that KSHV could efficiently infect, transform, and reprogram rat primary mesenchymal stem cells (MSCs) into KS-like tumor cells. In this study, we showed that human primary MSCs derived from diverse organs, including bone marrow (MSCbm), adipose tissue (MSCa), dental pulp, gingiva tissue (GMSC), and exfoliated deciduous teeth, were permissive to KSHV infection. We successfully established long-term cultures of KSHV-infected MSCa, MSCbm, and GMSC (LTC-KMSCs). While LTC-KMSCs had lower proliferation rates than the uninfected cells, they expressed mixtures of KS markers and displayed differential angiogenic, invasive, and transforming phenotypes. Genetic analysis identified KSHV-derived microRNAs that mediated KSHV-induced angiogenic activity by activating the AKT pathway. These results indicated that human MSCs could be the KSHV target cells in vivo and established valid models for delineating the mechanism of KSHV infection, replication, and malignant transformation in biologically relevant cell types. PMID:26814175

  6. Functional characterization of Kaposi's sarcoma-associated herpesvirus small capsid protein by bacterial artificial chromosome-based mutagenesis

    SciTech Connect

    Sathish, Narayanan; Yuan Yan

    2010-11-25

    A systematic investigation of interactions amongst KSHV capsid proteins was undertaken in this study to comprehend lesser known KSHV capsid assembly mechanisms. Interestingly the interaction patterns of the KSHV small capsid protein, ORF65 suggested its plausible role in viral capsid assembly pathways. Towards further understanding this, ORF65-null recombinant mutants (BAC-{Delta}65 and BAC-stop65) employing a bacterial artificial chromosome (BAC) system were generated. No significant difference was found in both overall viral gene expression and lytic DNA replication between stable monolayers of 293T-BAC36 (wild-type) and 293T-BAC-ORF65-null upon induction with 12-O-tetradecanoylphorbol-13-acetate, though the latter released 30-fold fewer virions to the medium than 293T-BAC36 cells. Sedimentation profiles of capsid proteins of ORF65-null recombinant mutants were non-reflective of their organization into the KSHV capsids and were also undetectable in cytoplasmic extracts compared to noticeable levels in nuclear extracts. These observations collectively suggested the pivotal role of ORF65 in the KSHV capsid assembly processes.

  7. Systematic Identification of Cellular Signals Reactivating Kaposi Sarcoma–Associated Herpesvirus

    PubMed Central

    Yu, Fuqu; Harada, Josephine N; Brown, Helen J; Deng, Hongyu; Song, Moon Jung; Wu, Ting-Ting; Kato-Stankiewicz, Juran; Nelson, Christian G; Vieira, Jeffrey; Tamanoi, Fuyuhiko; Chanda, Sumit K; Sun, Ren

    2007-01-01

    The herpesvirus life cycle has two distinct phases: latency and lytic replication. The balance between these two phases is critical for viral pathogenesis. It is believed that cellular signals regulate the switch from latency to lytic replication. To systematically evaluate the cellular signals regulating this reactivation process in Kaposi sarcoma–associated herpesvirus, the effects of 26,000 full-length cDNA expression constructs on viral reactivation were individually assessed in primary effusion lymphoma–derived cells that harbor the latent virus. A group of diverse cellular signaling proteins were identified and validated in their effect of inducing viral lytic gene expression from the latent viral genome. The results suggest that multiple cellular signaling pathways can reactivate the virus in a genetically homogeneous cell population. Further analysis revealed that the Raf/MEK/ERK/Ets-1 pathway mediates Ras-induced reactivation. The same pathway also mediates spontaneous reactivation, which sets the first example to our knowledge of a specific cellular pathway being studied in the spontaneous reactivation process. Our study provides a functional genomic approach to systematically identify the cellular signals regulating the herpesvirus life cycle, thus facilitating better understanding of a fundamental issue in virology and identifying novel therapeutic targets. PMID:17397260

  8. Kaposi’s Sarcoma Associated Herpesvirus Encoded Viral FLICE Inhibitory Protein K13 Activates NF-κB Pathway Independent of TRAF6, TAK1 and LUBAC

    PubMed Central

    Matta, Hittu; Gopalakrishnan, Ramakrishnan; Graham, Ciaren; Tolani, Bhairavi; Khanna, Akshat; Yi, Han; Suo, Yulan; Chaudhary, Preet M.

    2012-01-01

    Background Kaposi’s sarcoma associated herpesvirus encoded viral FLICE inhibitory protein (vFLIP) K13 activates the NF-κB pathway by binding to the NEMO/IKKγ subunit of the IκB kinase (IKK) complex. However, it has remained enigmatic how K13-NEMO interaction results in the activation of the IKK complex. Recent studies have implicated TRAF6, TAK1 and linear ubiquitin chains assembled by a linear ubiquitin chain assembly complex (LUBAC) consisting of HOIL-1, HOIP and SHARPIN in IKK activation by proinflammatory cytokines. Methodology/Principal Findings Here we demonstrate that K13-induced NF-κB DNA binding and transcriptional activities are not impaired in cells derived from mice with targeted disruption of TRAF6, TAK1 and HOIL-1 genes and in cells derived from mice with chronic proliferative dermatitis (cpdm), which have mutation in the Sharpin gene (Sharpincpdm/cpdm). Furthermore, reconstitution of NEMO-deficient murine embryonic fibroblast cells with NEMO mutants that are incapable of binding to linear ubiquitin chains supported K13-induced NF-κB activity. K13-induced NF-κB activity was not blocked by CYLD, a deubiquitylating enzyme that can cleave linear and Lys63-linked ubiquitin chains. On the other hand, NEMO was required for interaction of K13 with IKK1/IKKα and IKK2/IKKβ, which resulted in their activation by “T Loop” phosphorylation. Conclusions/Significance Our results demonstrate that K13 activates the NF-κB pathway by binding to NEMO which results in the recruitment of IKK1/IKKα and IKK2/IKKβ and their subsequent activation by phosphorylation. Thus, K13 activates NF-κB via a mechanism distinct from that utilized by inflammatory cytokines. These results have important implications for the development of therapeutic agents targeting K13-induced NF-κB for the treatment of KSHV-associated malignancies. PMID:22590573

  9. Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice

    PubMed Central

    Ballon, Gianna; Chen, Kang; Perez, Rocio; Tam, Wayne; Cesarman, Ethel

    2011-01-01

    Kaposi sarcoma herpesvirus (KSHV) is specifically associated with Kaposi sarcoma (KS) and 2 B cell lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KS, PEL, and MCD are largely incurable and poorly understood diseases most common in HIV-infected individuals. Here, we have revealed the role of viral FLICE-inhibitory protein (vFLIP) in the initiation of PEL and MCD by specifically expressing vFLIP at different stages of B cell differentiation in vivo. Mice showed MCD-like abnormalities and immunological defects including lack of germinal centers (GCs), impaired Ig class switching, and affinity maturation. In addition, they showed increased numbers of cells expressing cytoplasmic IgM-λ, a thus far enigmatic feature of the KSHV-infected cells in MCD. B cell–derived tumors arose at high incidence and displayed Ig gene rearrangement with downregulated expression of B cell–associated antigens, which are features of PEL. Interestingly, these tumors exhibited characteristics of transdifferentiation and acquired expression of histiocytic/dendritic cell markers. These results define immunological functions for vFLIP in vivo and reveal what we believe to be a novel viral-mediated tumorigenic mechanism involving B cell reprogramming. Additionally, the robust recapitulation of KSHV-associated diseases in mice provides a model to test inhibitors of vFLIP as potential anticancer agents. PMID:21339646

  10. Kaposi's Sarcoma

    MedlinePlus

    Kaposi's sarcoma (KS) is a cancer that causes patches of abnormal tissue to grow under the skin, in the lining of ... of cancer cells, blood vessels, and blood cells. KS is caused by infection with human herpesvirus-8 ( ...

  11. The 3D structure of Kaposi sarcoma herpesvirus LANA C-terminal domain bound to DNA

    PubMed Central

    Hellert, Jan; Weidner-Glunde, Magdalena; Krausze, Joern; Lünsdorf, Heinrich; Ritter, Christiane; Schulz, Thomas F.; Lührs, Thorsten

    2015-01-01

    Kaposi sarcoma herpesvirus (KSHV) persists as a latent nuclear episome in dividing host cells. This episome is tethered to host chromatin to ensure proper segregation during mitosis. For duplication of the latent genome, the cellular replication machinery is recruited. Both of these functions rely on the constitutively expressed latency-associated nuclear antigen (LANA) of the virus. Here, we report the crystal structure of the KSHV LANA DNA-binding domain (DBD) in complex with its high-affinity viral target DNA, LANA binding site 1 (LBS1), at 2.9 Å resolution. In contrast to homologous proteins such as Epstein-Barr virus nuclear antigen 1 (EBNA-1) of the related γ-herpesvirus Epstein-Barr virus, specific DNA recognition by LANA is highly asymmetric. In addition to solving the crystal structure, we found that apart from the two known LANA binding sites, LBS1 and LBS2, LANA also binds to a novel site, denoted LBS3. All three sites are located in a region of the KSHV terminal repeat subunit previously recognized as a minimal replicator. Moreover, we show that the LANA DBD can coat DNA of arbitrary sequence by virtue of a characteristic lysine patch, which is absent in EBNA-1 of the Epstein-Barr virus. Likely, these higher-order assemblies involve the self-association of LANA into supermolecular spirals. One such spiral assembly was solved as a crystal structure of 3.7 Å resolution in the absence of DNA. On the basis of our data, we propose a model for the controlled nucleation of higher-order LANA oligomers that might contribute to the characteristic subnuclear KSHV microdomains (“LANA speckles”), a hallmark of KSHV latency. PMID:25947153

  12. Human herpesvirus 8 and iron staining are useful in differentiating Kaposi sarcoma from interstitial granuloma annulare.

    PubMed

    Wada, David A; Perkins, Sherrie L; Tripp, Sheryl; Coffin, Cheryl M; Florell, Scott R

    2007-02-01

    We studied 20 granuloma annulare (GA) cases (10 interstitial and 10 palisaded) and 19 Kaposi sarcoma (KS) cases (9 "early" and 10 typical). Tissue sections were stained for iron, Hale colloidal iron, human herpesvirus 8 (HHV-8), CD31, CD34, CD68, collagen IV, factor XIIIa, and MIB-1. Iron staining of dermal tissue associated with the lesion was confirmed in all KS cases and no GA cases. Immunohistochemical stains for HHV-8 were positive in all 9 cases of early KS and most cases (9/10) of typical KS. All 20 cases of GA were HHV-8-. CD31, CD34, CD68, factor XIIIa, and MIB-1 were also stained but were difficult to interpret and did not seem specific for GA or KS. Iron staining and immunohistochemical HHV-8 staining in combination were reliable markers for KS compared with interstitial GA. MIB-1 fractions of less than 5% favored a diagnosis of GA, whereas fractions greater than 10% favored a diagnosis of KS. This study provides novel data characterizing iron staining in KS and details the use of iron staining, HHV-8, and MIB-1 to distinguish KS from GA. PMID:17210517

  13. Visceral Kaposi's Sarcoma Related to Human Herpesvirus-8 in Liver Transplant Recipient: Case Report and Literature Review.

    PubMed

    Benhammane, H; Mentha, G; Tschanz, E; El Mesbahi, O; Dietrich, P Y

    2012-01-01

    Background. Kaposi's sarcoma (KS) in transplant recipients is about 400 to 500 times rate in the general population. It is strongly associated to Human herpesvirus-8 (HHV-8) infection which has been found in 95% of KS lesions. The optimal approach to managing posttransplantation KS is to reduce or discontinue immunosuppressive therapy but this strategy carries a risk of the acute rejection of the graft. Recently, the use of an mTOR inhibitor has added new opportunities for KS treatment and prevention. Case Report. We report a case of 24 years-old Turkish woman with visceral HHV-8-associated Kaposi's sarcoma after orthotopic liver transplantation. Conclusion. Posttransplantation KS is considered an experimental model of virus induced tumor suggesting the usefulness of HHV-8 screening in transplant recipient and donor. Therapeutic approaches are complex and require a multidisciplinary team. PMID:23320218

  14. Probing the Solution Structure of IκB Kinase (IKK) Subunit γ and Its Interaction with Kaposi Sarcoma-associated Herpes Virus Flice-interacting Protein and IKK Subunit β by EPR Spectroscopy*

    PubMed Central

    Bagnéris, Claire; Rogala, Kacper B.; Baratchian, Mehdi; Zamfir, Vlad; Kunze, Micha B. A.; Dagless, Selina; Pirker, Katharina F.; Collins, Mary K.; Hall, Benjamin A.; Barrett, Tracey E.; Kay, Christopher W. M.

    2015-01-01

    Viral flice-interacting protein (vFLIP), encoded by the oncogenic Kaposi sarcoma-associated herpes virus (KSHV), constitutively activates the canonical nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway. This is achieved through subversion of the IκB kinase (IKK) complex (or signalosome), which involves a physical interaction between vFLIP and the modulatory subunit IKKγ. Although this interaction has been examined both in vivo and in vitro, the mechanism by which vFLIP activates the kinase remains to be determined. Because IKKγ functions as a scaffold, recruiting both vFLIP and the IKKα/β subunits, it has been proposed that binding of vFLIP could trigger a structural rearrangement in IKKγ conducive to activation. To investigate this hypothesis we engineered a series of mutants along the length of the IKKγ molecule that could be individually modified with nitroxide spin labels. Subsequent distance measurements using electron paramagnetic resonance spectroscopy combined with molecular modeling and molecular dynamics simulations revealed that IKKγ is a parallel coiled-coil whose response to binding of vFLIP or IKKβ is localized twisting/stiffening and not large-scale rearrangements. The coiled-coil comprises N- and C-terminal regions with distinct registers accommodated by a twist: this structural motif is exploited by vFLIP, allowing it to bind and subsequently activate the NF-κB pathway. In vivo assays confirm that NF-κB activation by vFLIP only requires the N-terminal region up to the transition between the registers, which is located directly C-terminal of the vFLIP binding site. PMID:25979343

  15. Probing the Solution Structure of IκB Kinase (IKK) Subunit γ and Its Interaction with Kaposi Sarcoma-associated Herpes Virus Flice-interacting Protein and IKK Subunit β by EPR Spectroscopy.

    PubMed

    Bagnéris, Claire; Rogala, Kacper B; Baratchian, Mehdi; Zamfir, Vlad; Kunze, Micha B A; Dagless, Selina; Pirker, Katharina F; Collins, Mary K; Hall, Benjamin A; Barrett, Tracey E; Kay, Christopher W M

    2015-07-01

    Viral flice-interacting protein (vFLIP), encoded by the oncogenic Kaposi sarcoma-associated herpes virus (KSHV), constitutively activates the canonical nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway. This is achieved through subversion of the IκB kinase (IKK) complex (or signalosome), which involves a physical interaction between vFLIP and the modulatory subunit IKKγ. Although this interaction has been examined both in vivo and in vitro, the mechanism by which vFLIP activates the kinase remains to be determined. Because IKKγ functions as a scaffold, recruiting both vFLIP and the IKKα/β subunits, it has been proposed that binding of vFLIP could trigger a structural rearrangement in IKKγ conducive to activation. To investigate this hypothesis we engineered a series of mutants along the length of the IKKγ molecule that could be individually modified with nitroxide spin labels. Subsequent distance measurements using electron paramagnetic resonance spectroscopy combined with molecular modeling and molecular dynamics simulations revealed that IKKγ is a parallel coiled-coil whose response to binding of vFLIP or IKKβ is localized twisting/stiffening and not large-scale rearrangements. The coiled-coil comprises N- and C-terminal regions with distinct registers accommodated by a twist: this structural motif is exploited by vFLIP, allowing it to bind and subsequently activate the NF-κB pathway. In vivo assays confirm that NF-κB activation by vFLIP only requires the N-terminal region up to the transition between the registers, which is located directly C-terminal of the vFLIP binding site. PMID:25979343

  16. Transgenic Expression of the Chemokine Receptor Encoded by Human Herpesvirus 8 Induces an Angioproliferative Disease Resembling Kaposi's Sarcoma

    PubMed Central

    Yang, Tong-Yuan; Chen, Shu-Cheng; Leach, Michael W.; Manfra, Denise; Homey, Bernhard; Wiekowski, Maria; Sullivan, Lee; Jenh, Chung-Her; Narula, Satwant K.; Chensue, Stephen W.; Lira, Sergio A.

    2000-01-01

    Human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma [KS]-associated herpesvirus) has been implicated as an etiologic agent for KS, an angiogenic tumor composed of endothelial, inflammatory, and spindle cells. Here, we report that transgenic mice expressing the HHV8-encoded chemokine receptor (viral G protein–coupled receptor) within hematopoietic cells develop angioproliferative lesions in multiple organs that morphologically resemble KS lesions. These lesions are characterized by a spectrum of changes ranging from erythematous maculae to vascular tumors, by the presence of spindle and inflammatory cells, and by expression of vGPCR, CD34, and vascular endothelial growth factor. We conclude that vGPCR contributes to the development of the angioproliferative lesions observed in these mice and suggest that this chemokine receptor may play a role in the pathogenesis of KS in humans. PMID:10662790

  17. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma.

    PubMed

    Yang, T Y; Chen, S C; Leach, M W; Manfra, D; Homey, B; Wiekowski, M; Sullivan, L; Jenh, C H; Narula, S K; Chensue, S W; Lira, S A

    2000-02-01

    Human herpesvirus 8 (HHV8, also known as Kaposi's sarcoma [KS]-associated herpesvirus) has been implicated as an etiologic agent for KS, an angiogenic tumor composed of endothelial, inflammatory, and spindle cells. Here, we report that transgenic mice expressing the HHV8-encoded chemokine receptor (viral G protein-coupled receptor) within hematopoietic cells develop angioproliferative lesions in multiple organs that morphologically resemble KS lesions. These lesions are characterized by a spectrum of changes ranging from erythematous maculae to vascular tumors, by the presence of spindle and inflammatory cells, and by expression of vGPCR, CD34, and vascular endothelial growth factor. We conclude that vGPCR contributes to the development of the angioproliferative lesions observed in these mice and suggest that this chemokine receptor may play a role in the pathogenesis of KS in humans. PMID:10662790

  18. Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

    PubMed Central

    Gjyshi, Olsi; Flaherty, Stephanie; Veettil, Mohanan Valiya; Johnson, Karen E.; Chandran, Bala

    2014-01-01

    ABSTRACT Nuclear factor erythroid 2-related factor 2 (Nrf2), the cellular master regulator of the antioxidant response, dissociates from its inhibitor Keap1 when activated by stress signals and participates in the pathogenesis of viral infections and tumorigenesis. Early during de novo infection of endothelial cells, KSHV induces Nrf2 through an intricate mechanism involving reactive oxygen species (ROS) and prostaglandin E2 (PGE2). When we investigated the Nrf2 activity during latent KSHV infection, we observed increased nuclear serine-40-phosphorylated Nrf2 in human KS lesions compared to that in healthy tissues. Using KSHV long-term-infected endothelial cells (LTC) as a cellular model for KS, we demonstrated that KSHV infection induces Nrf2 constitutively by extending its half-life, increasing its phosphorylation by protein kinase Cζ (PKCζ) via the infection-induced cyclooxygenase-2 (COX-2)/PGE2 axis and inducing its nuclear localization. Nrf2 knockdown in LTC decreased expression of antioxidant genes and genes involved in KS pathogenesis such as the NAD(P)H quinone oxidase 1 (NQO1), gamma glutamylcysteine synthase heavy unit (γGCSH), the cysteine transporter (xCT), interleukin 6 (IL-6), and vascular endothelial growth factor A (VEGF-A) genes. Nrf2 activation was independent of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1; p62). SQSTM1 levels were elevated in LTC, a consequence of protein accumulation due to decreased autophagy and Nrf2-mediated transcriptional activation. SQSTM1 was phosphorylated on serine-351 and -403, while Keap1 was polyubiquitinated with lysine-63–ubiquitin chains, modifications known to increase their mutual affinity and interaction, leading to Keap1 degradation and Nrf2 activation. The latent KSHV protein Fas-associated death domain-like interleukin-1β-converting enzyme-inhibitory protein (vFLIP) increased SQSTM1 expression and activated Nrf2. Collectively, these results demonstrate that KSHV induces SQSTM1 to constitutively activate Nrf2, which is involved in the regulation of genes participating in KSHV oncogenesis. IMPORTANCE The transcription factor Nrf2 is activated by stress signals, including viral infection, and responds by activating the transcription of cytoprotective genes. Recently, Nrf2 has been implicated in oncogenesis and was shown to be activated during de novo KSHV infection of endothelial cells through ROS-dependent pathways. The present study was undertaken to determine the mechanism of Nrf2 activation during prolonged latent infection of endothelial cells, using an endothelial cell line latently infected with KSHV. We show that Nrf2 activation was elevated in KSHV latently infected endothelial cells independently of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1), which was involved in the degradation of the Nrf2 inhibitor Keap1. Furthermore, our results indicated that the KSHV latent protein vFLIP participates in Nrf2 activation. This study suggests that KSHV hijacks the host's autophagic protein SQSTM1 to induce Nrf2 activation, thereby manipulating the infected host gene regulation to promote KS pathogenesis. PMID:25505069

  19. Requirement of UAP56, URH49, RBM15, and OTT3 in the expression of Kaposi sarcoma-associated herpesvirus ORF57

    SciTech Connect

    Majerciak, Vladimir; Deng, Merlyn; Zheng Zhiming

    2010-11-25

    Transport of mRNA from the nucleus to the cytoplasm is mediated by cellular RNA export factors. In this report, we examined how RNA export factors UAP56 and URH49, and RNA export cofactors RBM15 and OTT3, function in modulating KSHV ORF57 expression. We found that knockdown of each factor by RNAi led to decreased ORF57 expression. Specifically, reduced expression of either UAP56 or RBM15 led to nuclear export deficiency of ORF57 RNA. In the context of the KSHV genome, the near absence of UAP56 or RBM15 reduced the expression of both ORF57 and ORF59 (an RNA target of ORF57), but not ORF50. Collectively, our data indicate that the expression of KSHV ORF57 is regulated by cellular RNA export factors and cofactors at the posttranscriptional level.

  20. What Is Kaposi Sarcoma?

    MedlinePlus

    ... Endemic KS occurs in people living in Equatorial Africa and is sometimes called African KS . KSHV (Kaposi ... associated herpesvirus) infection is much more common in Africa than in other parts of the world, so ...

  1. Phase-dependent immune evasion of herpesviruses.

    PubMed

    Vider-Shalit, Tal; Fishbain, Vered; Raffaeli, Shai; Louzoun, Yoram

    2007-09-01

    Viruses employ various modes to evade immune detection. Two possible evasion modes are a reduction of the number of epitopes presented and the mimicry of host epitopes. The immune evasion efforts are not uniform among viral proteins. The number of epitopes in a given viral protein and the similarity of the epitopes to host peptides can be used as a measure of the viral attempts to hide this protein. Using bioinformatics tools, we here present a genomic analysis of the attempts of four human herpesviruses (herpes simplex virus type 1-human herpesvirus 1, Epstein-Barr virus-human herpesvirus 4, human cytomegalovirus-human herpesvirus 5, and Kaposi's sarcoma-associated herpesvirus-human herpesvirus 8) and one murine herpesvirus (murine herpesvirus 68) to escape from immune detection. We determined the full repertoire of CD8 T-lymphocyte epitopes presented by each viral protein and show that herpesvirus proteins present many fewer epitopes than expected. Furthermore, the epitopes that are presented are more similar to host epitopes than are random viral epitopes, minimizing the immune response. We defined a score for the size of the immune repertoire (the SIR score) based on the number of epitopes in a protein. The numbers of epitopes in proteins expressed in the latent and early phases of infection were significantly smaller than those in proteins expressed in the lytic phase in all tested viruses. The latent and immediate-early epitopes were also more similar to host epitopes than were lytic epitopes. A clear trend emerged from the analysis. In general, herpesviruses demonstrated an effort to evade immune detection. However, within a given herpesvirus, proteins expressed in phases critical to the fate of infection (e.g., early lytic and latent) evaded immune detection more than all others. The application of the SIR score to specific proteins allows us to quantify the importance of immune evasion and to detect optimal targets for immunotherapy and vaccine development

  2. Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS.

    PubMed

    Zhang, Guigen; Chan, Baca; Samarina, Naira; Abere, Bizunesh; Weidner-Glunde, Magdalena; Buch, Anna; Pich, Andreas; Brinkmann, Melanie M; Schulz, Thomas F

    2016-02-23

    The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING-dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS-mediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle. PMID:26811480

  3. Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS

    PubMed Central

    Zhang, Guigen; Chan, Baca; Samarina, Naira; Abere, Bizunesh; Weidner-Glunde, Magdalena; Buch, Anna; Pich, Andreas; Brinkmann, Melanie M.; Schulz, Thomas F.

    2016-01-01

    The latency-associated nuclear antigen (LANA) of Kaposi sarcoma herpesvirus (KSHV) is mainly localized and functions in the nucleus of latently infected cells, playing a pivotal role in the replication and maintenance of latent viral episomal DNA. In addition, N-terminally truncated cytoplasmic isoforms of LANA, resulting from internal translation initiation, have been reported, but their function is unknown. Using coimmunoprecipitation and MS, we found the cGMP-AMP synthase (cGAS), an innate immune DNA sensor, to be a cellular interaction partner of cytoplasmic LANA isoforms. By directly binding to cGAS, LANA, and particularly, a cytoplasmic isoform, inhibit the cGAS-STING–dependent phosphorylation of TBK1 and IRF3 and thereby antagonize the cGAS-mediated restriction of KSHV lytic replication. We hypothesize that cytoplasmic forms of LANA, whose expression increases during lytic replication, inhibit cGAS to promote the reactivation of the KSHV from latency. This observation points to a novel function of the cytoplasmic isoforms of LANA during lytic replication and extends the function of LANA from its role during latency to the lytic replication cycle. PMID:26811480

  4. Inhibition of Intracellular Transport of B Cell Antigen Receptor Complexes by Kaposi's Sarcoma–Associated Herpesvirus K1

    PubMed Central

    Lee, Bok-Soo; Alvarez, Xavier; Ishido, Satoshi; Lackner, Andrew A.; Jung, Jae U.

    2000-01-01

    The B cell antigen receptor (BCR) is a large complex that consists of a disulfide-linked tetramer of two transmembrane heavy (μ) chains and two light (λ or κ) chains in association with a heterodimer of Igα and Igβ. Kaposi's sarcoma–associated herpesvirus (KSHV) encodes a transforming protein called K1, which has structural and functional similarity to Igα and Igβ. We demonstrate that K1 downregulates the expression of BCR complexes on the surface. The NH2-terminal region of K1 specifically interacts with the μ chains of BCR complexes, and this interaction retains BCR complexes in the endoplasmic reticulum, preventing their intracellular transport to the cell surface. Thus, KSHV K1 resembles Igα and Igβ in its ability to induce signaling and to interact with μ chains of the BCR. However, unlike Igα and Igβ, which interact with μ chains to direct BCR complexes to the cell surface, K1 interacts with μ chains to block the intracellular transport of BCR complexes to the cell surface. These results demonstrate a unique feature of the K1 transforming protein, which may confer virus-infected cells with a long-term survival advantage. PMID:10880522

  5. Herpesvirus saimiri.

    PubMed Central

    Fickenscher, H; Fleckenstein, B

    2001-01-01

    Herpesvirus saimiri (saimiriine herpesvirus 2) is the classical prototype of the gamma(2)-herpesviruses or rhadinoviruses, which also contains a human member, the Kaposi's sarcoma-associated herpesvirus. The T-lymphotropic Herpesvirus saimiri establishes specific replicative and persistent conditions in different primate host species. Virtually all squirrel monkeys (Saimiri sciureus) are persistently infected with this virus. In its natural host, the virus does not cause disease, whereas it induces fatal acute T-cell lymphoma in other monkey species after experimental infection. The virus can be isolated by cocultivation of permissive epithelial cells with peripheral blood cells from naturally infected squirrel monkeys and from susceptible New World monkeys during the virus-induced disease. Tumour-derived and in vitro-transformed T-cell lines from New World monkeys release virus particles. Herpesvirus ateles is a closely related virus of spider monkeys (Ateles spp.) and has similar pathogenic properties to Herpesvirus saimiri in other New World primate species. Similar to other rhadinoviruses, the genome of Herpesvirus saimiri harbours a series of virus genes with pronounced homology to cellular counterparts including a D-type cyclin, a G-protein-coupled receptor, an interleukin-17, a superantigen homologue, and several inhibitors of the complement cascade and of different apoptosis pathways. Preserved function has been demonstrated for most of the homologues of cellular proteins. These viral functions are mostly dispensable for the transforming and pathogenic capability of the virus. However, they are considered relevant for the apathogenic persistence of Herpesvirus saimiri in its natural host. A terminal region of the non-repetitive coding part of the virus genome is essential for pathogenicity and T-cell transformation. Based on the pathogenic phenotypes and the different alleles of this variable region, the virus strains have been assigned to three subgroups

  6. Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome

    PubMed Central

    Polizzotto, Mark N.; Uldrick, Thomas S.; Hu, Duosha; Yarchoan, Robert

    2012-01-01

    Soon after the discovery of Kaposi sarcoma (KS)-associated herpesvirus (KSHV), it was appreciated that this virus was associated with most cases of multicentric Castleman disease (MCD) arising in patients infected with human immunodeficiency virus. It has subsequently been recognized that KSHV–MCD is a distinct entity from other forms of MCD. Like MCD that is unrelated to KSHV, the clinical presentation of KSHV–MCD is dominated by systemic inflammatory symptoms including fevers, cachexia, and laboratory abnormalities including cytopenias, hypoalbuminemia, hyponatremia, and elevated C-reactive protein. Pathologically KSHV–MCD is characterized by polyclonal, IgM-lambda restricted plasmacytoid cells in the intrafollicular areas of affected lymph nodes. A portion of these cells are infected with KSHV and a sizable subset of these cells express KSHV lytic genes including a viral homolog of interleukin-6 (vIL-6). Patients with KSHV–MCD generally have elevated KSHV viral loads in their peripheral blood. Production of vIL-6 and induction of human (h) IL-6 both contribute to symptoms, perhaps in combination with overproduction of IL-10 and other cytokines. Until recently, the prognosis of patients with KSHV–MCD was poor. Recent therapeutic advances targeting KSHV-infected B cells with the anti-CD20 monoclonal antibody rituximab and utilizing KSHV enzymes to target KSHV-infected cells have substantially improved patient outcomes. Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Its clinical manifestations resemble those of KSHV–MCD but lymphadenopathy is not prominent and the pathologic nodal changes of KSHV–MCD are absent. Patients with KICS exhibit elevated KSHV viral loads and elevation of vIL-6, homolog of human interleukin-6 and IL-10 comparable to those seen in KSHV–MCD; the cellular origin of these is a matter of investigation. KICS may contribute to the inflammatory symptoms seen in some

  7. Herpesviruses and the microbiome.

    PubMed

    Dreyfus, David H

    2013-12-01

    The focus of this article will be to examine the role of common herpesviruses as a component of the microbiome of atopic patients and to review clinical observations suggesting that atopic patients might be predisposed to more severe and atypical herpes-related illness because their immune response is biased toward a TH2 cytokine profile. Human populations are infected with 8 herpesviruses, including herpes simplex virus HSV1 and HSV2 (also termed HHV1 and HHV2), varicella zoster virus (VZV or HHV3), EBV (HHV4), cytomegalovirus (HHV5), HHV6, HHV7, and Kaposi sarcoma-associated herpesvirus (termed KSV or HHV8). Herpesviruses are highly adapted to lifelong infection of their human hosts and thus can be considered a component of the human "microbiome" in addition to their role in illness triggered by primary infection. HSV1 and HSV2 infection and reactivation can present with more severe cutaneous symptoms termed eczema herpeticum in the atopic population, similar to the more severe eczema vaccinatum, and drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) is associated with reactivation of HSV6 and possibly other herpesviruses in both atopic and nonatopic patients. In this review evidence is reviewed that primary infection with herpesviruses may have an atypical presentation in the atopic patient and conversely that childhood infection might alter the atopic phenotype. Reactivation of latent herpesviruses can directly alter host cytokine profiles through viral expression of cytokine-like proteins, such as IL-10 (EBV) or IL-6 (cytomegalovirus and HHV8), viral encoded and secreted siRNA and microRNAs, and modulation of expression of host transcription pathways, such as nuclear factor κB. Physicians caring for allergic and atopic populations should be aware of common and uncommon presentations of herpes-related disease in atopic patients to provide accurate diagnosis and avoid unnecessary laboratory testing or incorrect diagnosis of other conditions

  8. Sequence Analysis of Kaposi Sarcoma–Associated Herpesvirus (KSHV) MicroRNAs in Patients with Multicentric Castleman Disease and KSHV-Associated Inflammatory Cytokine Syndrome

    PubMed Central

    Ray, Alex; Marshall, Vickie; Uldrick, Thomas; Leighty, Robert; Labo, Nazzarena; Wyvill, Kathy; Aleman, Karen; Polizzotto, Mark N.; Little, Richard F.; Yarchoan, Robert; Whitby, Denise

    2012-01-01

    Background Kaposi sarcoma–associated herpesvirus (KSHV) encodes 12 pre-microRNAs that yield 25 mature microRNAs. We previously reported phylogenetic analysis of the microRNA-coding region of KSHV from Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD) patients. We observed a high level of conservation for most sequences but also a divergent cluster of 5 KSHV sequences, including 2 from MCD patients. Methods KSHV microRNA sequences from 23 MCD patients and 7 patients with a newly described KSHV-associated inflammatory cytokine syndrome (KICS) were examined by amplification, cloning, and sequencing of a 646-bp fragment of K12/T0.7 encoding microRNA-K12-10 and microRNA-K12-12 and a 2.8-kbp fragment containing the remaining 10 pre-microRNAs. Results Phylogenetic analysis showed a distinct variant cluster consisting exclusively of MCD and KICS patients in all trees. Pearson χ2 analysis revealed that 40 single-nucleotide polymorphisms (SNPs) at various loci were significantly associated with MCD and KICS risk. Cluster analysis of these SNPs generated several combinations of 3 SNPs as putative indicators of MCD and KICS risk. Conclusions These findings show that MCD and KICS patients frequently have unusual KSHV microRNA sequences and suggest an association between the observed sequence variation and risk of MCD and KICS. PMID:22448005

  9. Human Oncogenic Herpesvirus and Post-translational Modifications - Phosphorylation and SUMOylation.

    PubMed

    Chang, Pei-Ching; Campbell, Mel; Robertson, Erle S

    2016-01-01

    Pathogens, especially viruses, evolve abilities to utilize cellular machineries to facilitate their survival and propagation. Post-translational modifications (PTMs), especially phosphorylation and SUMOylation, that reversibly modulate the function and interactions of target proteins are among the most important features in cell signaling pathways. PTM-dependent events also serve as one of the favorite targets for viruses. Among the seven unambiguous human oncogenic viruses, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), human papillomavirus (HPV), Human T lymphotrophic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV), two are herpesviruses. The life cycle of herpesviruses consists of latent and lytic phases and the rapid switch between these states includes global remodeling of the viral genome from heterochromatin-to-euchromatin. The balance between lytic replication and latency is essential for herpesvirus to maintain a persistent infection through a combination of viral propagation and evasion of the host immune response, which consequently may contribute to tumorigenesis. It is no surprise that the swift reversibility of PTMs, especially SUMOylation, a modification that epigenetically regulates chromatin structure, is a major hijack target of the host for oncogenic herpesviruses. In this brief review, we summarize the varied ways in which herpesviruses engage the host immune components through PTMs, focusing on phosphorylation and SUMOylation. PMID:27379086

  10. Refractory ulcerative colitis and iatrogenic colorectal Kaposi's sarcoma.

    PubMed

    Girelli, C M; Serio, G; Rocca, E; Rocca, F

    2009-02-01

    Colorectal Kaposi's sarcoma, a human herpes virus-8 associated mesenchymal tumour, is exceedingly rare in human immunodeficiency virus-negative subjects and almost always reported in association with severe, refractory, inflammatory bowel disease. In this paper we report a case--the second from Italy--of a colorectal Kaposi's sarcoma in a human immunodeficiency virus-negative, heterosexual man with severe refractory ulcerative colitis. Kaposi's sarcoma developed after starting glucocorticosteroid therapy, supporting the theory that colorectal Kaposi's sarcoma associated with ulcerative colitis is iatrogenic. PMID:18054849

  11. Inhibition of MHC class I-restricted antigen presentation by gamma 2-herpesviruses.

    PubMed

    Stevenson, P G; Efstathiou, S; Doherty, P C; Lehner, P J

    2000-07-18

    The gamma-herpesviruses, in contrast to the alpha- and beta-herpesviruses, are not known to inhibit antigen presentation to CD8(+) cytotoxic T lymphocytes (CTLs) during lytic cycle replication. However, murine gamma-herpesvirus 68 causes a chronic lytic infection in CD4(+) T cell-deficient mice despite the persistence of a substantial CTL response, suggesting that CTL evasion occurs. Here we show that, distinct from host protein synthesis shutoff, gamma-herpesvirus 68 down-regulates surface MHC class I expression on lytically infected fibroblasts and inhibits their recognition by antigen-specific CTLs. The viral K3 gene, encoding a zinc-finger-containing protein, dramatically reduced the half-life of nascent class I molecules and the level of surface MHC class I expression and was by itself sufficient to block antigen presentation. The homologous K3 and K5 genes of the related Kaposi's sarcoma-associated virus also inhibited antigen presentation and decreased cell surface expression of HLA class I antigens. Thus it appears that an immune evasion strategy shared by at least two gamma-herpesviruses allows continued lytic infection in the face of strong CTL immunity. PMID:10890918

  12. Kaposi Sarcoma Herpesvirus Induces HO-1 during De Novo Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms

    PubMed Central

    Botto, Sara; Totonchy, Jennifer E.; Gustin, Jean K.

    2015-01-01

    ABSTRACT Kaposi sarcoma (KS) herpesvirus (KSHV) infection of endothelial cells (EC) is associated with strong induction of heme oxygenase-1 (HO-1), a stress-inducible host gene that encodes the rate-limiting enzyme responsible for heme catabolism. KS is an angioproliferative tumor characterized by the proliferation of KSHV-infected spindle cells, and HO-1 is highly expressed in such cells. HO-1 converts the pro-oxidant, proinflammatory heme molecule into metabolites with antioxidant, anti-inflammatory, and proliferative activities. Previously published work has shown that KSHV-infected EC in vitro proliferate in response to free heme in a HO-1-dependent manner, thus implicating virus-enhanced HO-1 activity in KS tumorigenesis. The present study investigated the molecular mechanisms underlying KSHV induction of HO-1 in lymphatic EC (LEC), which are the likely spindle cell precursors. In a time course analysis of KSHV-infected cells, HO-1 expression displays biphasic kinetics characterized by an early transient induction that is followed by a more sustained upregulation coincident with the establishment of viral latency. A viral microRNA miR-K12-11 deletion mutant of KSHV was found to be defective for induction of HO-1 during latency. A potential mechanism for this phenotype was provided by BACH1, a cellular HO-1 transcriptional repressor targeted by miR-K12-11. In fact, in KSHV-infected LEC, the BACH1 message level is reduced, BACH1 subcellular localization is altered, and miR-K12-11 mediates the inverse regulation of HO-1 and BACH1 during viral latency. Interestingly, the data indicate that neither miR-K12-11 nor de novo KSHV gene expression is required for the burst of HO-1 expression observed at early times postinfection, which suggests that additional virion components promote this phenotype. PMID:26045540

  13. Plasmacytoid dendritic cells in skin lesions of classic Kaposi's sarcoma.

    PubMed

    Karouni, Mirna; Kurban, Mazen; Abbas, Ossama

    2016-09-01

    Plasmacytoid dendritic cells (pDCs) are the most potent producers of type I interferons (IFNs), which allows them to provide anti-viral resistance and to link the innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer cells. pDCs are involved in the pathogenesis of several infectious [especially viral, such as Molluscum contagiosum (MC)], inflammatory/autoimmune, and neoplastic entities. Kaposi's sarcoma (KS) is a multifocal, systemic lympho-angioproliferative tumor associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Microscopy typically exhibits a chronic inflammatory lymphoplasmacytic infiltrate in addition to the vascular changes and spindle cell proliferation. Despite the extensive research done on the immune evasion strategies employed by KSHV, pDCs role in relation to KS has only rarely been investigated. Given this, we intend to investigate pDC occurrence and activity in the skin lesions of KS. Immunohistochemical staining for BDCA-2 (specific pDC marker) and MxA (surrogate marker for local type I IFN production) was performed on classic KS (n = 20) with the control group comprising inflamed MC (n = 20). As expected, BDCA-2+ pDCs were present in abundance with diffuse and intense MxA expression (indicative of local type I IFN production) in all inflamed MC cases (20 of 20, 100 %). Though present in all the KS cases, pDCs were significantly less abundant in KS than in inflamed MC cases, and MxA expression was patchy/weak in most KS cases. In summary, pDCs are part of the inflammatory host response in KS; however, they were generally low in number with decreased type I IFN production which is probably related to KSHV's ability to evade the immune system through the production of different viral proteins capable of suppressing IFN production as well as pDC function. PMID:27372661

  14. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8)

    PubMed Central

    Russo, James J.; Bohenzky, Roy A.; Chien, Ming-Cheng; Chen, Jing; Yan, Ming; Maddalena, Dawn; Parry, J. Preston; Peruzzi, Daniela; Edelman, Isidore S.; Chang, Yuan; Moore, Patrick S.

    1996-01-01

    The genome of the Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) was mapped with cosmid and phage genomic libraries from the BC-1 cell line. Its nucleotide sequence was determined except for a 3-kb region at the right end of the genome that was refractory to cloning. The BC-1 KSHV genome consists of a 140.5-kb-long unique coding region flanked by multiple G+C-rich 801-bp terminal repeat sequences. A genomic duplication that apparently arose in the parental tumor is present in this cell culture-derived strain. At least 81 ORFs, including 66 with homology to herpesvirus saimiri ORFs, and 5 internal repeat regions are present in the long unique region. The virus encodes homologs to complement-binding proteins, three cytokines (two macrophage inflammatory proteins and interleukin 6), dihydrofolate reductase, bcl-2, interferon regulatory factors, interleukin 8 receptor, neural cell adhesion molecule-like adhesin, and a D-type cyclin, as well as viral structural and metabolic proteins. Terminal repeat analysis of virus DNA from a KS lesion suggests a monoclonal expansion of KSHV in the KS tumor. PMID:8962146

  15. Rodent herpesvirus Peru encodes a secreted chemokine decoy receptor.

    PubMed

    Lubman, Olga Y; Cella, Marina; Wang, Xinxin; Monte, Kristen; Lenschow, Deborah J; Huang, Yina H; Fremont, Daved H

    2014-01-01

    Viruses have long been studied not only for their pathology and associated disease but also as model systems for understanding cellular and immunological processes. Rodent herpesvirus Peru (RHVP) is a recently characterized rhadinovirus related to murine gammaherpesvirus 68 (MHV68) and Kaposi's sarcoma-associated herpesvirus (KSHV) that establishes acute and latent infection in laboratory mice. RHVP encodes numerous unique proteins that we hypothesize might facilitate host immune evasion during infection. We report here that open reading frame (ORF) R17 encodes a high-affinity chemokine binding protein that broadly recognizes human and murine CC and C chemokines. The interaction of R17 with chemokines is generally characterized by rapid association kinetics, and in the case of CCL3, CCL4, CCL5, CCL24, and XCL1, extremely stable complexes are formed. Functionally, R17 potently inhibited CCL2-driven chemotaxis of the human monocytic cell line THP-1, CCL3-driven chemotaxis of peripheral blood mononuclear cells, and CCL2-mediated calcium flux. Our studies also reveal that R17 binds to glycosaminoglycans (GAGs) in a process dependent upon two BBXB motifs and that chemokine and GAG binding can occur simultaneously at distinct sites. Collectively, these studies suggest that R17 may play a role in RHVP immune evasion through the targeted sabotage of chemokine-mediated immune surveillance. PMID:24173234

  16. Non-Detection of Human Herpesvirus 8 (HHV-8) DNA in HHV-8-Seropositive Blood Donors from Three Brazilian Regions

    PubMed Central

    Levi, José Eduardo; Nascimento, Maria Claudia; Sumita, Laura Masami; de Souza, Vanda Akico Ueda Fick; Freire, Wilton S.; Mayaud, Philippe; Pannuti, Claudio S.

    2011-01-01

    Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the etiologic agent of all forms of Kaposi's sarcoma, primary effusion lymphoma and the plasmablastic cell variant of multicentric Castleman disease. In endemic areas of sub-Saharan Africa, blood transfusions have been associated with a substantial risk of HHV-8 transmission. By contrast, several studies among healthy blood donors from North America have failed to detect HHV-8 DNA in samples of seropositive individuals. In this study, using a real-time PCR assay, we investigated the presence of HHV-8 DNA in whole-blood samples of 803 HHV-8 blood donors from three Brazilian states (São Paulo, Amazon, Bahia) who tested positive for HHV-8 antibodies, in a previous multicenter study. HHV-8 DNA was not detected in any sample. Our findings do not support the introduction of routine HHV-8 screening among healthy blood donors in Brazil. (WC = 140). PMID:21858163

  17. γ-Herpesvirus Load as Surrogate Marker of Early Death in HIV-1 Lymphoma Patients Submitted to High Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation

    PubMed Central

    Pratesi, Chiara; Zanussi, Stefania; Tedeschi, Rosamaria; Bortolin, Maria Teresa; Talamini, Renato; Rupolo, Maurizio; Scaini, Chiara; Basaglia, Giancarlo; Di Maso, Matteo; Mazzucato, Mario; Zanet, Ernesto; Tirelli, Umberto; Michieli, Mariagrazia; Carbone, Antonino; De Paoli, Paolo

    2015-01-01

    Autologous stem cell transplantation (ASCT) is a feasible procedure for human immunodeficiency virus-1 (HIV-1) lymphoma patients, whose underlying disease and intrinsic HIV-1- and ASCT-associated immunodeficiency might increase the risk for γ-herpesvirus load persistence and/or reactivation. We evaluated this hypothesis by investigating the levels of Epstein-Barr virus (EBV)- and Kaposi sarcoma-associated herpesvirus (KSHV)-DNA levels in the peripheral blood of 22 HIV-1-associated lymphoma patients during ASCT, highlighting their relationship with γ-herpesvirus lymphoma status, immunological parameters, and clinical events. EBV-DNA was detected in the pre-treatment plasma and peripheral blood mononuclear cells (PBMCs) of 12 (median 12135 copies/mL) and 18 patients (median 417 copies/106 PBMCs), respectively; the values in the two compartments were correlated (r = 0.77, p = 0.0001). Only EBV-positive lymphomas showed detectable levels of plasma EBV-DNA. After debulking chemotherapy, plasma EBV-DNA was associated with lymphoma chemosensitivity (p = 0.03) and a significant higher mortality risk by multivariate Cox analysis adjusted for EBV-lymphoma status (HR, 10.46, 95% CI, 1.11–98.32, p = 0.04). After infusion, EBV-DNA was detectable in five EBV-positive lymphoma patients who died within six months. KSHV-DNA load was positive in only one patient, who died from primary effusion lymphoma. Fluctuations in levels of KSHV-DNA reflected the patient’s therapy and evolution of his underlying lymphoma. Other γ-herpesvirus-associated malignancies, such as multicentric Castleman disease and Kaposi sarcoma, or end-organ complications after salvage treatment were not found. Overall, these findings suggest a prognostic and predictive value of EBV-DNA and KSHV-DNA, the monitoring of which could be a simple, complementary tool for the management of γ-herpesvirus-positive lymphomas in HIV-1 patients submitted to ASCT. PMID:25668032

  18. γ-Herpesvirus load as surrogate marker of early death in HIV-1 lymphoma patients submitted to high dose chemotherapy and autologous peripheral blood stem cell transplantation.

    PubMed

    Pratesi, Chiara; Zanussi, Stefania; Tedeschi, Rosamaria; Bortolin, Maria Teresa; Talamini, Renato; Rupolo, Maurizio; Scaini, Chiara; Basaglia, Giancarlo; Di Maso, Matteo; Mazzucato, Mario; Zanet, Ernesto; Tirelli, Umberto; Michieli, Mariagrazia; Carbone, Antonino; De Paoli, Paolo

    2015-01-01

    Autologous stem cell transplantation (ASCT) is a feasible procedure for human immunodeficiency virus-1 (HIV-1) lymphoma patients, whose underlying disease and intrinsic HIV-1- and ASCT-associated immunodeficiency might increase the risk for γ-herpesvirus load persistence and/or reactivation. We evaluated this hypothesis by investigating the levels of Epstein-Barr virus (EBV)- and Kaposi sarcoma-associated herpesvirus (KSHV)-DNA levels in the peripheral blood of 22 HIV-1-associated lymphoma patients during ASCT, highlighting their relationship with γ-herpesvirus lymphoma status, immunological parameters, and clinical events. EBV-DNA was detected in the pre-treatment plasma and peripheral blood mononuclear cells (PBMCs) of 12 (median 12,135 copies/mL) and 18 patients (median 417 copies/10(6) PBMCs), respectively; the values in the two compartments were correlated (r = 0.77, p = 0.0001). Only EBV-positive lymphomas showed detectable levels of plasma EBV-DNA. After debulking chemotherapy, plasma EBV-DNA was associated with lymphoma chemosensitivity (p = 0.03) and a significant higher mortality risk by multivariate Cox analysis adjusted for EBV-lymphoma status (HR, 10.46, 95% CI, 1.11-98.32, p = 0.04). After infusion, EBV-DNA was detectable in five EBV-positive lymphoma patients who died within six months. KSHV-DNA load was positive in only one patient, who died from primary effusion lymphoma. Fluctuations in levels of KSHV-DNA reflected the patient's therapy and evolution of his underlying lymphoma. Other γ-herpesvirus-associated malignancies, such as multicentric Castleman disease and Kaposi sarcoma, or end-organ complications after salvage treatment were not found. Overall, these findings suggest a prognostic and predictive value of EBV-DNA and KSHV-DNA, the monitoring of which could be a simple, complementary tool for the management of γ-herpesvirus-positive lymphomas in HIV-1 patients submitted to ASCT. PMID:25668032

  19. Oncogenic Herpesvirus KSHV Hijacks BMP-Smad1-Id Signaling to Promote Tumorigenesis

    PubMed Central

    Li, Shasha; Dong, Jiazhen; Wang, Xing; Wang, Yuhan; He, Li; He, Zhiheng; Gao, Yuan; Gao, Shou-Jiang; Lan, Ke

    2014-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), a malignancy commonly found in AIDS patients. Whether KS is a true neoplasm or hyperplasia has been a subject of intensive debate until recently when KSHV is unequivocally shown to efficiently infect, immortalize and transform rat primary mesenchymal precursor cells (MM). Moreover, KSHV-transformed MM cells (KMM) efficiently induce tumors with hallmark features of KS when inoculated into nude mice. Here, we showed Smad1 as a novel binding protein of KSHV latency-associated nuclear antigen (LANA). LANA interacted with and sustained BMP-activated p-Smad1 in the nucleus and enhanced its loading on the Id promoters. As a result, Ids were significantly up-regulated in KMM cells and abundantly expressed in human KS lesions. Strikingly, genetic and chemical inhibition of the BMP-Smad1-Id pathway blocked the oncogenic phenotype of KSHV-transformed cells in vitro and in vivo. These findings illustrate a novel mechanism by which a tumor virus hijacks and converts a developmental pathway into an indispensable oncogenic pathway for tumorigenesis. Importantly, our results demonstrate the efficacy of targeting the BMP-Smad1-Id pathway for inhibiting the growth of KSHV-induced tumors, and therefore identify the BMP pathway as a promising therapeutic target for KS. PMID:25010525

  20. Early peripheral lymph node involvement of human herpesvirus 8-associated, body cavity-based lymphoma in a human immunodeficiency virus-negative patient.

    PubMed

    Ariad, S; Benharroch, D; Lupu, L; Davidovici, B; Dupin, N; Boshoff, C

    2000-05-01

    Human herpesvirus 8 (HHV-8), or Kaposi sarcoma-associated herpesvirus, is a gamma herpesvirus first detected in a specimen of Kaposi sarcoma from a human immunodeficiency virus (HIV)-positive patient. Human herpesvirus 8 is also found in an unusual clinicopathologic form of body cavity-based B-cell lymphoma, which has been named primary effusion lymphoma (PEL) and occurs primarily in HIV-positive patients. PEL is characterized by the formation of lymphomatous effusions, without obvious lymphadenopathy, tumor masses, or bone marrow involvement. Only a few cases of PEL in HIV-seronegative patients have been reported. We describe a case of an HHV-8-associated lymphoma, with ascites, pleural effusion, and axillary lymphadenopathy in an HIV-negative patient. The patient was a 68-year-old Jewish man of North African extraction, with a previous history of coronary bypass surgery and multiple blood transfusions. The pleural fluid contained large atypical lymphoid cells and was suggestive of lymphoma but could not provide a conclusive diagnosis of PEL. The lymph node contained groups of large anaplastic lymphoid cells. Polymerase chain reaction for HHV-8 performed on the lymph node specimen was positive, establishing the diagnosis of PEL. Polymerase chain reaction for Epstein-Barr virus was negative. Results of a gallium scan were normal. The patient did not respond to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone and progressively developed, massive intra-abdominal solid tumor formation. To our knowledge, this is the first report of a case of PEL that demonstrates peripheral lymph node involvement at diagnosis and the first report of PEL in an Israeli patient. PMID:10782162

  1. The first endogenous herpesvirus, identified in the tarsier genome, and novel sequences from primate rhadinoviruses and lymphocryptoviruses.

    PubMed

    Aswad, Amr; Katzourakis, Aris

    2014-06-01

    Herpesviridae is a diverse family of large and complex pathogens whose genomes are extremely difficult to sequence. This is particularly true for clinical samples, and if the virus, host, or both genomes are being sequenced for the first time. Although herpesviruses are known to occasionally integrate in host genomes, and can also be inherited in a Mendelian fashion, they are notably absent from the genomic fossil record comprised of endogenous viral elements (EVEs). Here, we combine paleovirological and metagenomic approaches to both explore the constituent viral diversity of mammalian genomes and search for endogenous herpesviruses. We describe the first endogenous herpesvirus from the genome of the Philippine tarsier, belonging to the Roseolovirus genus, and characterize its highly defective genome that is integrated and flanked by unambiguous host DNA. From a draft assembly of the aye-aye genome, we use bioinformatic tools to reveal over 100,000 bp of a novel rhadinovirus that is the first lemur gammaherpesvirus, closely related to Kaposi's sarcoma-associated virus. We also identify 58 genes of Pan paniscus lymphocryptovirus 1, the bonobo equivalent of human Epstein-Barr virus. For each of the viruses, we postulate gene function via comparative analysis to known viral relatives. Most notably, the evidence from gene content and phylogenetics suggests that the aye-aye sequences represent the most basal known rhadinovirus, and indicates that tumorigenic herpesviruses have been infecting primates since their emergence in the late Cretaceous. Overall, these data show that a genomic fossil record of herpesviruses exists despite their extremely large genomes, and expands the known diversity of Herpesviridae, which will aid the characterization of pathogenesis. Our analytical approach illustrates the benefit of intersecting evolutionary approaches with metagenomics, genetics and paleovirology. PMID:24945689

  2. The First Endogenous Herpesvirus, Identified in the Tarsier Genome, and Novel Sequences from Primate Rhadinoviruses and Lymphocryptoviruses

    PubMed Central

    Aswad, Amr; Katzourakis, Aris

    2014-01-01

    Herpesviridae is a diverse family of large and complex pathogens whose genomes are extremely difficult to sequence. This is particularly true for clinical samples, and if the virus, host, or both genomes are being sequenced for the first time. Although herpesviruses are known to occasionally integrate in host genomes, and can also be inherited in a Mendelian fashion, they are notably absent from the genomic fossil record comprised of endogenous viral elements (EVEs). Here, we combine paleovirological and metagenomic approaches to both explore the constituent viral diversity of mammalian genomes and search for endogenous herpesviruses. We describe the first endogenous herpesvirus from the genome of the Philippine tarsier, belonging to the Roseolovirus genus, and characterize its highly defective genome that is integrated and flanked by unambiguous host DNA. From a draft assembly of the aye-aye genome, we use bioinformatic tools to reveal over 100,000 bp of a novel rhadinovirus that is the first lemur gammaherpesvirus, closely related to Kaposi's sarcoma-associated virus. We also identify 58 genes of Pan paniscus lymphocryptovirus 1, the bonobo equivalent of human Epstein-Barr virus. For each of the viruses, we postulate gene function via comparative analysis to known viral relatives. Most notably, the evidence from gene content and phylogenetics suggests that the aye-aye sequences represent the most basal known rhadinovirus, and indicates that tumorigenic herpesviruses have been infecting primates since their emergence in the late Cretaceous. Overall, these data show that a genomic fossil record of herpesviruses exists despite their extremely large genomes, and expands the known diversity of Herpesviridae, which will aid the characterization of pathogenesis. Our analytical approach illustrates the benefit of intersecting evolutionary approaches with metagenomics, genetics and paleovirology. PMID:24945689

  3. Systemic expression of Kaposi sarcoma herpesvirus (KSHV) Vflip in endothelial cells leads to a profound proinflammatory phenotype and myeloid lineage remodeling in vivo.

    PubMed

    Ballon, Gianna; Akar, Gunkut; Cesarman, Ethel

    2015-01-01

    KSHV is the causative agent of Kaposi sarcoma (KS), a spindle-shaped endothelial cell neoplasm accompanied by an inflammatory infiltrate. To evaluate the role of KSHV vFLIP in the pathogenesis of KS, we constructed mice with inducible expression of vFLIP in endothelial cells. Abnormal cells with endothelial marker expression and fusiform appearance were observed in several tissues reminiscent of the spindle cells found in KS. Serum cytokines displayed a profound perturbation similar to that described in KSHV inflammatory cytokine syndrome (KICS), a recently described clinical condition characterized by elevated IL6 and IL10. An increased myeloid component with suppressive immune phenotype was found, which may contribute to functional changes in the microenvironment and cellular heterogeneity as observed in KS. These mice represent the first in vivo demonstration that vFLIP is capable of inducing vascular abnormalities and changes in host microenvironment with important implications for understanding the pathogenesis and treating KSHV-associated diseases. PMID:25607954

  4. Sarcoma-associated sarcoid reaction: Report of cutaneous sarcoid reaction in a patient with liposarcoma.

    PubMed

    Beutler, Bryce D; Cohen, Philip R

    2015-12-16

    Sarcoidosis is a systemic inflammatory condition in which noncaseating epithelioid cell granulomas appear within one or several body sites. Sarcoid reaction (also referred to as sarcoidal or sarcoid-like reaction) occurs in patients who do not fulfill the diagnostic criteria for systemic sarcoidosis but present with similar clinical and histological features. As sarcoma-associated sarcoid reactions are rare, we describe the features of sarcoid reaction that developed in a man with liposarcoma and summarize reports of other oncology patients with sarcoma-associated sarcoid reactions. A 68-year-old man with retroperitoneal liposarcoma presented for evaluation of erythematous dermal plaques on his left leg. Microscopic examination of a tissue specimen revealed multiple epithelioid granulomas in the superficial and mid-reticular dermis. Correlation of the clinical presentation and histopathologic findings established a diagnosis of liposarcoma-associated cutaneous sarcoid reaction. Sarcoid reactions have been described in only seven individuals with sarcoma, including two patients with leiomyosarcoma and one patient with either carcinosarcoma, Kaposi sarcoma, liposarcoma, malignant peripheral nerve sheath tumor, rhabdosarcoma, or synovial sarcoma. Sarcoidal granulomas most commonly develop within the locoregional draining lymph nodes. Sarcoid reactions may also affect other organs, such as the lungs, skin, and spleen. PMID:26677448

  5. Sarcoma-associated sarcoid reaction: Report of cutaneous sarcoid reaction in a patient with liposarcoma

    PubMed Central

    Beutler, Bryce D; Cohen, Philip R

    2015-01-01

    Sarcoidosis is a systemic inflammatory condition in which noncaseating epithelioid cell granulomas appear within one or several body sites. Sarcoid reaction (also referred to as sarcoidal or sarcoid-like reaction) occurs in patients who do not fulfill the diagnostic criteria for systemic sarcoidosis but present with similar clinical and histological features. As sarcoma-associated sarcoid reactions are rare, we describe the features of sarcoid reaction that developed in a man with liposarcoma and summarize reports of other oncology patients with sarcoma-associated sarcoid reactions. A 68-year-old man with retroperitoneal liposarcoma presented for evaluation of erythematous dermal plaques on his left leg. Microscopic examination of a tissue specimen revealed multiple epithelioid granulomas in the superficial and mid-reticular dermis. Correlation of the clinical presentation and histopathologic findings established a diagnosis of liposarcoma-associated cutaneous sarcoid reaction. Sarcoid reactions have been described in only seven individuals with sarcoma, including two patients with leiomyosarcoma and one patient with either carcinosarcoma, Kaposi sarcoma, liposarcoma, malignant peripheral nerve sheath tumor, rhabdosarcoma, or synovial sarcoma. Sarcoidal granulomas most commonly develop within the locoregional draining lymph nodes. Sarcoid reactions may also affect other organs, such as the lungs, skin, and spleen. PMID:26677448

  6. Kaposi's sarcoma in South Africa.

    PubMed

    Sitas, F; Newton, R

    2001-01-01

    Kaposi's sarcoma was endemic in South Africa even before the advent of the human immunodeficiency virus (HIV). Between 1988 and 1996, the incidence of Kaposi's sarcoma in South Africa has risen at least threefold and continues to increase as the HIV epidemic grows. Research from South Africa has shown that infection with human herpesvirus 8 (HHV8) is associated with Kaposi's sarcoma but not with any other major cancer site or type. In addition, the risk of Kaposi's sarcoma increases with increasing antibody titer to HHV8, but, for a given titer, the risk is greater in HIV-seropositive compared with HIV-seronegative individuals. The age- and sex-standardized seroprevalence of HHV8 in black South African hospital patients was found to be slightly more than 30%; the seroprevalence of HHV8 increased with age and was similar in men and in women. The modes of transmission of HHV8 are yet to be fully elucidated. Limited evidence exists for sexual transmission in black South African adults, but mother-to-child and person-to-person transmission in childhood is also likely. Furthermore, the seroprevalence of HHV8 decreases with increasing levels of education and is lower in whites than in blacks, suggesting that factors associated with poverty may be important determinants of transmission. Future research should focus on risk factors for Kaposi's sarcoma in HHV8-infected individuals, on determinants and mode of transmission of HHV8, and on the elucidation of the effect of primary HHV8 infection in adults and in children. PMID:11158199

  7. Molecularly targeted therapy for Kaposi's sarcoma in a kidney transplant patient: case report, "what worked and what did not"

    PubMed Central

    Volkow, Patricia; Zinser, Juan W; Correa-Rotter, Ricardo

    2007-01-01

    Background Imatinib is a tyrosine-kinase inhibitor; for which there is limited information regarding its effects on AIDS Kaposi's sarcoma and none in patients with transplant-associated Kaposi's sarcoma. Sirolimus, an immunosuppressive drug used for kidney transplant, exhibits antiangiogenic activity related to impaired production of VEGF (vascular endothelial growth factor), clinical benefit has been reported in Kaposi's sarcoma associated with renal graft. Case Presentation Here we report a case of an 80 year old male, who developed Kaposi's Sarcoma nine months after receiving a living non-related donor kidney transplant at age 74. Three years after treatment with different chemotherapeutic agents for progressive cutaneous Kaposi's Sarcoma with no visceral involvement, he was prescribed Imatinib (200 mg/day for two weeks followed by 400 mg/day) after four weeks of treatment he developed anasarca, further progression of KS and agranulocytosis. Imatinib was discontinued and there was significant clinical recovery. One year later his immunosuppressive therapy was changed to Sirolimus and regression of the Kaposi's sarcoma occurred. Conclusion The lack of benefit and severe toxicity associated with the use of Imatinib in this patient should alert clinicians of potentially adverse consequence of its use in patients with transplant associated Kaposi's sarcoma. On the other hand the positive response seen in this patient to Sirolimus even after a long evolution of Kaposi's sarcoma, multiple chemotherapy regimens and extensive cutaneous disease further suggest it therapeutical utility for transplant associated Kaposi's sarcoma. PMID:17386117

  8. Overview: cytomegalovirus and the herpesviruses in transplantation.

    PubMed

    Fishman, J A

    2013-02-01

    Herpesviruses infect most animal species. Infections due to the eight human herpesviruses (HHV) are exacerbated by immunosuppression in organ transplantation. The special features of the herpesvirus life cycle include the ability to establish latent, nonproductive infection and the life-long capacity for reactivation to productive, lytic infection. Interactions between latent virus and the immune system determine the frequency and severity of symptomatic infections. The immunologic and cellular effects of herpesvirus infections contribute to risk for opportunistic infections and graft rejection. Among the most important advances in transplantation are laboratory assays for the diagnosis and monitoring of herpesvirus infections and antiviral agents with improved efficacy in prophylaxis and therapy. For herpes simplex virus, varicella zoster virus and cytomegalovirus, these advances have significantly reduced the morbidity of infection. The syndromes of EBV-associated posttransplant lymphoproliferative disorders (PTLD) and Kaposi's sarcoma remain important complications of immunosuppression. The epidemiology and essential biology of human herpesvirus is reviewed. PMID:23347210

  9. Activation of DNA Damage Response Induced by the Kaposi’s Sarcoma-Associated Herpes Virus

    PubMed Central

    Di Domenico, Enea Gino; Toma, Luigi; Bordignon, Valentina; Trento, Elisabetta; D’Agosto, Giovanna; Cordiali-Fei, Paola; Ensoli, Fabrizio

    2016-01-01

    The human herpes virus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus (KSHV), can infect endothelial cells often leading to cell transformation and to the development of tumors, namely Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and the plasmablastic variant of multicentric Castleman’s disease. KSHV is prevalent in areas such as sub-Saharan Africa and the Mediterranean region presenting distinct genotypes, which appear to be associated with differences in disease manifestation, according to geographical areas. In infected cells, KSHV persists in a latent episomal form. However, in a limited number of cells, it undergoes spontaneous lytic reactivation to ensure the production of new virions. During both the latent and the lytic cycle, KSHV is programmed to express genes which selectively modulate the DNA damage response (DDR) through the activation of the ataxia telangiectasia mutated (ATM) pathway and by phosphorylating factors associated with the DDR, including the major tumor suppressor protein p53 tumor suppressor p53. This review will focus on the interplay between the KSHV and the DDR response pathway throughout the viral lifecycle, exploring the putative molecular mechanism/s that may contribute to malignant transformation of host cells. PMID:27258263

  10. Profile of Exosomal and Intracellular microRNA in Gamma-Herpesvirus-Infected Lymphoma Cell Lines.

    PubMed

    Hoshina, Shiho; Sekizuka, Tsuyoshi; Kataoka, Michiyo; Hasegawa, Hideki; Hamada, Hiromichi; Kuroda, Makoto; Katano, Harutaka

    2016-01-01

    Exosomes are small vesicles released from cells, into which microRNAs (miRNA) are specifically sorted and accumulated. Two gamma-herpesviruses, Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), encode miRNAs in their genomes and express virus-encoded miRNAs in cells and exosomes. However, there is little information about the detailed distribution of virus-encoded miRNAs in cells and exosomes. In this study, we thus identified virus- and host-encoded miRNAs in exosomes released from KSHV- or EBV-infected lymphoma cell lines and compared them with intracellular miRNAs using a next-generation sequencer. Sequencing analysis demonstrated that 48% of the annotated miRNAs in the exosomes from KSHV-infected cells originated from KSHV. Human mir-10b-5p and mir-143-3p were much more highly concentrated in exosomes than in cells. Exosomes contained more nonexact mature miRNAs that did not exactly match those in miRBase than cells. Among the KSHV-encoded miRNAs, miRK12-3-5p was the most abundant exact mature miRNA in both cells and exosomes that exactly matched those in miRBase. Recently identified EXOmotifs, nucleotide motifs that control the loading of miRNAs into exosomes were frequently found within the sequences of KSHV-encoded miRNAs, and the presence of the EXOmotif CCCT or CCCG was associated with the localization of miRNA in exosomes in KSHV-infected cells. These observations suggest that specific virus-encoded miRNAs are sorted by EXOmotifs and accumulate in exosomes in virus-infected cells. PMID:27611973

  11. A Toolbox for Herpesvirus miRNA Research: Construction of a Complete Set of KSHV miRNA Deletion Mutants.

    PubMed

    Jain, Vaibhav; Plaisance-Bonstaff, Karlie; Sangani, Rajnikumar; Lanier, Curtis; Dolce, Alexander; Hu, Jianhong; Brulois, Kevin; Haecker, Irina; Turner, Peter; Renne, Rolf; Krueger, Brian

    2016-02-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 viral microRNAs (miRNAs) that are expressed during latency. Research into KSHV miRNA function has suffered from a lack of genetic systems to study viral miRNA mutations in the context of the viral genome. We used the Escherichia coli Red recombination system together with a new bacmid background, BAC16, to create mutants for all known KSHV miRNAs. The specific miRNA deletions or mutations and the integrity of the bacmids have been strictly quality controlled using PCR, restriction digestion, and sequencing. In addition, stable viral producer cell lines based on iSLK cells have been created for wildtype KSHV, for 12 individual miRNA knock-out mutants (ΔmiR-K12-1 through -12), and for mutants deleted for 10 of 12 (ΔmiR-cluster) or all 12 miRNAs (ΔmiR-all). NGS, in combination with SureSelect technology, was employed to sequence the entire latent genome within all producer cell lines. qPCR assays were used to verify the expression of the remaining viral miRNAs in a subset of mutants. Induction of the lytic cycle leads to efficient production of progeny viruses that have been used to infect endothelial cells. Wt BAC16 and miR mutant iSLK producer cell lines are now available to the research community. PMID:26907327

  12. Deletion of Murid Herpesvirus 4 ORF63 Affects the Trafficking of Incoming Capsids toward the Nucleus

    PubMed Central

    Latif, Muhammad Bilal; Machiels, Bénédicte; Xiao, Xue; Mast, Jan; Vanderplasschen, Alain

    2015-01-01

    ABSTRACT Gammaherpesviruses are important human and animal pathogens. Despite the fact that they display the classical architecture of herpesviruses, the function of most of their structural proteins is still poorly defined. This is especially true for tegument proteins. Interestingly, a potential role in immune evasion has recently been proposed for the tegument protein encoded by Kaposi's sarcoma-associated herpesvirus open reading frame 63 (ORF63). To gain insight about the roles of ORF63 in the life cycle of a gammaherpesvirus, we generated null mutations in the ORF63 gene of murid herpesvirus 4 (MuHV-4). We showed that disruption of ORF63 was associated with a severe MuHV-4 growth deficit both in vitro and in vivo. The latter deficit was mainly associated with a defect of replication in the lung but did not affect the establishment of latency in the spleen. From a functional point of view, inhibition of caspase-1 or the inflammasome did not restore the growth of the ORF63-deficient mutant, suggesting that the observed deficit was not associated with the immune evasion mechanism identified previously. Moreover, this growth deficit was also not associated with a defect in virion egress from the infected cells. In contrast, it appeared that MuHV-4 ORF63-deficient mutants failed to address most of their capsids to the nucleus during entry into the host cell, suggesting that ORF63 plays a role in capsid movement. In the future, ORF63 could therefore be considered a target to block gammaherpesvirus infection at a very early stage of the infection. IMPORTANCE The important diseases caused by gammaherpesviruses in human and animal populations justify a better understanding of their life cycle. In particular, the role of most of their tegument proteins is still largely unknown. In this study, we used murid herpesvirus 4, a gammaherpesvirus infecting mice, to decipher the role of the protein encoded by the viral ORF63 gene. We showed that the absence of this protein is

  13. Pulmonary Kaposi sarcoma in patients with AIDS: Scintigraphic diagnosis with sequential thallium and gallium scanning

    SciTech Connect

    Lee, V.W.; Fuller, J.D.; O'Brien, M.J.; Parker, D.R.; Cooley, T.P.; Liebman, H.A. )

    1991-08-01

    Pulmonary Kaposi sarcoma associated with acquired immunodeficiency syndrome (AIDS) is difficult to diagnose because the clinical presentations and radiographic findings are nonspecific. The authors report three proved cases of AIDS-associated pulmonary Kaposi sarcoma diagnosed with sequential thallium and gallium scans. These scans demonstrated abnormal increase of pulmonary thallium uptake, whereas the gallium uptake was negative. In the authors' experience and in reports in the radiology literature, infected areas of the chest are generally thallium-negative on the delayed (3-hour) scans but are gallium-avid, whereas lymphomas are both thallium- and gallium-avid. The authors conclude that sequential thallium and gallium scans can be used to help diagnose pulmonary Kaposi sarcoma and distinguish it from other common AIDS-associated chest complications such as lymphoma and infections.

  14. Oncogenic Virus Infections in the General Population and End-stage Renal Disease Patients With Special Emphasis on Kaposi’s Sarcoma Associated Herpes Virus (KSHV) in Northeast of Iran

    PubMed Central

    Ahmadi Ghezeldasht, Sanaz; Hassannia, Tahereh; Rafatpanah, Houshang; Hekmat, Reza; Valizadeh, Narges; Ghayour Mobarhan, Majid; Rezaee, Seyed Abdolrahim

    2015-01-01

    Background: Globally, almost 20% of cancers are related to infectious agents that can be prevented. Oncogenicity refers to viruses that may cause cancers, more importantly in immunocompromised subjects such as transplant and hemodialysis patients. Therefore, epidemiological studies are the first line for understanding the importance of these agents in public health, particularly, in mobile populations, tourism and pilgrimage regions. Objectives: Oncogenic viral infections, such as hepatitis B virus (HBV), hepatitis C virus (HCV) and Epstein-barr virus (EBV) are the most common viral agents in immunocompromised patients. Furthermore, human T lymphocyte virus type I (HTLV-I), due to endemicity in Khorasan Razavi province located northeast of Iran as a pilgrimage region, and Kaposi's sarcoma associated herpes virus (KSHV), as an oncogenic herpesvirus in immunocompromised subjects have been investigated among the general population and those with end-stage renal diseases (ESRD). Patients and Methods: A cross-sectional study was carried out among 1227 randomly selected individuals; 25 donors and 195 patients with ESRD, including 60 kidney transplant recipients and 135 dialysis patients from the Khorasan Razavi province, Iran. Serological tests were carried out using commercial enzyme-immunoassay kits. To confirm positive serology tests, the extracted viral DNA or RNA was examined for the presence of KSHV, HTLV-I and HCV by conventional PCR. Results: The prevalence of KSHV infection in the general population was 1.71% (21/1227); 2.60% (10/384) males and 1.30% (11/843) females. In kidney transplants, viral infections occurred in 23.3% of subjects; including EBV, HTLV-I and HBV-HCV co-infection in 8.3%, 3.3% and 1.7%, respectively. In patients on hemodialysis, viral infections were present in 29.6% including EBV, HTLV-I and HBV-HCV co-infection in 2.2%, 5.9% and 16.3%, respectively. Seroprevalence of KSHV in patients with kidney transplants was 1.7% and in patients on

  15. Epidemic Kaposi Sarcoma

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  16. Classic Kaposi Sarcoma

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  17. General Information about Kaposi Sarcoma

    MedlinePlus

    ... Research Kaposi Sarcoma Treatment (PDQ®)–Patient Version General Information About Kaposi Sarcoma Go to Health Professional Version ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  18. Dissecting host-virus interaction in lytic replication of a model herpesvirus.

    PubMed

    Dong, Xiaonan; Feng, Pinghui

    2011-01-01

    In response to viral infection, a host develops various defensive responses, such as activating innate immune signaling pathways that lead to antiviral cytokine production. In order to colonize the host, viruses are obligate to evade host antiviral responses and manipulate signaling pathways. Unraveling the host-virus interaction will shed light on the development of novel therapeutic strategies against viral infection. Murine γHV68 is closely related to human oncogenic Kaposi's sarcoma-associated herpesvirus and Epsten-Barr virus. γHV68 infection in laboratory mice provides a tractable small animal model to examine the entire course of host responses and viral infection in vivo, which are not available for human herpesviruses. In this protocol, we present a panel of methods for phenotypic characterization and molecular dissection of host signaling components in γHV68 lytic replication both in vivo and ex vivo. The availability of genetically modified mouse strains permits the interrogation of the roles of host signaling pathways during γHV68 acute infection in vivo. Additionally, mouse embryonic fibroblasts (MEFs) isolated from these deficient mouse strains can be used to further dissect roles of these molecules during γHV68 lytic replication ex vivo. Using virological and molecular biology assays, we can pinpoint the molecular mechanism of host-virus interactions and identify host and viral genes essential for viral lytic replication. Finally, a bacterial artificial chromosome (BAC) system facilitates the introduction of mutations into the viral factor(s) that specifically interrupt the host-virus interaction. Recombinant γHV68 carrying these mutations can be used to recapitulate the phenotypes of γHV68 lytic replication in MEFs deficient in key host signaling components. This protocol offers an excellent strategy to interrogate host-pathogen interaction at multiple levels of intervention in vivo and ex vivo. Recently, we have discovered that γHV68 usurps

  19. Variable Episomal Silencing of a Recombinant Herpesvirus Renders Its Encoded GFP an Unreliable Marker of Infection in Primary Cells

    PubMed Central

    Ellison, Thomas J.; Kedes, Dean H.

    2014-01-01

    The availability of reliable recombinant reporter virus systems has been a great boon to the study of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8). Unexpectedly, we found that expression of the ostensibly constitutive green fluorescent protein (GFP) marker was progressively lost during unselected passage in primary rat mesenchymal precursor cells (MM), despite efficient maintenance of latent viral gene expression and episomal partitioning. This repression of EF1-α promoter-driven GFP expression appeared to be passage-dependent, however, since functionally immortalized MM cells derived from long serial passage retained stable expression of GFP following rKSHV.219 infection. Chromatin analysis of cultures that we had infected in parallel demonstrated an increase in repressive H3K27 tri-methylation across the viral episome with the exception of the LANA control region in MM cells infected at early rather than late passage post-isolation. The silencing of GFP expression in the MM cells was reversible in a dose-dependent fashion by the histone deacetylase inhibitor valproic acid, further implicating cellular silencing on incoming viral genomes, and underscoring potential differences in viral gene regulation between primary and functionally immortalized cells. Furthermore, using multispectral imaging flow cytometry, we also determined that the extent of GFP expression per cell among those that were positive did not correlate with the number of LANA dots per nucleus nor the extent of overall LANA expression per cell. This suggests a more complex mode of local gene regulation, rather than one that simply reflects the relative intracellular viral copy number. In sum, we have demonstrated the significant potential for false-negative data when using a constitutive marker gene as a sole means of evaluating herpesviral infection, especially in primary cells. PMID:25402328

  20. Co-Existence of Multicentric Castleman's Disease and Kaposi's Sarcoma.

    PubMed

    Yaghoobi, Reza; Pazyar, Nader; Tavakoli, Sadigheh

    2015-01-01

    Castleman's disease (CD) or giant lymph node hyperplasia is a rare disorder that can be unicentric or multicentric. Multicentric Castleman's disease (MCD) is manifested by generalized lymphadenopathy, hepatosplenomegaly, polyclonal hypergammaglobulinemia, hematological abnormality, and constitutional symptoms. Human herpesvirus 8 (HHV-8) infection is present in nearly 100% MCD associated with HIV-1 infection, but in about 50% of cases of HIV negative. Herein, we report a 77-year-old man with systemic involvement and skin lesions on the anterior aspect of both legs in the previous site of saphenous vein angioplasty. Co-existence of MCD with Kaposi's sarcoma (KS) led us to present this rare case. PMID:26120185

  1. Kaposi's sarcoma in homosexual men. A seroepidemiologic case-control study.

    PubMed

    Marmor, M; Friedman-Kien, A E; Zolla-Pazner, S; Stahl, R E; Rubinstein, P; Laubenstein, L; William, D C; Klein, R J; Spigland, I

    1984-06-01

    The cases of 20 male homosexuals with Kaposi's sarcoma and the acquired immunodeficiency syndrome were compared with those of 40 age- and race-matched male homosexual controls. Patients with Kaposi's sarcoma had lower OKT4/OKT8 (T-helper/T-suppressor) ratios than controls, due to smaller numbers of OKT4 cells. Serum IgG concentrations and antibody titers to cytomegalovirus in patients exceeded those in controls, but patients had lower antibody titers to Epstein-Barr virus. Logistic regression analysis comparing patients with controls showed significant relative risks for Kaposi's sarcoma associated with the number of partners per month in receptive anal-genital intercourse, occasions per month of " fisting ," and cytomegalovirus antibody titers. Cytomegalovirus titers also were inversely correlated with OKT4 cell concentrations in the control group. Significantly greater OKT4 cell concentrations were found at diagnosis in HLA-DR5-positive patients than in HLA-DR5-negative patients. Patients who have HLA-DR5 may express disease at lesser degrees of immunodeficiency than HLA-DR5-negative patients. PMID:6326631

  2. Herpesvirus systematics.

    PubMed

    Davison, Andrew J

    2010-06-16

    This paper is about the taxonomy and genomics of herpesviruses. Each theme is presented as a digest of current information flanked by commentaries on past activities and future directions. The International Committee on Taxonomy of Viruses recently instituted a major update of herpesvirus classification. The former family Herpesviridae was elevated to a new order, the Herpesvirales, which now accommodates 3 families, 3 subfamilies, 17 genera and 90 species. Future developments will include revisiting the herpesvirus species definition and the criteria used for taxonomic assignment, particularly in regard to the possibilities of classifying the large number of herpesviruses detected only as DNA sequences by polymerase chain reaction. Nucleotide sequence accessions in primary databases, such as GenBank, consist of the sequences plus annotations of the genetic features. The quality of these accessions is important because they provide a knowledge base that is used widely by the research community. However, updating the accessions to take account of improved knowledge is essentially reserved to the original depositors, and this activity is rarely undertaken. Thus, the primary databases are likely to become antiquated. In contrast, secondary databases are open to curation by experts other than the original depositors, thus increasing the likelihood that they will remain up to date. One of the most promising secondary databases is RefSeq, which aims to furnish the best available annotations for complete genome sequences. Progress in regard to improving the RefSeq herpesvirus accessions is discussed, and insights into particular aspects of herpesvirus genomics arising from this work are reported. PMID:20346601

  3. Drugs Approved for Kaposi Sarcoma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for Kaposi sarcoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  4. Treatment Options for Kaposi Sarcoma

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  5. Treatment Option Overview (Kaposi Sarcoma)

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  6. Utilising proteomic approaches to understand oncogenic human herpesviruses (Review)

    PubMed Central

    OWEN, CHRISTOPHER B.; HUGHES, DAVID J.; BAQUERO-PEREZ, BELINDA; BERNDT, ANJA; SCHUMANN, SOPHIE; JACKSON, BRIAN R.; WHITEHOUSE, ADRIAN

    2014-01-01

    The γ-herpesviruses Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus are successful pathogens, each infecting a large proportion of the human population. These viruses persist for the life of the host and may each contribute to a number of malignancies, for which there are currently no cures. Large-scale proteomic-based approaches provide an excellent means of increasing the collective understanding of the proteomes of these complex viruses and elucidating their numerous interactions within the infected host cell. These large-scale studies are important for the identification of the intricacies of viral infection and the development of novel therapeutics against these two important pathogens. PMID:25279171

  7. Immunological methods for the detection of porcine lymphotropic herpesviruses (PLHV).

    PubMed

    Plotzki, Elena; Keller, Martina; Ehlers, Bernhard; Denner, Joachim

    2016-07-01

    Porcine lymphotropic herpesviruses (PLHV-1, -2, and -3) are widespread in pigs and closely related to the human pathogenic gammaherpesviruses Epstein-Barr virus (human herpesvirus 4, HHV-4) and Kaposi sarcoma herpesvirus (HHV-8). In minipigs, PLHV-1 causes a porcine post-transplantation lymphoproliferative disorder (PTLD) after experimental transplantations. Porcine PTLD comes with clinical symptoms similar to those of human PTLD, a serious complication of solid organ and allogeneic bone marrow transplantation linked to HHV-4. Since PLHVs may be transmitted from donor pigs to the human recipient of xenotransplants (pig cells, tissues or organs), sensitive and specific methods should be developed to detect and eliminate PLHVs. Here we describe an ELISA and a Western blot assay using recombinant glycoprotein B of PLHV-1. Using both assays, the presence of specific antibodies in different pig breeds as well as in German slaughterhouse workers was analysed. Antibodies were detected in some animals, but not in human subjects. PMID:27036503

  8. Molecular analysis of Kaposi's sarcoma occurring during haemodialysis.

    PubMed

    Metaxa-Mariatou, V; Chiras, T; Loli, A; Gazouli, M; Vallis, D; Nasioulas, G

    2004-03-01

    Human Herpesvirus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi's sarcoma (KS). In this paper we attempted to confirm the connection between dialysis, HHV-8, and KS by examining the case of an elderly haemodialysis nonimmunosuppressed male patient with end-stage renal disease, who developed KS. By using PCR we have verified the presence of DNA from two different genomic regions (ORF 26 and ORF K1) of HHV-8. In addition, our RT-PCR results suggest active replication of HHV-8 in blood and KS lesions of the patient. Phylogenetic analysis revealed identical DNA sequence to ORF K1, and a close relation to its C1 variant. In conclusion, we document the case of KS and HHV-8 coexistence in a Greek elderly patient undergoing regular haemodialysis. Furthermore, our results indicate that factors other than immunosuppression could lead to KS development possibly due to activation of HHV-8. PMID:14987280

  9. Broad-Spectrum Allosteric Inhibition of Herpesvirus Proteases

    PubMed Central

    2015-01-01

    Herpesviruses rely on a homodimeric protease for viral capsid maturation. A small molecule, DD2, previously shown to disrupt dimerization of Kaposi’s sarcoma-associated herpesvirus protease (KSHV Pr) by trapping an inactive monomeric conformation and two analogues generated through carboxylate bioisosteric replacement (compounds 2 and 3) were shown to inhibit the associated proteases of all three human herpesvirus (HHV) subfamilies (α, β, and γ). Inhibition data reveal that compound 2 has potency comparable to or better than that of DD2 against the tested proteases. Nuclear magnetic resonance spectroscopy and a new application of the kinetic analysis developed by Zhang and Poorman [Zhang, Z. Y., Poorman, R. A., et al. (1991) J. Biol. Chem. 266, 15591–15594] show DD2, compound 2, and compound 3 inhibit HHV proteases by dimer disruption. All three compounds bind the dimer interface of other HHV proteases in a manner analogous to binding of DD2 to KSHV protease. The determination and analysis of cocrystal structures of both analogues with the KSHV Pr monomer verify and elaborate on the mode of binding for this chemical scaffold, explaining a newly observed critical structure–activity relationship. These results reveal a prototypical chemical scaffold for broad-spectrum allosteric inhibition of human herpesvirus proteases and an approach for the identification of small molecules that allosterically regulate protein activity by targeting protein–protein interactions. PMID:24977643

  10. Steroids are a risk factor for Kaposi's sarcoma-immune reconstitution inflammatory syndrome and mortality in HIV infection

    PubMed Central

    Fernández-Sánchez, Mónica; Iglesias, María C.; Ablanedo-Terrazas, Yuria; Ormsby, Christopher E.; Alvarado-de la Barrera, Claudia; Reyes-Terán, Gustavo

    2016-01-01

    Objectives: To investigate the association between Kaposi's sarcoma-associated immune reconstitution inflammatory syndrome (KS-IRIS) and mortality, with the use of glucocorticoids in HIV-infected individuals. Design: Case–control study. Methods: We reviewed the medical records of 145 individuals with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. The association of different variables with KS-IRIS and Kaposi's sarcoma-related mortality was explored by univariate and multivariate analyses. The main exposure of interest was the use of glucocorticoids. We also compared the time to KS-IRIS and the time to death of individuals treated with glucocorticoids vs. those nontreated with glucocorticoids, and the time to death of individuals with KS-IRIS vs. those without KS-IRIS by hazards regression. Results: Sixty of 145 individuals received glucocorticoids (41.4%) for the management or suspicion of Pneumocystis jirovecii pneumonia. Fifty individuals had KS-IRIS (37%). The use of glucocorticoids was more frequent in individuals with KS-IRIS than in those without KS-IRIS (54.9 vs. 36.47%, P = 0.047). Kaposi's sarcoma-related mortality occurred in 17 cases (11.7%), and glucocorticoid use was more frequent in this group (76.47 vs. 36.7%, P = 0.003). Glucocorticoid use was a risk factor for mortality (adjusted odds ratio = 4.719, 95% confidence interval = 1.383–16.103, P = 0.0132), and was associated with shorter periods to KS-IRIS (P = 0.03) and death (P = 0.0073). KS-IRIS was a risk factor for mortality (P = 0.049). Conclusion: In HIV-infected individuals, the use of glucocorticoids is a risk factor for KS-IRIS and Kaposi's sarcoma-associated mortality. In addition, KS-IRIS is a risk factor for mortality. Therefore, glucocorticoid administration in this population requires careful consideration based on individualized risk–benefit analysis. PMID:26636923

  11. What Should You Ask Your Doctor about Kaposi Sarcoma?

    MedlinePlus

    ... for Kaposi sarcoma? What should you ask your doctor about Kaposi sarcoma? As you cope with Kaposi ... need to have honest, open discussions with your doctor. You should ask any question on your mind ...

  12. Post-Translational Modifications of Kaposi’s Sarcoma-Associated Herpesvirus Regulatory Proteins – SUMO and KSHV

    PubMed Central

    Campbell, Mel; Izumiya, Yoshihiro

    2011-01-01

    KSHV latency can be envisioned as an outcome that is balanced between factors that promote viral gene expression and lytic replication against those that facilitate gene silencing and establish or maintain latency. A large body of work has focused on the activities of the key viral regulatory proteins involved in KSHV latent or lytic states. Moreover, recent studies have also begun to document the importance of epigenetic landscape evolution of the KSHV viral genome during latency and reactivation. However, one area of KSHV molecular virology that remains largely unanswered is the precise role of post-translational modifications on the activities of viral factors that function during latency and reactivation. In this review, we will summarize the post-translational modifications associated with three viral factors whose activities contribute to the viral state. The viral proteins discussed are the two major KSHV encoded transcription factors, K-Rta (KSHV replication and transcriptional activator) and K-bZIP (KSHV basic leucine zipper) and the viral latency-associated nuclear antigen (LANA). A special emphasis will be placed on the role of the sumoylation pathway in the modulation of the KSHV lifecycle. Newly uncovered small ubiquitin-like modifier (SUMO)-associated properties of LANA and K-Rta will also be presented, namely LANA histone targeting SUMO E3 ligase activity and K-Rta SUMO-targeted ubiquitin ligase function. PMID:22347876

  13. Human Oncogenic Herpesvirus and Post-translational Modifications – Phosphorylation and SUMOylation

    PubMed Central

    Chang, Pei-Ching; Campbell, Mel; Robertson, Erle S.

    2016-01-01

    Pathogens, especially viruses, evolve abilities to utilize cellular machineries to facilitate their survival and propagation. Post-translational modifications (PTMs), especially phosphorylation and SUMOylation, that reversibly modulate the function and interactions of target proteins are among the most important features in cell signaling pathways. PTM-dependent events also serve as one of the favorite targets for viruses. Among the seven unambiguous human oncogenic viruses, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), human papillomavirus (HPV), Human T lymphotrophic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV), two are herpesviruses. The life cycle of herpesviruses consists of latent and lytic phases and the rapid switch between these states includes global remodeling of the viral genome from heterochromatin-to-euchromatin. The balance between lytic replication and latency is essential for herpesvirus to maintain a persistent infection through a combination of viral propagation and evasion of the host immune response, which consequently may contribute to tumorigenesis. It is no surprise that the swift reversibility of PTMs, especially SUMOylation, a modification that epigenetically regulates chromatin structure, is a major hijack target of the host for oncogenic herpesviruses. In this brief review, we summarize the varied ways in which herpesviruses engage the host immune components through PTMs, focusing on phosphorylation and SUMOylation. PMID:27379086

  14. Herpesviruses that Infect Fish

    PubMed Central

    Hanson, Larry; Dishon, Arnon; Kotler, Moshe

    2011-01-01

    Herpesviruses are host specific pathogens that are widespread among vertebrates. Genome sequence data demonstrate that most herpesviruses of fish and amphibians are grouped together (family Alloherpesviridae) and are distantly related to herpesviruses of reptiles, birds and mammals (family Herpesviridae). Yet, many of the biological processes of members of the order Herpesvirales are similar. Among the conserved characteristics are the virion structure, replication process, the ability to establish long term latency and the manipulation of the host immune response. Many of the similar processes may be due to convergent evolution. This overview of identified herpesviruses of fish discusses the diseases that alloherpesviruses cause, the biology of these viruses and the host-pathogen interactions. Much of our knowledge on the biology of Alloherpesvirdae is derived from research with two species: Ictalurid herpesvirus 1 (channel catfish virus) and Cyprinid herpesvirus 3 (koi herpesvirus). PMID:22163339

  15. Kaposi sarcoma in unusual locations

    PubMed Central

    Pantanowitz, Liron; Dezube, Bruce J

    2008-01-01

    Kaposi sarcoma (KS) is a multifocal, vascular lesion of low-grade malignant potential that presents most frequently in mucocutaneous sites. KS also commonly involves lymph nodes and visceral organs. This article deals with the manifestation of KS in unusual anatomic regions. Unusual locations of KS involvement include the musculoskeletal system, central and peripheral nervous system, larynx, eye, major salivary glands, endocrine organs, heart, thoracic duct, urinary system and breast. The development of KS within wounds and blood clots is also presented. KS in these atypical sites may prove difficult to diagnose, resulting in patient mismanagement. Theories to explain the rarity and development of KS in these unusual sites are discussed. PMID:18605999

  16. Kaposi’s Sarcoma Herpesvirus Genome Persistence

    PubMed Central

    Juillard, Franceline; Tan, Min; Li, Shijun; Kaye, Kenneth M.

    2016-01-01

    Kaposi’s sarcoma-associated herpesvirus (KSHV) has an etiologic role in Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. These diseases are most common in immunocompromised individuals, especially those with AIDS. Similar to all herpesviruses, KSHV infection is lifelong. KSHV infection in tumor cells is primarily latent, with only a small subset of cells undergoing lytic infection. During latency, the KSHV genome persists as a multiple copy, extrachromosomal episome in the nucleus. In order to persist in proliferating tumor cells, the viral genome replicates once per cell cycle and then segregates to daughter cell nuclei. KSHV only expresses several genes during latent infection. Prominent among these genes, is the latency-associated nuclear antigen (LANA). LANA is responsible for KSHV genome persistence and also exerts transcriptional regulatory effects. LANA mediates KSHV DNA replication and in addition, is responsible for segregation of replicated genomes to daughter nuclei. LANA serves as a molecular tether, bridging the viral genome to mitotic chromosomes to ensure that KSHV DNA reaches progeny nuclei. N-terminal LANA attaches to mitotic chromosomes by binding histones H2A/H2B at the surface of the nucleosome. C-terminal LANA binds specific KSHV DNA sequence and also has a role in chromosome attachment. In addition to the essential roles of N- and C-terminal LANA in genome persistence, internal LANA sequence is also critical for efficient episome maintenance. LANA’s role as an essential mediator of virus persistence makes it an attractive target for inhibition in order to prevent or treat KSHV infection and disease. PMID:27570517

  17. Do We Know What Causes Kaposi Sarcoma?

    MedlinePlus

    ... escape to close saved articles window. My Saved Articles » My ACS » Kaposi Sarcoma + - Text Size Download Printable Version [PDF] » Causes, Risk Factors, and Prevention TOPICS Document Topics ...

  18. Immunosuppressive Therapy-Related Kaposi Sarcoma

    MedlinePlus

    ... therapy are used to treat Kaposi sarcoma lesions . Photon radiation therapy treats lesions with high-energy light. ... complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information ...

  19. Acroangiodermatitis (Pseudo-Kaposi sarcoma)

    PubMed Central

    Singh, Satyendra Kumar; Manchanda, Kajal

    2014-01-01

    Acroangiodermatitis or Pseudo-Kaposi sarcoma is a rare angioproliferative entity, related to chronic venous insufficiency or certain other vascular anomalies. It is often associated with chronic venous insufficiency, arteriovenous malformation of the legs, chronic renal failure treated with dialysis, paralyzed legs and amputation stumps. We hereby describe a case of 45 year old female presenting with pitting pedal edema, multiple ulcers over bilateral lower limbs with irregular margins with erythema and hyperpigmentation of the surrounding skin. Color Doppler study of bilateral lower limbs was normal. Histopathological examination from one of the lesions showed hyperplastic epidermis, proliferation of capillaries in dermis, hemosiderin deposits and lymphocytic infiltrate. These features thus confirmed the diagnosis of Acroangiodermatitis. PMID:25165656

  20. Clinical course of disseminated Kaposi sarcoma in a HIV and hepatitis B co-infected heterosexual male

    PubMed Central

    Agarwala, Manoj Kumar; George, Renu; Sudarsanam, Thambu David; Chacko, Raju Titus; Thomas, Meera; Nair, Sheila

    2015-01-01

    AIDS associated Kaposi sarcoma (AIDS-KS) was first reported from India in 1993. Since then only 16 cases have been reported. Three of them had proven Human Herpesvirus 8 (HHV-8) infection. We report a case of disseminated KS in a heterosexual male from India with HIV, hepatitis B and HHV-8 infection. He was given six cycles of chemotherapy with liposomal doxorubicin over three months to which he showed a good response. The case highlights the clinical course and management of a HHV-8 positive disseminated KS in a patient co-infected with Hepatitis B and HIV. PMID:26225336

  1. What's New in Kaposi Sarcoma Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for Kaposi sarcoma What’s new in Kaposi sarcoma research and treatment? A great ... once it has developed. Treatment Researchers are studying new and different ways to treat KS. Imiquimod (Aldara) ...

  2. What Are the Key Statistics about Kaposi Sarcoma?

    MedlinePlus

    ... key statistics about Kaposi sarcoma? Before the AIDS epidemic, Kaposi sarcoma (KS) was rare in the United ... were classic and transplant-related. With the AIDS epidemic, the rate of KS in this country increased ...

  3. RNA of simian sarcoma-associated virus type 1 produced in human tumor cells.

    PubMed Central

    Fidanián, H M; Drohán, W N; Baluda, M A

    1975-01-01

    Simian sarcoma-associated virus type 1 propagated in human rhabdomyosarcoma cells exhibited characteristics typical of oncornaviruses but seemed to have several aberrant properties. It had a buoyant density of 1.14 g/cm3, had RNA-dependent DNA polymerase activity, seemed to be labile to high salt concentrations, and contained little 50 to 60S RNA but relatively large amounts of human ribosomal RNA. In addition to 50 to 60S RNA, purified virions contained smaller RNA molecules with sedimentation coefficients of 28 to 30S, 18 TO 20S, and 4 to 10S. Unlike the 50 to 60S RNA species, the smaller virion-associated RNAs lacked polyadenylic acid, and the 28 to 30S RNA had an average base composition similar to that of human ribosomal RNA. Upon heat denaturation, the native 50 to 60S RNA genome yielded polyadenylic acid-containing 28 to 30S subunits that degraded in to 18 to 20S molecules upon further heat treatment. The 50 to 60S viral RNA had a guanine plus cytosine content of 56%. PMID:46285

  4. Detection and typing of lymphotropic herpesviruses by multiplex polymerase chain reaction.

    PubMed

    Pozo, F; Tenorio, A

    1999-04-01

    A multiplex nested-polymerase chain reaction (PCR) method was developed for the simultaneous detection and typing of all human lymphotropic herpesviruses described to date, including Ebstein Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6, variants A and B (HHV6-A, HHV6-B), human herpesvirus 7 (HHV7) and human herpesvirus 8 (HHV8). Oligonucleotide primers were designed to amplify a highly conserved region within the DNA polymerase gene. Each reaction component and thermal cycling parameters were thoroughly standardized to achieve optimal specificity and sensitivity for the PCR assay, which was estimated at about 10-100 molecules for each virus. An internal control, consisting of 100 molecules of a cloned fragment of the porcine pseudorabies herpesvirus (PrV) genome, was included to detect false negative results. To assess suitability and clinical application of the multiplex PCR method, a total of 35 well-characterized specimens, including Kaposi's sarcoma skin lesions, serum, cerebrospinal fluid, saliva and urine samples, were tested. Results obtained suggest this technique could be applied as a sole diagnostic tool in several clinical settings in which herpesviral infection is suspected and differential diagnosis required, avoiding the need to test specimens by separate PCR methods. PMID:10328531

  5. Risk of classic Kaposi sarcoma with residential exposure to volcanic and related soils in Sicily

    PubMed Central

    Pelser, Colleen; Dazzi, Carmelo; Graubard, Barry I.; Lauria, Carmela; Vitale, Francesco; Goedert, James J.

    2009-01-01

    Purpose Before AIDS, endemic (African) Kaposi sarcoma (KS) was noted to occur in volcanic areas and was postulated to result from dirt chronically embedded in the skin of the lower extremities. The primary cause of all KS types is KS-associated herpesvirus (KSHV) infection, but co-factors contribute to the neoplasia. We investigated whether residential exposure volcanic or related soils was associated with the risk of classic Kaposi sarcoma (cKS) in Sicily. Methods Risk of incident cKS (n=141) compared to population-based KSHV seropositive controls (n=123) was estimated for residential exposure to four types of soil, categorized with maps from the European Soil Database and direct surveying. Questionnaire data provided covariates. Results Residents in communities high in luvisols were approximately 2.7-times more likely to have cKS than those in communities with no luvisols. Risk was not specific for cKS on the limbs, but it was elevated approximately 4–5-fold with frequent bathing or tap water drinking in high luvisols communities. Risk was unrelated to communities high in andosols, tephra, or clay soils. Conclusions Iron and alumino-silicate clay, major components of luvisols, may increase cKS risk, but formal investigation and consideration of other soil types and exposures are needed. PMID:19576540

  6. Pulmonary Kaposi sarcoma and disseminated Mycobacterium genavense infection in an HIV-infected patient.

    PubMed

    Tribuna, Cindy; Ângela, Cristina; Eira, Isabel; Carvalho, Alexandre

    2015-01-01

    We report a case of Kaposi sarcoma (KS) and disseminated infection by Mycobacterium genavense in a 40-year-old HIV-positive man with CD4+ T-cell count 5/µL. He presented with anorexia, diarrhoea, cachexia and multiple firm violaceous nodules distributed over the face, neck and upper and lower extremities. Biopsy of a skin nodule was performed, confirming KS. Immunoperoxidase staining for human herpesvirus 8 was strongly positive. Endoscopic examination revealed erosive duodenopathy. Multiple biopsy samples showed numerous acid-fast bacilli at direct microscopic examination. Real-time PCR (RT-PCR) identified M. genavense. A CT scan showed diffuse pulmonary infiltrates with a 'tree-in-bud' appearance, striking splenomegaly and abdominal lymphadenopathy. A bronchoscopy was performed, revealing typical Kaposi's lesions in the upper respiratory tract. RT-PCR of bronchial aspirate identified M. genavense and Pneumocystis jirovecii. Despite treatment with highly active antiretroviral therapy, antimycobacterial therapy and trimethoprim/sulfamethoxazole, the outcome was fatal. PMID:26452414

  7. Kaposi's varicelliform eruption: A case series

    PubMed Central

    Ferrari, Bruno; Taliercio, Vanina; Luna, Paula; Abad, María Eugenia; Larralde, Margarita

    2015-01-01

    Kaposi's varicelliform eruption is a rare and potentially fatal viral infection caused mainly by reactivation of herpes simplex virus. It concomitantly occurs with pre-existing skin conditions, mostly atopic dermatitis, so it is predominately found in children. We present a case series that includes four adults, familial cases, and previously healthy patients. We also highlight clinical features, associations and therapeutic options. PMID:26753139

  8. Combination Therapy for Advanced Kaposi Sarcoma

    Cancer.gov

    In this clinical trial, adult patients with any form of advanced Kaposi sarcoma will be treated with liposomal doxorubicin and bevacizumab every 3 weeks for a maximum of six treatments.  Patients who respond to this therapy or have stable disease will rec

  9. Herpesvirus infections in childhood: 2.

    PubMed

    Nathwani, D; Wood, M J

    Infections due to herpesviruses have received increasing attention over the past decade, culminating in the isolation in 1986 of human herpesvirus-6. This is the second of two articles in which we examine the clinical spectrum of acquired herpesvirus infections in children and review developments in our understanding of the molecular biology, pathogenesis, treatment and prevention of these infections. PMID:8242213

  10. Lymphangiectatic Kaposi's sarcoma in a patient with AIDS.

    PubMed

    Santos, Mônica; Vilasboas, Virginia; Mendes, Luciana; Talhari, Carolina; Talhari, Sinésio

    2013-01-01

    Kaposi's sarcoma is a malignant disease that originates in the lymphatic endothelium. It has a broad spectrum of clinical manifestations. Its four distinct clinical forms are: classic, endemic, iatrogenic and epidemic Kaposi's sarcoma. In non-HIV-associated Kaposi's sarcoma, the disease is typically limited to the lower extremities, but in immunodeficient patients, it is a multifocal systemic disease. The clinical course of the disease differs among patients, ranging from a single or a few indolent lesions to an aggressive diffuse disease. Advanced Kaposi's sarcoma lesions, typically those on the lower extremities, are often associated with lymphedema. In this paper, we report a case of a patient with a rare form of AIDS-associated Kaposi sarcoma called lymphangiectatic Kaposis's sarcoma. PMID:23739700

  11. Structural Proteomics of Herpesviruses

    PubMed Central

    Leroy, Baptiste; Gillet, Laurent; Vanderplasschen, Alain; Wattiez, Ruddy

    2016-01-01

    Herpesviruses are highly prevalent viruses associated with numerous pathologies both in animal and human populations. Until now, most of the strategies used to prevent or to cure these infections have been unsuccessful because these viruses have developed numerous immune evasion mechanisms. Therefore, a better understanding of their complex lifecycle is needed. In particular, while the genome of numerous herpesviruses has been sequenced, the exact composition of virions remains unknown for most of them. Mass spectrometry has recently emerged as a central method and has permitted fundamental discoveries in virology. Here, we review mass spectrometry-based approaches that have recently allowed a better understanding of the composition of the herpesvirus virion. In particular, we describe strategies commonly used for proper sample preparation and fractionation to allow protein localization inside the particle but also to avoid contamination by nonstructural proteins. A collection of other important data regarding post-translational modifications or the relative abundance of structural proteins is also described. This review also discusses the poorly studied importance of host proteins in herpesvirus structural proteins and the necessity to develop a quantitative workflow to better understand the dynamics of the structural proteome. In the future, we hope that this collaborative effort will assist in the development of new strategies to fight these infections. PMID:26907323

  12. Structural Proteomics of Herpesviruses.

    PubMed

    Leroy, Baptiste; Gillet, Laurent; Vanderplasschen, Alain; Wattiez, Ruddy

    2016-02-01

    Herpesviruses are highly prevalent viruses associated with numerous pathologies both in animal and human populations. Until now, most of the strategies used to prevent or to cure these infections have been unsuccessful because these viruses have developed numerous immune evasion mechanisms. Therefore, a better understanding of their complex lifecycle is needed. In particular, while the genome of numerous herpesviruses has been sequenced, the exact composition of virions remains unknown for most of them. Mass spectrometry has recently emerged as a central method and has permitted fundamental discoveries in virology. Here, we review mass spectrometry-based approaches that have recently allowed a better understanding of the composition of the herpesvirus virion. In particular, we describe strategies commonly used for proper sample preparation and fractionation to allow protein localization inside the particle but also to avoid contamination by nonstructural proteins. A collection of other important data regarding post-translational modifications or the relative abundance of structural proteins is also described. This review also discusses the poorly studied importance of host proteins in herpesvirus structural proteins and the necessity to develop a quantitative workflow to better understand the dynamics of the structural proteome. In the future, we hope that this collaborative effort will assist in the development of new strategies to fight these infections. PMID:26907323

  13. Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) Induces the Oncogenic miR-17-92 Cluster and Down-Regulates TGF-β Signaling

    PubMed Central

    Choi, Hong Seok; Jain, Vaibhav; Krueger, Brian; Marshall, Vickie; Kim, Chang Hee; Shisler, Joanna L.; Whitby, Denise; Renne, Rolf

    2015-01-01

    KSHV is a DNA tumor virus that causes Kaposi’s sarcoma. Upon KSHV infection, only a limited number of latent genes are expressed. We know that KSHV infection regulates host gene expression, and hypothesized that latent genes also modulate the expression of host miRNAs. Aberrant miRNA expression contributes to the development of many types of cancer. Array-based miRNA profiling revealed that all six miRNAs of the oncogenic miR-17-92 cluster are up-regulated in KSHV infected endothelial cells. Among candidate KSHV latent genes, we found that vFLIP and vCyclin were shown to activate the miR-17-92 promoter, using luciferase assay and western blot analysis. The miR-17-92 cluster was previously shown to target TGF-β signaling. We demonstrate that vFLIP and vCyclin induce the expression of the miR-17-92 cluster to strongly inhibit the TGF-β signaling pathway by down-regulating SMAD2. Moreover, TGF-β activity and SMAD2 expression were fully restored when antagomirs (inhibitors) of miR-17-92 cluster were transfected into cells expressing either vFLIP or vCyclin. In addition, we utilized viral genetics to produce vFLIP or vCyclin knock-out viruses, and studied the effects in infected TIVE cells. Infection with wildtype KSHV abolished expression of SMAD2 protein in these endothelial cells. While single-knockout mutants still showed a marked reduction in SMAD2 expression, TIVE cells infected by a double-knockout mutant virus were fully restored for SMAD2 expression, compared to non-infected TIVE cells. Expression of either vFLIP or vCycIin was sufficient to downregulate SMAD2. In summary, our data demonstrate that vFLIP and vCyclin induce the oncogenic miR-17-92 cluster in endothelial cells and thereby interfere with the TGF-β signaling pathway. Manipulation of the TGF-β pathway via host miRNAs represents a novel mechanism that may be important for KSHV tumorigenesis and angiogenesis, a hallmark of KS. PMID:26545119

  14. Roles of avian herpesvirus microRNAs in infection, latency, and oncogenesis.

    PubMed

    Morgan, Robin W; Burnside, Joan

    2011-01-01

    MicroRNAs have been reported for the avian herpesviruses Marek's disease virus 1 (MDV1; oncogenic), Marek's disease virus 2 (MDV2; non-oncogenic), herpesvirus of turkeys (HVT), and infectious laryngotracheitis virus (ILTV). No obvious phylogenetic relationships exist among the avian herpesvirus microRNAs, but the general genomic locations of microRNA clusters are conserved, with microRNAs being located in the repeat regions of the genomes. In some cases, microRNAs are antisense to open reading frames. Among MDV1 field isolates with different virulence properties, microRNAs are highly conserved, and variations that have been observed lie in putative promoter regions. One cluster of MDV1 microRNAs lies upstream of the meq gene, and this cluster is more highly expressed in tumors caused by an extremely virulent MDV1 isolate compared to tumors caused by a less virulent isolate. Several of the avian herpesvirus microRNAs are orthologs of microRNAs in other species. For example, mdv1-miR-M4 shares a seed sequence with gga-miR-155 (also shared with Kaposi sarcoma herpesvirus (KSHV) kshv-miR-K12), mdv2-miR-M21 shares a seed with miR-29b, and hvt-miR-H14 shares a seed sequence with miR-221. Functional analyses of avian herpesvirus microRNAs include a variety of in vitro assays to demonstrate potential function as well as the use of mutants that can exploit the ability to assess phenotypes experimentally in the natural host. This article is part of a Special Issue entitled:MicroRNA's in viral gene regulation. PMID:21683170

  15. The human herpesvirus 8 chemokine receptor vGPCR triggers autonomous proliferation of endothelial cells

    PubMed Central

    Grisotto, Marcos G.; Garin, Alexandre; Martin, Andrea P.; Jensen, Kristian K.; Chan, PokMan; Sealfon, Stuart C.; Lira, Sergio A.

    2006-01-01

    We have used a novel conditional transgenic system to study the mechanisms of angioproliferation induced by viral G protein–coupled receptor (vGPCR), the constitutively active chemokine receptor encoded by human herpesvirus 8 (HHV8, also known as Kaposi sarcoma herpesvirus). Using this system, we were able to control temporal expression of vGPCR and to monitor its expression in situ via the use of the surrogate marker LacZ. Upon treatment with doxycycline (DOX), cells expressing vGPCR and LacZ (vGPCR/LacZ+ cells) progressively accumulated in areas where angioproliferation was observed. Sorted vGPCR/LacZ+ cells from angiogenic lesions expressed markers characteristic of endothelial progenitor cells, produced angiogenic factors, and proliferated in vitro. Prolonged treatment of transgenic mice with DOX led to development of tumors in the skin of ears, tail, nose, and paws. vGPCR/LacZ+ cells were frequent in early lesions but scarce within these tumors. Finally, transfer of vGPCR/LacZ+ cells into Rag1–/– mice treated with DOX led to angioproliferation and, with time, to development of tumors containing both vGPCR/LacZ+ and vGPCR/LacZ– cells. Taken together, these results indicate that vGPCR triggers angioproliferation directly and suggest a novel role for this molecule in the pathogenesis of Kaposi sarcoma. PMID:16604194

  16. Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication.

    PubMed

    Balistreri, Giuseppe; Viiliäinen, Johanna; Turunen, Mikko; Diaz, Raquel; Lyly, Lauri; Pekkonen, Pirita; Rantala, Juha; Ojala, Krista; Sarek, Grzegorz; Teesalu, Mari; Denisova, Oxana; Peltonen, Karita; Julkunen, Ilkka; Varjosalo, Markku; Kainov, Denis; Kallioniemi, Olli; Laiho, Marikki; Taipale, Jussi; Hautaniemi, Sampsa; Ojala, Päivi M

    2016-02-01

    Kaposi's sarcoma herpesvirus (KSHV) causes Kaposi's sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication. PMID:26891221

  17. Actin in Herpesvirus Infection

    PubMed Central

    Roberts, Kari L.; Baines, Joel D.

    2011-01-01

    Actin is important for a variety of cellular processes, including uptake of extracellular material and intracellular transport. Several emerging lines of evidence indicate that herpesviruses exploit actin and actin-associated myosin motors for viral entry, intranuclear transport of capsids, and virion egress. The goal of this review is to explore these processes and to highlight potential future directions for this area of research. PMID:21994736

  18. Human herpesvirus 6.

    PubMed Central

    Braun, D K; Dominguez, G; Pellett, P E

    1997-01-01

    Human herpesvirus 6 variant A (HHV-6A) and human herpesvirus 6 variant B (HHV-6B) are two closely related yet distinct viruses. These visuses belong to the Roseolovirus genus of the betaherpesvirus subfamily; they are most closely related to human herpesvirus 7 and then to human cytomegalovirus. Over 95% of people older than 2 years of age are seropositive for either or both HHV-6 variants, and current serologic methods are incapable of discriminating infection with one variant from infection with the other. HHV-6A has not been etiologically linked to any human disease, but such an association will probably be found soon. HHV-6B is the etiologic agent of the common childhood illness exanthem subitum (roseola infantum or sixth disease) and related febrile illnesses. These viruses are frequently active and associated with illness in immunocompromised patients and may play a role in the etiology of Hodgkin's disease and other malignancies. HHV-6 is a commensal inhabitant of brains; various neurologic manifestations, including convulsions and encephalitis, can occur during primary HHV-6 infection or in immunocompromised patients. HHV-6 and distribution in the central nervous system are altered in patients with multiple sclerosis; the significance of this is under investigation. PMID:9227865

  19. Kaposi sarcoma incidence in Mozambique: national and regional estimates.

    PubMed

    Meireles, Paula; Albuquerque, Gabriela; Vieira, Mariana; Foia, Severiano; Ferro, Josefo; Carrilho, Carla; Lunet, Nuno

    2015-11-01

    Kaposi sarcoma is expressed in four clinical variants, all associated with human herpes virus type 8 infection, namely, classic, endemic, immunosuppression-related and AIDS-related. The latter currently accounts for most of the burden of Kaposi sarcoma in sub-Saharan Africa, reflecting the frequency of HIV infection and its management. We aimed to estimate the incidence of Kaposi sarcoma in Mozambique and in its provinces. We estimated the number of incident cases of Kaposi sarcoma by adding up the expected number of endemic and AIDS-related cases. The former were estimated from the rates observed in Kyandondo, Uganda (1960-1971). The latter were computed from the number of AIDS-related deaths in each region, assuming that the ratio between the AIDS-related Kaposi sarcoma incident cases and the number of AIDS-related deaths observed in the city of Beira applies to all regions. A total of 3862 Kaposi sarcoma cases were estimated to have occurred in Mozambique in 2007, mostly AIDS-related, in the age group 25-49 years, and in provinces from South/Centre. The age-standardized incidence rates were 36.1/100 000 in men and 11.5/100 000 in women, with a more than three-fold variation across provinces. We estimated a high incidence of Kaposi sarcoma in Mozambique, along with large regional differences. These results can be used to improve disease management and to sustain political decisions on health policies. PMID:25494288

  20. Anguillid herpesvirus 1 transcriptome.

    PubMed

    van Beurden, Steven J; Gatherer, Derek; Kerr, Karen; Galbraith, Julie; Herzyk, Pawel; Peeters, Ben P H; Rottier, Peter J M; Engelsma, Marc Y; Davison, Andrew J

    2012-09-01

    We used deep sequencing of poly(A) RNA to characterize the transcriptome of an economically important eel virus, anguillid herpesvirus 1 (AngHV1), at a stage during the lytic life cycle when infectious virus was being produced. In contrast to the transcription of mammalian herpesviruses, the overall level of antisense transcription from the 248,526-bp genome was low, amounting to only 1.5% of transcription in predicted protein-coding regions, and no abundant, nonoverlapping, noncoding RNAs were identified. RNA splicing was found to be more common than had been anticipated previously. Counting the 10,634-bp terminal direct repeat once, 100 splice junctions were identified, of which 58 were considered likely to be involved in the expression of functional proteins because they represent splicing between protein-coding exons or between 5' untranslated regions and protein-coding exons. Each of the 30 most highly represented of these 58 splice junctions was confirmed by RT-PCR. We also used deep sequencing to identify numerous putative 5' and 3' ends of AngHV1 transcripts, confirming some and adding others by rapid amplification of cDNA ends (RACE). The findings prompted a revision of the AngHV1 genome map to include a total of 129 protein-coding genes, 5 of which are duplicated in the terminal direct repeat. Not counting duplicates, 11 genes contain integral, spliced protein-coding exons, and 9 contain 5' untranslated exons or, because of alternative splicing, 5' untranslated and 5' translated exons. The results of this study sharpen our understanding of AngHV1 genomics and provide the first detailed view of a fish herpesvirus transcriptome. PMID:22787220

  1. Global mapping of herpesvirus-host protein complexes reveals a novel transcription strategy for late genes

    PubMed Central

    Davis, Zoe H.; Verschueren, Erik; Jang, Gwendolyn M.; Kleffman, Kevin; Johnson, Jeffrey R.; Park, Jimin; Von Dollen, John; Maher, M. Cyrus; Johnson, Tasha; Newton, William; Jäger, Stefanie; Shales, Michael; Horner, Julie; Hernandez, Ryan D.; Krogan, Nevan J.; Glaunsinger, Britt A.

    2014-01-01

    SUMMARY Mapping host-pathogen interactions has proven instrumental for understanding how viruses manipulate host machinery and how numerous cellular processes are regulated. DNA viruses such as herpesviruses have relatively large coding capacity and thus can target an extensive network of cellular proteins. To identify the host proteins hijacked by this pathogen, we systematically affinity tagged and purified all 89 proteins of Kaposi’s sarcoma-associated herpesvirus (KSHV) from human cells. Mass spectrometry of this material identified over 500 virus-host interactions. KSHV causes AIDS-associated cancers and its interaction network is enriched for proteins linked to cancer and overlaps with proteins that are also targeted by HIV-1. We found that the conserved KSHV protein ORF24 binds to RNA polymerase II and brings it to viral late promoters by mimicking and replacing cellular TATA-box-binding protein (TBP). This is required for herpesviral late gene expression, a complex and poorly understood phase of the viral lifecycle. PMID:25544563

  2. Human Herpesvirus 8 Induces Polyfunctional B Lymphocytes That Drive Kaposi’s Sarcoma

    PubMed Central

    Knowlton, Emilee R.; Rappocciolo, Giovanna; Piazza, Paolo; Lepone, Lauren M.; Nadgir, Sagar V.; Bullotta, Arlene; Berendam, Stella J.; Li, Jun; Reinhart, Todd A.; Jenkins, Frank J.

    2014-01-01

    ABSTRACT Kaposi’s sarcoma (KS) is an unusual neoplasia wherein the tumor consists primarily of endothelial cells infected with human herpesvirus 8 (HHV-8; Kaposi’s sarcoma-associated herpesvirus) that are not fully transformed but are instead driven to excess proliferation by inflammatory and angiogenic factors. This oncogenic process has been postulated but unproven to depend on a paracrine effect of an abnormal excess of host cytokines and chemokines produced by HHV-8-infected B lymphocytes. Using newly developed measures for intracellular detection of lytic cycle proteins and expression of cytokines and chemokines, we show that HHV-8 targets a range of naive B cell, IgM memory B cell, and plasma cell-like populations for infection and induction of interleukin-6, tumor necrosis factor alpha, macrophage inhibitory protein 1α, macrophage inhibitory protein 1β, and interleukin-8 in vitro and in the blood of HHV-8/HIV-1-coinfected subjects with KS. These B cell lineage subsets that support HHV-8 infection are highly polyfunctional, producing combinations of 2 to 5 of these cytokines and chemokines, with greater numbers in the blood of subjects with KS than in those without KS. Our study provides a new paradigm of B cell polyfunctionality and supports a key role for B cell-derived cytokines and chemokines produced during HHV-8 infection in the development of KS. PMID:25182322

  3. The human herpes virus 8-encoded chemokine receptor is required for angioproliferation in a murine model of Kaposi's sarcoma.

    PubMed

    Jensen, Kristian K; Manfra, Denise J; Grisotto, Marcos G; Martin, Andrea P; Vassileva, Galya; Kelley, Kevin; Schwartz, Thue W; Lira, Sergio A

    2005-03-15

    Kaposi's sarcoma (KS)-associated herpesvirus or human herpes virus 8 is considered the etiological agent of KS, a highly vascularized neoplasm that is the most common tumor affecting HIV/AIDS patients. The KS-associated herpesvirus/human herpes virus 8 open reading frame 74 encodes a constitutively active G protein-coupled receptor known as vGPCR that binds CXC chemokines with high affinity. In this study, we show that conditional transgenic expression of vGPCR by cells of endothelial origin triggers an angiogenic program in vivo, leading to development of an angioproliferative disease that resembles KS. This angiogenic program consists partly in the expression of the angiogenic factors placental growth factor, platelet-derived growth factor B, and inducible NO synthase by the vGPCR-expressing cells. Finally, we show that continued vGPCR expression is essential for progression of the KS-like phenotype and that down-regulation of vGPCR expression results in reduced expression of angiogenic factors and regression of the lesions. Together, these findings implicate vGPCR as a key element in KS pathogenesis and suggest that strategies to block its function may represent a novel approach for the treatment of KS. PMID:15749907

  4. Predictors of immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma: a case report.

    PubMed

    Cattelan, Anna Maria; Mattiolo, Adriana; Grassi, Angela; Piano, Maria Assunta; Sasset, Lolita; Trevenzoli, Marco; Zanovello, Paola; Calabrò, Maria Luisa

    2016-01-01

    We present here a case of immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma (KS-IRIS) developed in an AIDS patient two months after initiation of antiretroviral therapy (ART). Baseline characteristics of this IRIS-KS case, within a cohort of 12 naïve AIDS-KS patients, were analyzed. No statistically significant differences in CD4 cell counts, plasma HIV RNA load, KS clinical staging, human herpesvirus 8 (HHV8) antibody titers and HHV8 load in peripheral blood mononuclear cells and saliva were evidenced. HHV8 load in plasma was found to be significantly higher in the KS-IRIS patient (> 6 log10 genome equivalents/ml, p = 0.01, t-test) compared to the 11 patients with KS regression. This case highlights that measurement of HHV8 load in plasma may be useful to identify patients at risk for KS-IRIS, and that this parameter should be included in the design of larger studies to define KS-IRIS risk predictors. PMID:26848307

  5. Pulmonary Kaposi's Sarcoma and Its Complications in the HAART Era: A Contemporary Case-Based Review.

    PubMed

    Epelbaum, Oleg; Go, Ronaldo; Patel, Geminikumar; Braman, Sidney

    2016-02-01

    The early years of the acquired immunodeficiency syndrome (AIDS) epidemic introduced the global medical community to Kaposi's sarcoma (KS), a heretofore seldom encountered angiosarcomatous neoplasm associated with human herpesvirus-8. At that time, clinicians treating these KS patients were routinely exposed to the pulmonary manifestations of this malignancy, including characteristic airway lesions, peribronchovascular opacities, and the typically hemorrhagic pleural effusions. They also witnessed uncommon complications of pulmonary KS such as chylous effusions, diffuse alveolar hemorrhage, and immune reconstitution inflammatory syndrome. Since the advent of highly active antiretroviral therapy, the incidence of KS has steadily declined and with that so has clinician familiarity with this disease. Herein, we present four KS cases recently encountered at our institution that illustrate both typical manifestations of pulmonary KS as well as its thoracic complications. The case descriptions are followed by a review of these clinical entities with the aim of restoring awareness among frontline physicians of what is now a rare but not quite extinct AIDS-defining neoplasm. PMID:26826066

  6. Fatal Outcome of Multiple Clinical Presentations of Human Herpesvirus 8-related Disease After Solid Organ Transplantation.

    PubMed

    Vijgen, Sandrine; Wyss, Caroline; Meylan, Pascal; Bisig, Bettina; Letovanec, Igor; Manuel, Oriol; Pascual, Manuel; de Leval, Laurence

    2016-01-01

    Kaposi sarcoma is the most common human herpesvirus 8 (HHV-8)-related disease described after solid organ transplantation. Multicentric Castleman disease and hemophagocytic syndrome are other potential HHV-8-induced entities but are less frequently reported. We describe the case of a liver transplant recipient who presented with an acute febrile illness 1 year after transplantation with a rapidly fatal outcome. Autopsy revealed 3 distinct HHV-8-related entities: Kaposi sarcoma, HHV-8-associated multicentric Castleman disease with microlymphomas and a severe hemophagocytic syndrome. Retrospective serologic tests suggested that HHV-8 was likely transmitted by the seropositive donor at the time of transplantation. To our knowledge, this is the first case of copresentation of 3 clinical presentations of HHV-8-mediated human disease in the post-transplant setting. Considering the absence of systematic screening of organ donors/recipients for HHV-8 infection, HHV-8-related illness should be suspected in transplant recipients who present with acute febrile illness, systemic symptoms, lymphadenopathies, and/or multiorgan failure to rapidly document the diagnosis and provide timely an adequate treatment. PMID:26120765

  7. Pleuropulmonary Kaposi Sarcoma in the Setting of Immune Reactivation

    PubMed Central

    Suresh, Karthik; Semaan, Roy; Arias, Sixto; Karakousis, Petros; Lee, Hans

    2016-01-01

    We present a case of a 26 year with history of HIV/AIDS who presented with a pleural effusion. Serial radiography, pleural fluid analysis as well as clinical symptoms revealed development of Kaposi Sarcoma related immune reconstitution inflammatory syndrome (KS-IRIS) in the setting of initiation of effective anti- retroviral therapy. PMID:27429861

  8. Instantánea del sarcoma de Kaposi

    Cancer.gov

    Información sobre las tendencias de incidencia, mortalidad y financiamiento del NCI sobre el sarcoma de Kaposi; así como ejemplos de actividades del NCI y adelantos en la investigación de este tipo de cáncer.

  9. Comparative Genomics of Carp Herpesviruses

    PubMed Central

    Kurobe, Tomofumi; Gatherer, Derek; Cunningham, Charles; Korf, Ian; Fukuda, Hideo; Hedrick, Ronald P.; Waltzek, Thomas B.

    2013-01-01

    Three alloherpesviruses are known to cause disease in cyprinid fish: cyprinid herpesviruses 1 and 3 (CyHV1 and CyHV3) in common carp and koi and cyprinid herpesvirus 2 (CyHV2) in goldfish. We have determined the genome sequences of CyHV1 and CyHV2 and compared them with the published CyHV3 sequence. The CyHV1 and CyHV2 genomes are 291,144 and 290,304 bp, respectively, in size, and thus the CyHV3 genome, at 295,146 bp, remains the largest recorded among the herpesviruses. Each of the three genomes consists of a unique region flanked at each terminus by a sizeable direct repeat. The CyHV1, CyHV2, and CyHV3 genomes are predicted to contain 137, 150, and 155 unique, functional protein-coding genes, respectively, of which six, four, and eight, respectively, are duplicated in the terminal repeat. The three viruses share 120 orthologous genes in a largely colinear arrangement, of which up to 55 are also conserved in the other member of the genus Cyprinivirus, anguillid herpesvirus 1. Twelve genes are conserved convincingly in all sequenced alloherpesviruses, and two others are conserved marginally. The reference CyHV3 strain has been reported to contain five fragmented genes that are presumably nonfunctional. The CyHV2 strain has two fragmented genes, and the CyHV1 strain has none. CyHV1, CyHV2, and CyHV3 have five, six, and five families of paralogous genes, respectively. One family unique to CyHV1 is related to cellular JUNB, which encodes a transcription factor involved in oncogenesis. To our knowledge, this is the first time that JUNB-related sequences have been reported in a herpesvirus. PMID:23269803

  10. Comparative genomics of carp herpesviruses.

    PubMed

    Davison, Andrew J; Kurobe, Tomofumi; Gatherer, Derek; Cunningham, Charles; Korf, Ian; Fukuda, Hideo; Hedrick, Ronald P; Waltzek, Thomas B

    2013-03-01

    Three alloherpesviruses are known to cause disease in cyprinid fish: cyprinid herpesviruses 1 and 3 (CyHV1 and CyHV3) in common carp and koi and cyprinid herpesvirus 2 (CyHV2) in goldfish. We have determined the genome sequences of CyHV1 and CyHV2 and compared them with the published CyHV3 sequence. The CyHV1 and CyHV2 genomes are 291,144 and 290,304 bp, respectively, in size, and thus the CyHV3 genome, at 295,146 bp, remains the largest recorded among the herpesviruses. Each of the three genomes consists of a unique region flanked at each terminus by a sizeable direct repeat. The CyHV1, CyHV2, and CyHV3 genomes are predicted to contain 137, 150, and 155 unique, functional protein-coding genes, respectively, of which six, four, and eight, respectively, are duplicated in the terminal repeat. The three viruses share 120 orthologous genes in a largely colinear arrangement, of which up to 55 are also conserved in the other member of the genus Cyprinivirus, anguillid herpesvirus 1. Twelve genes are conserved convincingly in all sequenced alloherpesviruses, and two others are conserved marginally. The reference CyHV3 strain has been reported to contain five fragmented genes that are presumably nonfunctional. The CyHV2 strain has two fragmented genes, and the CyHV1 strain has none. CyHV1, CyHV2, and CyHV3 have five, six, and five families of paralogous genes, respectively. One family unique to CyHV1 is related to cellular JUNB, which encodes a transcription factor involved in oncogenesis. To our knowledge, this is the first time that JUNB-related sequences have been reported in a herpesvirus. PMID:23269803

  11. Recent advances in the treatment of AIDS-related Kaposi's sarcoma.

    PubMed

    Cattelan, Anna M; Trevenzoli, Marco; Aversa, Savina M L

    2002-01-01

    Kaposi's sarcoma (KS) is the most common malignancy associated with HIV infection and is considered an AIDS defining condition by the US Centers of Disease Control Guidelines. Several advances in the treatment of AIDS-related KS have been achieved over the past few years, even though a gold standard therapy for KS has not yet been defined and treatment must be tailored to individual needs. Since the availability of highly active antiretroviral therapy (HAART), a dramatic clinical response has been documented in patients with KS, making HAART an essential approach in the management of KS in most, if not all, patients with AIDS-related KS. However, in case of aggressive, visceral, and/or life-threatening KS, more complex therapeutic schedules have to be taken into account, including chemotherapy, radiotherapy, and/or immunotherapy. In general, systemic treatment for KS is limited to widespread, symptomatic disease, whereas local interventions are indicated for minimal, cosmetically troublesome lesions. Among new cytotoxic agents, liposomal anthracyclines and paclitaxel are highly effective molecules for KS and have been approved by the US Food and Drug Administration (FDA) as first-line and second-line monotherapy, respectively, for advanced KS. Furthermore, a greater understanding of the pathogenesis of KS has lead to the development of an array of new experimental agents. Many antiangiogenic agents such as AGM 1470 (TNP 470), thalidomide, and glufanide disodium (IM 862) have produced encouraging responses in patients with KS and large clinical trials are in progress. Retinoic acids may also block neoangiogenesis as well as proliferation of KS cells in vitro, and they have been used either systemically or topically with a high response rate. Thus, a topical compound 0.1% alitretinoin gel was approved in 1999 by the FDA for the treatment of skin lesions associated with KS. Human chorionic gonadotropin, a hormonal agent, has shown a strong inhibitory activity in KS

  12. Herpesvirus BACs: Past, Present, and Future

    PubMed Central

    Warden, Charles; Tang, Qiyi; Zhu, Hua

    2011-01-01

    The herpesviridae are a large family of DNA viruses with large and complicated genomes. Genetic manipulation and the generation of recombinant viruses have been extremely difficult. However, herpesvirus bacterial artificial chromosomes (BACs) that were developed approximately 10 years ago have become useful and powerful genetic tools for generating recombinant viruses to study the biology and pathogenesis of herpesviruses. For example, BAC-directed deletion mutants are commonly used to determine the function and essentiality of viral genes. In this paper, we discuss the creation of herpesvirus BACs, functional analyses of herpesvirus mutants, and future applications for studies of herpesviruses. We describe commonly used methods to create and mutate herpesvirus BACs (such as site-directed mutagenesis and transposon mutagenesis). We also evaluate the potential future uses of viral BACs, including vaccine development and gene therapy. PMID:21048927

  13. A rare complication of follicular hair unit extraction: Kaposi's varicelliform eruption.

    PubMed

    Mansur, A Tulin; Demirci, Gulsen T; Uzunismail, M Adnan; Yildiz, Semsi

    2016-01-01

    Follicular hair unit extraction (FUE) is becoming a popular type of hair transplantation recently. Kaposi's varicelliform eruption (KVE) is an uncommon skin emergency due to cutaneous dissemination of several types of viruses, most notably herpes virus, over the lesions of preexisting skin disorders. A 34-year-old man visited our dermatology outpatient clinic with a blistering, itchy and tender eruption on his head and body. He had undergone follicular FUE for androgenic alopecia 12 days previously, and 5 days after the procedure, umbilicated and/or hemorrhagic vesiculopustules appeared firstly on the occipital scalp skin where the hair units were taken. The lesions had rapidly spread over the upper chest and back. After the operation, he had taken oral methylprednisolone, amoxicillin clavulanate and had used fusidic acid ointment without any benefit. Bacterial culture of the pustules yielded no microorganism, while Tzanck smear from the vesicles revealed multinuclear giant cell groups. Based on a diagnosis of KVE, we treated the patient with oral valacyclovir hydrochloride 1000 mg 3 times a day for 14 days. Symptoms cleared rapidly, pustules and vesicles dried in a few days, and re-epithelialization of the eroded areas started at the end of the first week. The reported complications of FUE include necrosis of the donor site, postoperative hyperesthesia, recipient area folliculitis, keloids, bleeding, infection and pyogenic granuloma. Up to this date there are only three reports of KVE developing just after dermatological surgery, including dermabrasion, laser resurfacing, and skin grafting. According to our knowledge, this is the first case of KVE occurring after the FUE procedure. We think that the traumatic effects and skin barrier disruption due to operation and immune alteration due to postsurgical steroid treatment might have precipitated the activation and dissemination of latent herpesvirus infection. PMID:26937302

  14. Ruminant alphaherpesviruses related to bovine herpesvirus 1.

    PubMed

    Thiry, Julien; Keuser, Véronique; Muylkens, Benoît; Meurens, François; Gogev, Sacha; Vanderplasschen, Alain; Thiry, Etienne

    2006-01-01

    Herpesviruses have mainly co-evolved with their hosts for millions of years. Consequently, different related host species may have been infected by various genetically related herpesviruses. Illustrating this concept, several ruminant alphaherpesviruses have been shown to form a cluster of viruses closely related to bovine herpesvirus 1 (BoHV-1): namely bovine herpesvirus 5, bubaline herpesvirus 1, caprine herpesvirus 1, cervid herpesviruses 1 and 2 and elk herpesvirus 1. These viruses share common antigenic properties and the serological relationships between them can be considered as a threat to BoHV-1 eradication programmes. BoHV-1 is a herpesvirus responsible for infectious bovine rhinotracheitis, which is a disease of major economic concern. In this article, the genetic properties of these ruminant alphaherpesviruses are reviewed on a comparative basis and the issue of interspecific recombination is assessed. The pathogenesis of these infections is described with emphasis on the host range and crossing of the host species barrier. Indeed, the non bovine ruminant species susceptible to these ruminant alphaherpesviruses may be potential BoHV-1 reservoirs. The differential diagnosis of these related infections is also discussed. In addition, available epidemiological data are used to assess the potential of cross-infection in ruminant populations. A better knowledge of these ruminant alphaherpesvirus infections is essential to successfully control infectious bovine rhinotracheitis. PMID:16472518

  15. Autophagy and immunity - insights from human herpesviruses.

    PubMed

    Williams, Luke R; Taylor, Graham S

    2012-01-01

    The herpesviruses are a family of double-stranded DNA viruses that infect a wide variety of organisms. Having co-evolved with their hosts over millennia, herpesviruses have developed a large repertoire of mechanisms to manipulate normal cellular processes for their own benefit. Consequently, studies on these viruses have made important contributions to our understanding of fundamental biological processes. Here we describe recent research on the human herpesviruses that has contributed to our understanding of, and interactions between, viruses, autophagy, and the immune system. The ability of autophagy to degrade proteins located within the nucleus, the site of herpesvirus latency and replication, is also considered. PMID:22783253

  16. Kaposi's sarcoma in an HIV-positive person successfully treated with paclitaxel.

    PubMed

    Dongre, Atul; Montaldo, Chiara

    2009-01-01

    Epidemic Kaposi's sarcoma is one of the malignant neoplasms, which can develop in HIV-infected patients. Although the prevalence of HIV infection is reported to be high in Asian countries, Kaposi's sarcoma is rarely reported. We report a case of Kaposi's sarcoma involving the skin and oral mucosa along with extensive bilateral lymphedema of lower extremities, treated successfully with paclitaxel and antiretrovirals. PMID:19439884

  17. Dynamic ubiquitination drives herpesvirus neuroinvasion

    PubMed Central

    Huffmaster, Nicholas J.; Sollars, Patricia J.; Richards, Alexsia L.; Pickard, Gary E.; Smith, Gregory A.

    2015-01-01

    Neuroinvasive herpesviruses display a remarkable propensity to enter the nervous system of healthy individuals in the absence of obvious trauma at the site of inoculation. We document a repurposing of cellular ubiquitin during infection to switch the virus between two invasive states. The states act sequentially to defeat consecutive host barriers of the peripheral nervous system and together promote the potent neuroinvasive phenotype. The first state directs virus access to nerve endings in peripheral tissue, whereas the second delivers virus particles within nerve fibers to the neural ganglia. Mutant viruses locked in either state remain competent to overcome the corresponding barrier but fail to invade the nervous system. The herpesvirus “ubiquitin switch” may explain the unusual ability of these viruses to routinely enter the nervous system and, as a consequence, their prevalence in human and veterinary hosts. PMID:26407585

  18. [Vaccine application of recombinant herpesviruses].

    PubMed

    Yokoyama, N; Xuan, X; Mikami, T

    2000-04-01

    Recently, genetic engineering using recombinant DNA techniques has been applied to design new viral vaccines in order to reduce some problems which the present viral vaccines have. Up to now, many viruses have been investigated for development of recombinant attenuated vaccines or live viral vectors for delivery of foreign genes coding immunogenic antigens. In this article, we introduced the new vaccine strategy using genetically engineered herpesviruses. PMID:10774221

  19. Genome Sequence of Canine Herpesvirus

    PubMed Central

    Papageorgiou, Konstantinos V.; Suárez, Nicolás M.; Wilkie, Gavin S.; McDonald, Michael; Graham, Elizabeth M.; Davison, Andrew J.

    2016-01-01

    Canine herpesvirus is a widespread alphaherpesvirus that causes a fatal haemorrhagic disease of neonatal puppies. We have used high-throughput methods to determine the genome sequences of three viral strains (0194, V777 and V1154) isolated in the United Kingdom between 1985 and 2000. The sequences are very closely related to each other. The canine herpesvirus genome is estimated to be 125 kbp in size and consists of a unique long sequence (97.5 kbp) and a unique short sequence (7.7 kbp) that are each flanked by terminal and internal inverted repeats (38 bp and 10.0 kbp, respectively). The overall nucleotide composition is 31.6% G+C, which is the lowest among the completely sequenced alphaherpesviruses. The genome contains 76 open reading frames predicted to encode functional proteins, all of which have counterparts in other alphaherpesviruses. The availability of the sequences will facilitate future research on the diagnosis and treatment of canine herpesvirus-associated disease. PMID:27213534

  20. KS-Detect - Validation of Solar Thermal PCR for the Diagnosis of Kaposi's Sarcoma Using Pseudo-Biopsy Samples.

    PubMed

    Snodgrass, Ryan; Gardner, Andrea; Jiang, Li; Fu, Cheng; Cesarman, Ethel; Erickson, David

    2016-01-01

    Resource-limited settings present unique engineering challenges for medical diagnostics. Diagnosis is often needed for those unable to reach central healthcare systems, making portability and independence from traditional energy infrastructure essential device parameters. In 2014, our group presented a microfluidic device that performed a solar-powered variant of the polymerase chain reaction, which we called solar thermal PCR. In this work, we expand on our previous effort by presenting an integrated, portable, solar thermal PCR system targeted towards the diagnosis of Kaposi's sarcoma. We call this system KS-Detect, and we now report the system's performance as a diagnostic tool using pseudo-biopsy samples made from varying concentrations of human lymphoma cell lines positive for the KS herpesvirus (KSHV). KS-Detect achieved 83% sensitivity and 70% specificity at high (≥ 10%) KSHV+ cell concentrations when diagnosing pseudo-biopsy samples by smartphone image. Using histology, we confirm that our prepared pseudo-biopsies contain similar KSHV+ cell concentrations as human biopsies positive for KS. Through our testing of samples derived from human cell lines, we validate KS-Detect as a viable, portable KS diagnostic tool, and we identify critical engineering considerations for future solar-thermal PCR devices. PMID:26799834

  1. Goat herpesviruses: biological and physicochemical properties.

    PubMed

    Engels, M; Gelderblom, H; Darai, G; Ludwig, H

    1983-10-01

    Two herpesvirus isolates from goats are known which cause afflictions of the digestive tract in kids and, in some cases, abortion. An antigenic relationship of these goat herpesviruses with infectious bovine rhinotracheitis/infectious pustular vulvo-vaginitis virus (bovid herpesvirus 1, BHV-1) was reported and because of the species-specific pathogenicity, the goat isolates were named caprine herpesvirus 1. In this report the two isolates are further characterized and compared with BHV-1. Although the caprine herpesviruses share many biological and physicochemical properties with BHV-1, they can be differentiated from the bovine viruses with respect to growth cycle, one-way cross-neutralization and, most importantly, the restriction endonuclease fragments of their DNAs. The molecular weight of the caprine herpesvirus DNA, based on electron microscopic length measurement is 90 X 10(6), similar to that of BHV-1 (95 X 10(6]. On the basis of these genomic differences, we propose that DNA restriction endonuclease patterns of the caprine herpesviruses should be designated as prototypic of bovid herpesvirus 6 (BHV-6). PMID:6311953

  2. Human herpesvirus infections: Pathogenesis, diagnosis, and treatment

    SciTech Connect

    Lopez, C.; Roizman, B.

    1986-01-01

    This book contains 24 selections. Some of the titles are: Molecular Biology of Latent HSV-1; Molecular Genetics of Antiviral Chemotherapy of Herpes Viruses; Molecular Basis of Foscarnet Action; Use of Vaccinia Virus as a Vector for Expression of Herpesvirus Genes; and Diagnosis of Herpesvirus with Monoclonal Antibodies.

  3. Phylogenetic analysis of marine mammal herpesviruses.

    PubMed

    Maness, Heather T D; Nollens, Hendrik H; Jensen, Eric D; Goldstein, Tracey; LaMere, Sarah; Childress, April; Sykes, John; St Leger, Judy; Lacave, Géraldine; Latson, F Ed; Wellehan, James F X

    2011-04-21

    Five novel DNA-dependent DNA polymerase (Dpol) herpesviral sequences were generated using nested consensus polymerase chain reaction (PCR) in clinical samples from a harbor seal (Phoca vitulina), bottlenose dolphin (Tursiops truncatus), orca (Orcinus orca), California sea lion (Zalophus californianus), and a Phocid herpesvirus 2 (PhHV-2) isolate from a harbor seal (used as positive control). These novel sequences and other representative herpesvirus sequences were included in Bayesian and Maximum Likelihood analyses to illustrate the phylogeny of herpesviruses amongst the marine mammal host species and in comparison to those of other animals. All 19 novel and known marine mammal herpesviruses included in the analyses aligned with members of the Alphaherpesvirinae or Gammaherpesvirinae subfamilies. The novel harbor seal herpesvirus clustered with members of the Macavirus genus, subfamily Gammaherpesvirinae. The novel bottlenose dolphin herpesvirus clustered together in a monophyletic group with another delphinid alphaherpesvirus but could not be associated with an established genus. The orca herpesvirus also clustered with a delphinid alphaherpesvirus and formed a separate clade. The sea lion herpesvirus clustered with PhHV-2. PhHV-1 clustered with varicelloviruses and PhHV-2 clustered strongly in the Gammaherpesvirinae genus Percavirus. All cetacean gammaherpesviruses formed a monophyletic clade and could not be associated with an established gammaherpesviral genus. PMID:21055885

  4. Herpes virus-like sequences are specifically found in Kaposi sarcoma lesions.

    PubMed Central

    O'Neill, E; Henson, T H; Ghorbani, A J; Land, M A; Webber, B L; Garcia, J V

    1996-01-01

    AIM: To detect the prevalence of herpes virus-like DNA sequences in AIDS associated Kaposi sarcoma (KSHV) lesions and normal tissue. METHODS: KSHV detection was performed by polymerase chain reaction (PCR) using four different sets of primers. PCR products were cloned, sequenced, and analysed. RESULTS: All of four biopsies of Kaposi sarcoma lesions and all of three paraffin embedded Kaposi sarcoma tissues were positive for KSHV, while normal tissue from the same patients was negative. Sequence analysis of amplification products revealed polymorphisms that result in amino acid changes of the predicted sequence. CONCLUSIONS: KSHV is prevalent in tissues from Kaposi sarcoma, suggesting a role in the development of the tumour. On this basis, anti-herpes virus agents should be considered to control Kaposi sarcoma. Images PMID:8655706

  5. Prevention and control of herpesvirus diseases

    PubMed Central

    1985-01-01

    This is the second of two articles summarizing the information currently available on herpes virus diseases. The first described the different members of the herpesvirus group, clinical expression of infection, laboratory diagnosis, and chemotherapy. This article dealing with the epidemiological and immunological aspects of herpesvirus infections also brings up the special problems caused by virus latency and risks associated with congenital infection and immunodeficiency or immunodepressive treatment. The prospects of preventing herpesvirus infections by vaccination and treatment with immune sera are also discussed. PMID:2994897

  6. Arrangement of repetitive sequences in the genome of herpesvirus Sylvilagus.

    PubMed

    Medveczky, M M; Geck, P; Clarke, C; Byrnes, J; Sullivan, J L; Medveczky, P G

    1989-02-01

    Herpesvirus sylvilagus is a lymphotropic (type gamma) herpesvirus of cottontail rabbits (Sylvilagus floridanus). Analysis of virion DNA of herpesvirus sylvilagus has revealed that the genome consists of one stretch of about 120 kilobase pairs of internal, unique DNA flanked by a variable number of 553-base-pair tandem repeats. The G + C content of the repetitive DNA is extremely high (83%), as determined by sequencing. The organization of the herpesvirus sylvilagus genome is, therefore, similar to that of the primate lymphotropic viruses herpesvirus saimiri and herpesvirus ateles. PMID:2911114

  7. Visceral Kaposi's Sarcoma Presenting as Upper Gastrointestinal Bleeding

    PubMed Central

    Hauser, Naomi; McKenzie, Devon; Fonseca, Xavier

    2015-01-01

    Since the advent of highly active antiretroviral therapy (HAART), the incidence of acquired immunodeficiency syndrome- (AIDS-) related Kaposi's sarcoma (KS) has decreased dramatically. While cutaneous KS is the most common and well-known manifestation, knowledge of alternative sites such as the gastrointestinal (GI) tract is important. GI-KS is particularly dangerous because of its potential for serious complications including perforation, obstruction, or bleeding. We report a rare case of GI-KS presenting as upper GI bleeding in a human immunodeficiency virus- (HIV-) infected transgendered individual. Prompt diagnosis and early initiation of therapy are the cornerstones for management of this potentially severe disease. PMID:26064706

  8. Herpesvirus infections in rock hyraxes (Procavia capensis).

    PubMed

    Galeota, Judith A; Napier, Julia E; Armstrong, Douglas L; Riethoven, Jean-Jack; Rogers, Douglas G

    2009-07-01

    Seven juveniles and 3 adults from a closed group of 19 rock hyraxes (Procavia capensis) housed in a zoo's indoor rock exhibit died or were euthanized after developing blepharoconjunctivitis and orofacial ulcers over a 2-week period. Histopathologic examination of dermal ulcers and ulcerated tongues revealed amphophilic to basophilic intranuclear inclusion bodies in epithelial cells bordering ulcers. Epithelial cells with inclusion bodies were often characterized by cytomegaly and karyomegaly, and many cells had formed syncytia. Examination of inclusion bodies in tongue epithelium by transmission electron microscopy revealed icosahedral nucleocapsids, approximately 80-95 nm in diameter, with morphologic features consistent with herpesvirus. Cytopathic effect (CPE) typical of alphaherpesvirus infection was seen in bovine turbinate, equine dermal, and Vero cell monolayers after inoculation with homogenates of the skin lesions, but CPE was not seen after inoculation onto Madin-Darby canine kidney or swine testicle cell monolayers. Polymerase chain reaction analysis using degenerate primers that targeted a portion of the herpesvirus polymerase gene generated a product of approximately 227 base pairs. The product was cloned, sequenced, and then analyzed using BLAST. At the nucleotide level, there was 86%, 77%, and 76% shared identity with Eidolon herpesvirus 1, Human herpesviruses 1 and 2, and Cercopithecine herpesvirus 2, respectively. Herpesvirus infections in rock hyraxes have not been characterized. The data presented in the current study suggest that a novel alphaherpesvirus caused the lesions seen in these rock hyraxes. The molecular characteristics of this virus would tentatively support its inclusion in the genus Simplexvirus. PMID:19564505

  9. Human herpesvirus 8-associated hemophagocytic lymphohistiocytosis in human immunodeficiency virus-infected patients.

    PubMed

    Fardet, L; Blum, L; Kerob, D; Agbalika, F; Galicier, L; Dupuy, A; Lafaurie, M; Meignin, V; Morel, P; Lebbé, C

    2003-07-15

    We retrospectively reviewed 5 cases of hemophagocytic lymphohistiocytosis (HL) associated with human herpesvirus 8 (HHV-8) reactivation in human immunodeficiency virus (HIV)-infected patients. All patients had clinical and biological features characteristic of HL. Pulmonary symptoms were present in all patients and were frequently life threatening. The mean number of HL episodes was 6. Four patients had HL-associated Kaposi sarcoma, and 3 had multicentric Castleman disease. The mean CD4 cell count was 200 cells/mm(3). HIV loads were stable in all patients. All patients had high levels of HHV-8 in peripheral blood mononuclear cells during attacks, and a significant increase in this parameter before the attacks was seen in 3 patients. Although 2 patients died of HL, 3 are still alive and receiving etoposide therapy (mean follow-up, 3 years). HHV-8-related HL is associated with life-threatening symptoms and biological HHV-8 reactivation, and it may be controlled in the long term by etoposide therapy combined with highly active antiretroviral therapy. PMID:12856221

  10. Incidence rates of classical Kaposi's sarcoma and multiple myeloma do not correlate.

    PubMed

    Hjalgrim, H; Frisch, M; Melbye, M

    1998-08-01

    We compared population-based incidence rates for classical Kaposi's sarcoma and multiple myeloma. Neither for men (Spearman's rank correlation coefficient (r) = 0.01, P = 0.97, 13 pairs) nor for women (r = 0.24, P = 0.42, 13 pairs) did the incidences of the two conditions correlate. This absence of correlation does not support the hypothesis that Kaposi's sarcoma and multiple myeloma share a common aetiology, such as HHV-8. PMID:9703293

  11. Disseminated Kaposi's Sarcoma with the Involvement of Penis in the Setting of HIV Infection

    PubMed Central

    Farshidpour, Maham; Marjani, Majid; Baghaei, Parvaneh; Tabarsi, Payam; Masjedi, Heidar; Asadi Kani, Zahra Farzaneh; Nadji, Seyed Alireza; Mansouri, Davood

    2015-01-01

    Kaposi's sarcoma (KS) is a malignant proliferation of the endothelial cells. It typically presents with several vascular nodules on the skin and other organs. The penile localization of KS, particularly on the shaft area, is exceptional. We report an HIV-positive 34-year-old man who had multiple purplish-black plaques on his extremities and several small violaceous macules on the glans and shaft of the penis. Kaposi's sarcoma was diagnosed by histopathology. PMID:25657424

  12. Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis.

    PubMed

    Dong, Xiaonan; Cheng, Adam; Zou, Zhongju; Yang, Yih-Sheng; Sumpter, Rhea M; Huang, Chou-Long; Bhagat, Govind; Virgin, Herbert W; Lira, Sergio A; Levine, Beth

    2016-03-15

    The ubiquitin-proteasome system degrades viral oncoproteins and other microbial virulence factors; however, the role of endolysosomal degradation pathways in these processes is unclear. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, and a constitutively active viral G protein-coupled receptor (vGPCR) contributes to the pathogenesis of KSHV-induced tumors. We report that a recently discovered autophagy-related protein, Beclin 2, interacts with KSHV GPCR, facilitates its endolysosomal degradation, and inhibits vGPCR-driven oncogenic signaling. Furthermore, monoallelic loss of Becn2 in mice accelerates the progression of vGPCR-induced lesions that resemble human Kaposi's sarcoma. Taken together, these findings indicate that Beclin 2 is a host antiviral molecule that protects against the pathogenic effects of KSHV GPCR by facilitating its endolysosomal degradation. More broadly, our data suggest a role for host endolysosomal trafficking pathways in regulating viral pathogenesis and oncogenic signaling. PMID:26929373

  13. Mitochondrial haplogroups and control region polymorphisms in Kaposi's sarcoma patients.

    PubMed

    Jalilvand, Somayeh; Shoja, Zabihollah; Marashi, Sayed Mahdi; Shahmahmoodi, Shohreh; Safaie-Naraghi, Zahra; Nourijelyani, Keramat; Nesheli, Asgar Baghernejad; Mokhtari-Azad, Talat

    2015-09-01

    Inflammation and reactive oxygen species (ROS) production have recently considered as key mechanisms in the pathogenesis of Kaposi's sarcoma (KS). Since mitochondria are the major source of ROS production, this organelle may play a main role in KS development. However, there are no studies on mtDNA variations and haplogroups in this area. The focus of this study was to investigate the mtDNA variants and haplogroups in KS patients and their relationship to tumor development. To address this, we have genotyped mtDNA in 45 Iranian KS patients and 48 age and sex-matched Iranian controls. A strong positive correlation was observed between UK cluster and decreased risk of KS. Our results suggest that the UK cluster might be a protective haplogroup for KS development. It is probably superhaplogroup UK, with lower ATP and ROS production, may prevent KSHV reactivation from latent to lytic phase that is essential for KS development. PMID:25879916

  14. [Lymph drainage with secondary lymphedema caused by Kaposi sarcoma].

    PubMed

    Einfeldt, H

    1992-12-01

    For reasons not yet known HIV infected patients in the final state of their aids disease often tend to develop Kaposi's sarcoma. These tumours result in secondary lymphatic edema which is found on both sides of the sarcoma up to the regional lymphatic nodes, transferred by the tumour cells. Depending on the state of the edema, a lymph drainage treatment is indicated palliatively; the patients can thus be relieved. A fundamental deterioration of the prognosis is not to be expected, the more as all patients are in the final state of this not yet curable disease. Differing from treatment of other lymphatic edema, it is of special importance to the therapist--apart from the difficult and specifically psychic burden--to pay attention to a protection from infection by gloves as a precaution for each single treatment. PMID:1288026

  15. [Lymph drainage therapy in secondary lymphedema caused by Kaposi sarcoma].

    PubMed

    Einfeldt, H

    1989-07-01

    For reasons not yet known HIV infected patients in the final state of their aids disease often tend to develop Kaposi's sarcoma. These tumours result in secondary lymphatic edemas which are found on both sides of the sarcoma. They reach up to the regional lymphatic nodes blocked by the tumour cells. Depending on the state of the edema a lymphaticdrainage treatment is indicated palliatively; the patients can thus be relieved. A fundamental deterioration of prognosis is not to be expected, as all patients are anyway in the final stage of this not yet curable disease. Differing from treatment of other lymphatic edema, it is of special importance to the therapist - apart from the particular and difficult psychic burden - to pay attention to infection protection by using gloves for each single treatment. PMID:2672661

  16. Psychosocial considerations in the therapy of epidemic Kaposi's sarcoma.

    PubMed

    Holland, J C; Tross, S

    1987-06-01

    Since the acquired immune deficiency syndrome (AIDS) burst into prominence in 1981, it has claimed victims at an exponential rate and taxed the resources of physicians, health workers, and social support agencies. A sizeable minority of AIDS patients, mainly male homosexuals, have been presented with epidemic Kaposi's sarcoma (EKS). Although life expectancy with this presentation may be greater than with Pneumocystis carinii pneumonia or other opportunistic infection, the underlying immunodeficiency still foreshadows an untimely death, usually from infection. Those remaining months or years are frequently marked by a poor quality of life attended by pain, functional impairment, cosmetic stigmata, central nervous system (CNS) complications, loss of employment, poverty, ostracism, guilt, and anger. Psychologic burdens may disrupt the patient's efforts to deal with the disease. Health care workers must often overcome their own prejudices and fears about AIDS to provide effective management. PMID:3603057

  17. Clinicopathological Proficiency in the Diagnosis of Kaposi's Sarcoma

    PubMed Central

    van Bogaert, Louis-Jacques

    2012-01-01

    Background. The prevalence of Kaposi's sarcoma (KS), an AIDS-defining illness, has increased in parallel with the HIV/AIDS epidemic. The presence of violaceous skin lesions should raise suspicion of KS. However, especially on dark skin, KS mimics a variety of non-KS skin conditions. Histologically, there is a wide range of expressions of KS and a large number of mimickers. For all these reasons, a HHV-8 immunohistochemically biopsy-proven diagnosis of KS should be the gold standard. Methods. Prospective study of 490 consecutive skin biopsies from the general community in the Limpopo Province of South Africa, from April 2010 through December 2011. Results. The clinical discordance rate (over-/underdiagnosis of KS) was 30.5%; the histological discordance rate was 9.2%. Conclusion. Because of the magnitude of diagnostic error, both clinical and histological, all clinical lesions suspicious of KS should be biopsied and HHV-8 LAN-1 immunophenotyped. PMID:24052878

  18. Primary Structure of the Herpesvirus Ateles Genome†

    PubMed Central

    Albrecht, Jens-Christian

    2000-01-01

    Herpesvirus ateles is an agent indigenous to spider monkeys (Ateles spp.) and causes fulminant lymphomas in various New World primates. Structural and genetic relatedness led to the classification of this virus as a member of the genus Rhadinovirus. It is most closely related to Herpesvirus saimiri. The 108,409-bp light DNA segment of the herpesvirus ateles strain 73 genome has two genes for U-RNA-like transcripts and 73 open reading frames, of which at least 6 show significant homologies to cellular genes (encoding complement control proteins, apoptosis-regulatory proteins, D-type cyclins, interleukin-8 receptors, and enzymes involved in nucleotide metabolism). The left terminal region of the light DNA segment bears the putative rhadinovirus oncogene tio. PMID:10623770

  19. Genome structure of cottontail rabbit herpesvirus.

    PubMed

    Cebrian, J; Berthelot, N; Laithier, M

    1989-02-01

    The genome structure of a herpesvirus isolated from primary cultures of kidney cells from the cottontail rabbit Sylvilagus floridanus was elucidated by using electron microscopy and restriction enzyme analysis. The genome, which was about 150 kilobase pairs long and which had an average G + C composition of 45%, consisted of two regions with unique base sequences (54 and 47 kilobase pairs) enclosed by reiterations of a 925-base-pair sequence with a variable copy number. The internal repeats were in opposite polarity with respect to the terminal repeats, and both unique regions underwent inversion. The nucleotide sequence of the repeat unit was determined, and virion DNA termini were precisely localized within this sequence. Elements showing homology with the cleavage-packaging signals common to other herpesviruses were detected. The data indicate that this virus is different from the previously described herpesvirus sylvilagus. PMID:2911115

  20. Thymidylate synthase gene of herpesvirus ateles.

    PubMed Central

    Richter, J; Puchtler, I; Fleckenstein, B

    1988-01-01

    The putative thymidylate synthase (TS) gene of herpesvirus ateles, a T-lymphotropic tumor virus of New World primates, has a single large open reading frame encoding a polypeptide of 32.9 kilodaltons. The gene is transcribed into an unspliced 2.4-kilobase mRNA that is abundantly expressed late in virus replication. The AT-rich 5' untranslated leader sequence of TS mRNA in herpesvirus ateles-infected cells is remarkable in length (1,184 nucleotides), containing 29 minicistrons; this may indicate a role in translation regulation. Images PMID:3404583

  1. Imatinib for highly chemoresistant Kaposi sarcoma in a patient with long-term HIV control: a case report and literature review.

    PubMed

    Cao, W; Vyboh, K; Routy, B; Chababi-Atallah, M; Lemire, B; Routy, J P

    2015-10-01

    Kaposi sarcoma (ks) is a vascular tumour caused by oncogenic human herpesvirus type 8; it often occurs with hiv-associated immunosuppression. Numerous cellular signalling pathways are involved in the pathogenesis of ks, among which receptor tyrosine kinases such as the c-Kit and platelet-derived growth factor receptors play an important role. Imatinib mesylate, a tyrosine kinase inhibitor, has resulted in partial regression of ks lesions in one third of treated patients, but its mechanism of action remains unclear. Here, we report the case of a white man with recurrent ks despite well-suppressed hiv infection and multiple chemotherapies who received imatinib and showed a complete and sustained tumour response. To our knowledge, this report is the first showing the value of imatinib in the management of ks in the context of long-lasting hiv control with adequate quantitative CD4 recovery. Our case indicates that imatinib can be a treatment option for highly chemoresistant recurrent ks in patients on long-term antiretroviral therapy. PMID:26628884

  2. Imatinib for highly chemoresistant Kaposi sarcoma in a patient with long-term HIV control: a case report and literature review

    PubMed Central

    Cao, W.; Vyboh, K.; Routy, B.; Chababi-Atallah, M.; Lemire, B.; Routy, J.P.

    2015-01-01

    Kaposi sarcoma (ks) is a vascular tumour caused by oncogenic human herpesvirus type 8; it often occurs with hiv-associated immunosuppression. Numerous cellular signalling pathways are involved in the pathogenesis of ks, among which receptor tyrosine kinases such as the c-Kit and platelet-derived growth factor receptors play an important role. Imatinib mesylate, a tyrosine kinase inhibitor, has resulted in partial regression of ks lesions in one third of treated patients, but its mechanism of action remains unclear. Here, we report the case of a white man with recurrent ks despite well-suppressed hiv infection and multiple chemotherapies who received imatinib and showed a complete and sustained tumour response. To our knowledge, this report is the first showing the value of imatinib in the management of ks in the context of long-lasting hiv control with adequate quantitative CD4 recovery. Our case indicates that imatinib can be a treatment option for highly chemoresistant recurrent ks in patients on long-term antiretroviral therapy. PMID:26628884

  3. Structural proteins of Herpesvirus saimiri.

    PubMed Central

    Keil, G; Fleckenstein, B; Bodemer, W

    1983-01-01

    Herpesvirus saimiri particles were purified from productively infected owl monkey kidney cell cultures, and the virion polypeptides were analyzed by polyacrylamide gel electrophoresis. A total of 21 predominant proteins were found in lysates of H. saimiri 11 particles by Coomassie blue staining or by [35S]methionine labeling and autoradiography; all proteins were between 160,000 and 12,000 daltons in size. They are most probably virion constituents, as most of them were precipitated by immune sera, and no dominant proteins of equivalent sizes were found in mock-infected cultures. Four glycoproteins (gp 155/160, gp 128, gp 84/90, gp 55) and three polypeptides that appeared not to be glycosylated (p71, p35, p28) were assigned to the envelope or matrix of virions, whereas at least four phosphoproteins (pp132, pp118, pp55, pp13) and ten polypeptides without apparent secondary modification (p155/160, p106, p96, p67, p53, p36, p32, p15, p14, p12) were found in the nucleocapsid fraction. Analysis of virion proteins from different H. saimiri strains did not reveal appreciable differences in the migration behavior of most polypeptides, including all glycoproteins; however, determination of a strain-specific size pattern was possible for three of four phosphoproteins. The overall similarity in protein architecture of H. saimiri strains obviously does not reflect the variability in biology, such as oncogenic properties. In comparison, DNA sequence divergences appear to remain a better taxonomic criterion for strain distinction. Images PMID:6312078

  4. Microtissue Culture Plaque Assay for Herpesvirus saimiri

    PubMed Central

    Chan, Emerson W.; Dunkel, Virginia C.

    1973-01-01

    A microtissue culture method for the plaque assay of Herpesvirus saimiri has been developed. Virus titrations carried out in Microtest II tissue culture plates (Falcon) yielded reproducible results that agreed well with those obtained by employing macrocultures. The described method is quantitative, reproducible, economical, and suitable for routine assay of large numbers of virus samples. Images PMID:4201642

  5. New Hosts for Equine Herpesvirus 9

    PubMed Central

    Tucker, Tammy A.; Donovan, Taryn A.; Busch, Martin D.M.; Wise, Annabel G.; Maes, Roger K.; Kiupel, Matti

    2008-01-01

    Equine herpesvirus 9 was detected in a polar bear with progressive encephalitis; the source was traced to 2 members of a potential equid reservoir species, Grevy’s zebras. The virus was also found in an aborted Persian onager. Thus, the natural host range is extended to 6 species in 3 mammalian orders. PMID:18826828

  6. Gamma herpesvirus carrier status of captive artiodactyls.

    PubMed

    Flach, E J; Reid, H; Pow, I; Klemt, A

    2002-08-01

    Between 1998 and 2000, 103 individuals of 19 species of the order Artiodactyla at Whipsnade Wild Animal Park were tested for evidence of infection with gamma herpesviruses in order to distinguish between species which are susceptible to malignant catarrhal fever (MCF), caused by alcelaphine herpesvirus-1 (AlHV-1) of wildebeest (Connochaetes sp.) or ovine herpesvirus-2 (OvHV-2) of domestic sheep, and species which carry related viruses sub-clinically. Gamma herpesvirus DNA was detected in the known, or suspected, carrier species: roan antelope (Hippotragus equinus), scimitar-horned oryx (Oryx dammah), gemsbok (Oryx gazella), musk ox (Ovibos muschatus) and mouflon (Ovis musimon). In six other species: lowland anoa (Bubalus depressicornis) yak (Bos grunniens), sitatunga (Tragelaphus spekei), greater kudu (Tragelaphus strepsiceros), waterbuck (Kobus ellipsiprymnus) and Nile lechwe (Kobus megaceros), DNA was present in some newborn calves and over 30% of adults, strongly suggesting a carrier state. In contrast five Père David's deer (Elaphurus davidianus) and two swamp deer (Cervus duvauceli) died of MCF during the study. A virus isolated from scimitar-horned oryx calves produced cytopathic effects in scimitar-horned oryx kidney cell-culture and caused MCF in a rabbit. PMID:12208112

  7. Iatrogenic colorectal Kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative-virus patient.

    PubMed

    Hamzaoui, Lamine; Kilani, Houda; Bouassida, Mahdi; Mahmoudi, Moufida; Chalbi, Emna; Siai, Karima; Ezzine, Heykel; Touinsi, Hassen; Azzouz, Mohamed M'saddak; Sassi, Sadok

    2013-01-01

    Kaposi sarcoma is a mesenchymal tumor associated to a human herpes virus-8. It often occurs in human immunodeficiency virus-positive subjects. Colorectal localization is rare. We report the case of a colorectal Kaposi sarcoma complicating a refractory ulcerative colitis treated with surgery after the failure of immunomodulator therapy in a human immunodeficiency virus-negative heterosexual man. PMID:24396560

  8. Biclustering of time series microarray data.

    PubMed

    Meng, Jia; Huang, Yufei

    2012-01-01

    Clustering is a popular data exploration technique widely used in microarray data analysis. In this chapter, we review ideas and algorithms of bicluster and its applications in time series microarray analysis. We introduce first the concept and importance of biclustering and its different variations. We then focus our discussion on the popular iterative signature algorithm (ISA) for searching biclusters in microarray dataset. Next, we discuss in detail the enrichment constraint time-dependent ISA (ECTDISA) for identifying biologically meaningful temporal transcription modules from time series microarray dataset. In the end, we provide an example of ECTDISA application to time series microarray data of Kaposi's Sarcoma-associated Herpesvirus (KSHV) infection. PMID:22130875

  9. Three Novel Herpesviruses of Endangered Clemmys and Glyptemys Turtles

    PubMed Central

    Ossiboff, Robert J.; Raphael, Bonnie L.; Ammazzalorso, Alyssa D.; Seimon, Tracie A.; Newton, Alisa L.; Chang, Tylis Y.; Zarate, Brian; Whitlock, Alison L.; McAloose, Denise

    2015-01-01

    The rich diversity of the world’s reptiles is at risk due to significant population declines of broad taxonomic and geographic scope. Significant factors attributed to these declines include habitat loss, pollution, unsustainable collection and infectious disease. To investigate the presence and significance of a potential pathogen on populations of critically endangered bog turtles (Glyptemys muhlenbergii) as well sympatric endangered wood (G. insculpta) and endangered spotted (Clemmys guttata) turtles in the northeastern United States, choanal and cloacal swabs collected from 230 turtles from 19 sites in 5 states were screened for herpesvirus by polymerase chain reaction. We found a high incidence of herpesvirus infection in bog turtles (51.5%; 105/204) and smaller numbers of positive wood (5) and spotted (1) turtles. Sequence and phylogenetic analysis revealed three previously uncharacterized alphaherpesviruses. Glyptemys herpesvirus 1 was the predominant herpesvirus detected and was found exclusively in bog turtles in all states sampled. Glyptemys herpesvirus 2 was found only in wood turtles. Emydid herpesvirus 2 was found in a small number of bog turtles and a single spotted turtle from one state. Based on these findings, Glyptemys herpesvirus 1 appears to be a common infection in the study population, whereas Glyptemys herpesvirus 2 and Emydid herpesvirus 2 were not as frequently detected. Emydid herpesvirus 2 was the only virus detected in more than one species. Herpesviruses are most often associated with subclinical or mild infections in their natural hosts, and no sampled turtles showed overt signs of disease at sampling. However, infection of host-adapted viruses in closely related species can result in significant disease. The pathogenic potential of these viruses, particularly Emydid herpesvirus 2, in sympatric chelonians warrants additional study in order to better understand the relationship of these viruses with their endangered hosts. PMID

  10. Regulation of Herpesvirus Reactivation by Host MicroRNAs

    PubMed Central

    2014-01-01

    The interplay between latent and lytic modes of infection is central to successful infection of all herpesviruses, yet knowledge of the determinants that govern reactivation of these viruses from latent to lytic infection is limited. Recently, several studies have identified roles for specific cellular microRNAs in inhibiting reactivation of various herpesviruses, thereby promoting latent infections. These studies are discussed in the context of current knowledge on mechanisms of regulation of reactivation of specific herpesviruses. PMID:25540363

  11. HHV8 and Kaposi's sarcoma: a time cohort study.

    PubMed Central

    Kennedy, M M; Lucas, S B; Jones, R R; Howells, D D; Picton, S J; Hanks, E E; McGee, J O; O'Leary, J J

    1997-01-01

    AIMS: The recent finding that human herpes virus 8 (HHV8) is found in the majority of Kaposi's sarcoma (KS) cases supports the epidemiological observation that the tumour may be caused by an infectious agent. This study aimed to address when and how HHV8 evolved. METHODS: A cohort of African endemic KS (49 samples from 45 patients) and European KS (18 samples from 13 patients), spanning 27 years, was assessed for the presence of HHV8 by both standard solution phase polymerase chain reaction (PCR) and the newly described technique of TaqMan PCR. RESULTS: HHV8 was present in approximately 49% (24 of 49 tissue samples) of the African cases and in more than 90% (16 of 18 tissue samples) of the European cohort, in keeping with recent seroepidemiological data. CONCLUSIONS: HHV8 is strongly linked to the development of KS; however, in some patients, other factors may operate. The utility and flexibility of TaqMan PCR in detecting low copy viral target in human tissues was demonstrated. Images PMID:9231158

  12. Complete regression of visceral Kaposi's sarcoma after conversion to sirolimus.

    PubMed

    Mohsin, N; Budruddin, M; Pakkyara, A; Darweesh, A; Nayyer, M; Amitabh, J; Daar, A S

    2005-12-01

    The prevalence of Kaposi's sarcoma (KS) is much greater in organ transplant recipients than it is in the general population. Its etiology appears to be related to geographic, genetic, and viral factors. Treatment of transplant-related KS has, until now, consisted mainly of reduction of, or withholding of, immunosuppression, often with deleterious effects on both graft and patient survival. In recent years, the immunosuppressive drug, sirolimus, has been demonstrated as possessing anti-neoplastic properties in both in vitro and animal models. In view of these properties and some preliminary clinical experience, we postulated that sirolimus would be beneficial in our patients who developed transplant-related KS. Here, we report the first case of a patient with both cutaneous and visceral KS who was successfully treated in the Middle East by conversion from a cyclosporine-based to a sirolimus-based immunosuppression regimen. The KS regressed completely within a few months after the conversion. The chronologic events and the extensive documentation, which included repeat computed tomography scans, are very suggestive of a selective anti-neoplastic effect of sirolimus. PMID:16417445

  13. Toll-like receptor sensing of human herpesvirus infection

    PubMed Central

    West, John A.; Gregory, Sean M.; Damania, Blossom

    2012-01-01

    Toll-like receptors (TLRs) are evolutionarily conserved pathogen sensors that constitute the first line of defense in the human immune system. Herpesviruses are prevalent throughout the world and cause significant disease in the human population. Sensing of herpesviruses via TLRs has only been documented in the last 10 years and our understanding of the relationship between these sentinels of the immune system and herpesvirus infection has already provided great insight into how the host cell responds to viral infection. This report will summarize the activation and modulation of TLR signaling in the context of human herpesvirus infections. PMID:23061052

  14. Piracy on the molecular level: human herpesviruses manipulate cellular chemotaxis.

    PubMed

    Cornaby, Caleb; Tanner, Anne; Stutz, Eric W; Poole, Brian D; Berges, Bradford K

    2016-03-01

    Cellular chemotaxis is important to tissue homeostasis and proper development. Human herpesvirus species influence cellular chemotaxis by regulating cellular chemokines and chemokine receptors. Herpesviruses also express various viral chemokines and chemokine receptors during infection. These changes to chemokine concentrations and receptor availability assist in the pathogenesis of herpesviruses and contribute to a variety of diseases and malignancies. By interfering with the positioning of host cells during herpesvirus infection, viral spread is assisted, latency can be established and the immune system is prevented from eradicating viral infection. PMID:26669819

  15. ACUTE UPPER GASTROINTESTINAL BLEEDING SECONDARY TO KAPOSI SARCOMA AS INITIAL PRESENTATION OF HIV INFECTION

    PubMed Central

    Mansfield, Sara A.; Stawicki, Stanislaw P.A.; Forbes, Rachel C.; Papadimos, Thomas J.; Lindsey, David E.

    2014-01-01

    Despite our decades of experience with Kaposi Sarcoma its true nature remains elusive. This angioproliferative disease of the vascular endothelium has a propensity to involve visceral organs in the immunocompromised population. There are four variants of the disease and each has its own pathogenesis and evolution. While the common sources of upper gastrointestinal bleeding are familiar to surgeons and critical care physicians, here we present the exceedingly rare report of upper gastrointestinal bleeding attributable to this malady, explore its successful management, and review the various forms of Kaposi Sarcoma including the strategies in regard to their management. PMID:24369327

  16. IL-10 gene polymorphism and herpesvirus infections.

    PubMed

    Hurme, M; Haanpää, M; Nurmikko, T; Wang, X-Y; Virta, M; Pessi, T; Kilpinen, S; Hulkkonen, J; Helminen, M

    2003-01-01

    Genetics has an important role in resistance to various infections and it also may modify the clinical picture of an infectious disease. Here, we briefly review our recent data demonstrating that the polymorphism of the IL-10 gene is associated with resistance to some common herpesviruses and, additionally, that this same gene is involved in the regulation of the severity of the infection and in the reactivation process. PMID:12627487

  17. The A, B, Cs of Herpesvirus Capsids

    PubMed Central

    Tandon, Ritesh; Mocarski, Edward S.; Conway, James F.

    2015-01-01

    Assembly of herpesvirus nucleocapsids shares significant similarities with the assembly of tailed dsDNA bacteriophages; however, important differences exist. A unique feature of herpesviruses is the presence of different mature capsid forms in the host cell nucleus during infection. These capsid forms, referred to as A-, B-, and C-capsids, represent empty capsids, scaffold containing capsids and viral DNA containing capsids, respectively. The C-capsids are the closest in form to those encapsidated into mature virions and are considered precursors to infectious virus. The evidence supporting A- and B-capsids as either abortive forms or assembly intermediates has been lacking. Interaction of specific capsid forms with viral tegument proteins has been proposed to be a mechanism for quality control at the point of nuclear egress of mature particles. Here, we will review the available literature on these capsid forms and present data to debate whether A- and B-capsids play an important or an extraneous role in the herpesvirus life cycle. PMID:25730559

  18. L'atteinte osseuse dans le sarcome de Kaposi classique et agressif: à propos d'un cas

    PubMed Central

    Sbiyaa, Mouhcine; El Alaoui, Adil; El Bardai, Mohammed; Mezzani, Amine; Lahrach, Kamal; Marzouki, Amine; Boutayeb, Fawzi

    2016-01-01

    Le sarcome de Kaposi classique est une tumeur rare multifocale d'origine des cellules endothéliales vasculaires à caractère évolutif progressif et peu maligne. L'atteinte viscérale dans le sarcome de kaposi est parfois observée chez les patients VIH positif par contre la dissémination tumorale dans les ganglions lymphatiques viscérales dans le SK classique reste très rare. On rapporte un cas rare de sarcome de kaposi classique agressif de la main avec une évolution rapide et destructive. PMID:27347285

  19. Herpesvirus sylvilagus infects both B and T lymphocytes in vivo.

    PubMed Central

    Kramp, W J; Medveczky, P; Mulder, C; Hinze, H C; Sullivan, J L

    1985-01-01

    Herpesvirus sylvilagus infection of cottontail rabbits (Sylvilagus floridanus) was studied as a model of herpesvirus-induced lymphoproliferative disorders. Leukocytosis, splenomegaly, proliferation of T cells and virus production by lymphocytes characterized this infectious mononucleosis-like disease. Approximately two copies of circular herpesvirus sylvilagus genomes per cell were detected in spleen cells at 2 weeks postinfection, and circular genomes could still be observed after 4 months. Circular viral genomes were found in both B and T lymphocytes. Small amounts of linear viral DNA (0.1 to 0.3 copies per cell) were also detected in both B and T cells. These results indicated that the virus did not replicate in the majority of lymphocytes in vivo. Herpesvirus sylvilagus infection in cottontail rabbits could be useful as a model for studying the complex virus-host relationships of lymphotropic herpesviruses and perhaps as an animal model for Epstein-Barr virus infection in humans. Images PMID:2993667

  20. Herpesvirus sylvilagus infects both B and T lymphocytes in vivo.

    PubMed

    Kramp, W J; Medveczky, P; Mulder, C; Hinze, H C; Sullivan, J L

    1985-10-01

    Herpesvirus sylvilagus infection of cottontail rabbits (Sylvilagus floridanus) was studied as a model of herpesvirus-induced lymphoproliferative disorders. Leukocytosis, splenomegaly, proliferation of T cells and virus production by lymphocytes characterized this infectious mononucleosis-like disease. Approximately two copies of circular herpesvirus sylvilagus genomes per cell were detected in spleen cells at 2 weeks postinfection, and circular genomes could still be observed after 4 months. Circular viral genomes were found in both B and T lymphocytes. Small amounts of linear viral DNA (0.1 to 0.3 copies per cell) were also detected in both B and T cells. These results indicated that the virus did not replicate in the majority of lymphocytes in vivo. Herpesvirus sylvilagus infection in cottontail rabbits could be useful as a model for studying the complex virus-host relationships of lymphotropic herpesviruses and perhaps as an animal model for Epstein-Barr virus infection in humans. PMID:2993667

  1. Factors associated with Kaposi's sarcoma in a cohort of homosexual and bisexual men.

    PubMed

    Kaldor, J M; Tindall, B; Williamson, P; Elford, J; Cooper, D A

    1993-10-01

    The relationship between the occurrence of Kaposi's sarcoma (KS) and a range of factors was studied in a cohort of homosexual and bisexual men. Overall, 134 men had AIDS, including 46 for whom KS was the first AIDS-defining illness. The proportion of men diagnosed with AIDS whose first AIDS-defining illness was KS declined from 54 to 24% between 1984-85 and 1989-90 (p = 0.03 for linear trend). Kaposi's sarcoma was not associated with a history of any specific communicable disease, nor with the reported use of selected nontherapeutic drugs, at the 0.05 level of significance. No single sexual practice was significantly associated with KS, and only the relative risks for insertive oroanal contact (1.5, 95% confidence limits 0.73-2.4) and receptive fisting (1.3, 0.61-2.6) exceeded unity. Kaposi's sarcoma occurred significantly less frequently in men who reported orogenital intercourse than in those who did not (relative risk 0.47, 0.23-0.98 for receptive orogenital intercourse). History of sexual contact in the United States was associated with KS, but this association was not statistically significant. While this study provides some support for the hypothesis that Kaposi's sarcoma in people with AIDS may be caused by a sexually transmissible infectious agent, no specific sexual practice could be implicated. In particular, there was little evidence that the postulated KS agent was transmitted by fecal-oral contact. PMID:8105074

  2. Kaposi's sarcoma in a steroid-treated antisynthethase antibody syndrome patient.

    PubMed

    Bragado, Laura; Ruiz Gutiérrez, Lucía; Cuende, Eduardo; López González, José Luis

    2013-01-01

    Kaposi's sarcoma (KS) is a malignant vascular tumor widely known as a complication of acquired immunodeficiency syndrome (AIDS) but also related to immunosupression in renal transplants, and less frequently, to other diseases. We describe a case of KS in a patient affected by anti-synthetase syndrome treated with steroids. PMID:23271139

  3. Comparative full genome sequence analysis of columbid herpesvirus-1 and falconid herpesvirus-1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Columbid herpesvirus type 1 (CoHV-1) is an alphaherpesvirus in the genus Mardivirus that infect pigeons and causes fatal disseminated infections in birds of prey: owls, falcons and hawks. A common feature of captive raptures that have succumbed to CoHV-1 infection is that they all have been fed pige...

  4. The spindle-shaped cells in cutaneous Kaposi's sarcoma. Histologic simulators include factor XIIIa dermal dendrocytes.

    PubMed Central

    Nickoloff, B. J.; Griffiths, C. E.

    1989-01-01

    Kaposi's sarcoma is a neoplasm that develops as multifocal lesions, often involving the skin, characterized by a complex histologic picture including numerous vascular spaces, perivascular and interstitial spindle-shaped cells, and extravasated erythrocytes, lymphocytes, and plasma cells. Using an antibody against factor XIIIa, which identifies dermal dendrocytes, numerous factor XIIIa-positive dermal dendrocytes were detected among the spindle-shaped cells in 12 acquired immune deficiency syndrome (AIDS)-associated, and five non-AIDS-associated Kaposi's sarcoma lesions. The factor XIIIa-positive dermal dendrocytes were also increased in histologic simulators of Kaposi's sarcoma such as dermatofibroma, angiomatoid malignant fibrous histiocytoma, granuloma annulare, and early wound healing, but were absent in keloids. The increased number of dermal dendrocytes, which are often in an angiocentric configuration and which also express CD4, lymphocyte function associated antigen-1 (LFA-1), and Leu M3 in Kaposi's sarcoma, may be important to the angioproliferative response. The results suggested that the spindle-shaped cells that are present in a variety of cutaneous lesions are dermal dendrocytes and belong to the reticuloendothelial system, unlike other mesenchymal cell types such as the endothelial cell. Apparently a diverse array of stimuli, including human immunodeficiency virus type-1 (HIV-1) infection and trauma, can stimulate the accumulation of factor XIIIa expressing dermal dendrocytes in the skin. These cells can then participate in different stages of a variety of cutaneous alterations including Kaposi's sarcoma, dermatofibroma, granuloma annulare, and early wound healing. Thus, the factor XIIIa-positive dermal dendrocyte is a common cellular denominator among diverse clinical entities that share some histologic features. Images Figure 1 Figure 2 Figure 3 p797-a PMID:2573283

  5. The spindle-shaped cells in cutaneous Kaposi's sarcoma. Histologic simulators include factor XIIIa dermal dendrocytes.

    PubMed

    Nickoloff, B J; Griffiths, C E

    1989-11-01

    Kaposi's sarcoma is a neoplasm that develops as multifocal lesions, often involving the skin, characterized by a complex histologic picture including numerous vascular spaces, perivascular and interstitial spindle-shaped cells, and extravasated erythrocytes, lymphocytes, and plasma cells. Using an antibody against factor XIIIa, which identifies dermal dendrocytes, numerous factor XIIIa-positive dermal dendrocytes were detected among the spindle-shaped cells in 12 acquired immune deficiency syndrome (AIDS)-associated, and five non-AIDS-associated Kaposi's sarcoma lesions. The factor XIIIa-positive dermal dendrocytes were also increased in histologic simulators of Kaposi's sarcoma such as dermatofibroma, angiomatoid malignant fibrous histiocytoma, granuloma annulare, and early wound healing, but were absent in keloids. The increased number of dermal dendrocytes, which are often in an angiocentric configuration and which also express CD4, lymphocyte function associated antigen-1 (LFA-1), and Leu M3 in Kaposi's sarcoma, may be important to the angioproliferative response. The results suggested that the spindle-shaped cells that are present in a variety of cutaneous lesions are dermal dendrocytes and belong to the reticuloendothelial system, unlike other mesenchymal cell types such as the endothelial cell. Apparently a diverse array of stimuli, including human immunodeficiency virus type-1 (HIV-1) infection and trauma, can stimulate the accumulation of factor XIIIa expressing dermal dendrocytes in the skin. These cells can then participate in different stages of a variety of cutaneous alterations including Kaposi's sarcoma, dermatofibroma, granuloma annulare, and early wound healing. Thus, the factor XIIIa-positive dermal dendrocyte is a common cellular denominator among diverse clinical entities that share some histologic features. PMID:2573283

  6. Bioactive activities of natural products against herpesvirus infection.

    PubMed

    Son, Myoungki; Lee, Minjung; Sung, Gi-Ho; Lee, Taeho; Shin, Yu Su; Cho, Hyosun; Lieberman, Paul M; Kang, Hyojeung

    2013-10-01

    More than 90% of adults have been infected with at least one human herpesvirus, which establish long-term latent infection for the life of the host. While anti-viral drugs exist that limit herpesvirus replication, many of these are ineffective against latent infection. Moreover, drug-resistant strains of herpesvirus emerge following chemotherapeutic treatment. For example, resistance to acyclovir and related nucleoside analogues can occur when mutations arise in either HSV thymidine kinase or DNA polymerases. Thus, there exists an unmet medical need to develop new anti-herpesvirus agents with different mechanisms of action. In this Review, we discuss the promise of anti-herpetic substances derived from natural products including extracts and pure compounds from potential herbal medicines. One example is Glycyrrhizic acid isolated from licorice that shows promising antiviral activity towards human gammaherpesviruses. Secondly, we discuss anti-herpetic mechanisms utilized by several natural products in molecular level. While nucleoside analogues inhibit replicating herpesviruses in lytic replication, some natural products can disrupt the herpesvirus latent infection in the host cell. In addition, natural products can stimulate immune responses against herpesviral infection. These findings suggest that natural products could be one of the best choices for development of new treatments for latent herpesvirus infection, and may provide synergistic anti-viral activity when supplemented with nucleoside analogues. Therefore, it is important to identify which natural products are more efficacious anti-herpetic agents, and to understand the molecular mechanism in detail for further advance in the anti-viral therapies. PMID:24173639

  7. Analysis of the genome of leporid herpesvirus 4.

    PubMed

    Babra, Bobby; Watson, Gregory; Xu, Wayne; Jeffrey, Brendan M; Xu, Jia-Rong; Rockey, Daniel D; Rohrmann, George F; Jin, Ling

    2012-11-10

    The genome of a herpesvirus highly pathogenic to rabbits, leporid herpesvirus 4 (LHV-4), was analyzed using high-throughput DNA sequencing technology and primer walking. The assembled DNA sequences were further verified by restriction endonuclease digestion and Southern blot analyses. The total length of the LHV-4 genome was determined to be about 124 kb. Genes encoded in the LHV-4 genome are most closely related to herpesvirus of the Simplexvirus genus, including human herpesviruses (HHV-1 and HHV-2), monkey herpesviruses including cercopithicine (CeHV-2 and CeHV-16), macacine (McHV-1), bovine herpesvirus 2 (BHV-2), and a lineage of wallaby (macropodid) herpesviruses (MaHV-1 and -2). Similar to other simplexvirus genomes, LHV-4 has a high overall G+C content of 65-70% in the unique regions and 75-77% in the inverted repeat regions. Orthologs of ICP34.5 and US5 were not identified in the LHV-4 genome. This study shows that LHV-4 has the smallest simplexvirus genome characterized to date. PMID:22921533

  8. Human herpesvirus 8 infections in the Amsterdam Cohort Studies (1984–1997): Analysis of seroconversions to ORF65 and ORF73

    PubMed Central

    Goudsmit, Jaap; Renwick, Neil; Dukers, Nicole H. T. M.; Coutinho, Roel A.; Heisterkamp, Siem; Bakker, Margreet; Schulz, Thomas F.; Cornelissen, Marion; Weverling, Gerrit J.

    2000-01-01

    We have shown previously that human herpesvirus 8 (HHV8) seroconversion for antibodies to the latency-associated nuclear antigen encoded by ORF73 and/or the lytic capsid antigen (vp19) encoded by ORF65 is associated with orogenital contact and is strongly linked to the development of Kaposi's sarcoma among HIV-infected individuals in the Amsterdam Cohort Studies. Here, we investigate the relationship between seroconversion to these antigens and primary HHV8 infection. Between 1984 and 1997, 215 HHV8 seroconversions to ORF73 (106 cases or 49%) and/or to ORF65 (159 cases or 74%) were recorded in the cohort of homosexual men. The HHV8 seroconversion rate among HIV-infected homosexual men (6.2 per 100 person years) was consistently higher than among HIV-uninfected men (2.6 per 100 person years). In HIV-infected but not in uninfected individuals, seroconversion to ORF73/latency-associated nuclear antigen precedes that to ORF65/vp19. Antibody levels to both ORF65- and ORF73-encoded antigens were higher in HIV-infected than in HIV-uninfected men, and among HIV-seropositives, antibody levels to ORF65/vp19 rise even higher with declining CD4 cell counts and peak with Kaposi's sarcoma development, suggesting continuing and increasing viral replication. In 10.3% of HHV8 seroconversions, transient serum viremia could be demonstrated before or at seroconversion. Together with the previously reported link between unprotected orogenital sex and HHV8 seroconversion, our observations suggest that HHV8 seroconversions result from primary infections. PMID:10781089

  9. Ethnomedicines and ethnomedicinal phytophores against herpesviruses.

    PubMed

    Chattopadhyay, Debprasad; Khan, Mahmud Tareq Hassan

    2008-01-01

    Herpesviruses are important human pathogens that can cause mild to severe lifelong infections with high morbidity in susceptible adults. Moreover, Herpes simplex virus (HSV) type 2, for example, has been reported to be responsible for increased transmission and disease progression of human immunodeficiency virus (HIV). Therefore, the discovery of novel anti-HSV drugs deserves great efforts. Herbal medicinal products have been used as source of putative candidate drugs in many diseases. However, in case of viral diseases the development of antivirals from natural source is less explored probably because within the virus there are few specific targets where the small molecules can interact to inhibit or kill the virus. The currently available antiherpes drugs are nucleoside analogs that did not cure the lifelong or recurrent infections and the use of these drugs often lead to the development of viral resistance coupled with the problem of side effects, recurrence and viral latency. However a wide array of herbal products, used by diverse medicinal systems throughout the world, showed high level of antiherpesvirus activities and many of them have complementary and overlapping mechanism of action, either by inhibiting viral replication, or viral genome synthesis. This chapter will summarize some of the promising herbal extracts and purified compounds isolated from the herbal sources by several laboratories. Cases with proven in vitro and documented in vivo activities, along with their structure-activity relationship against herpesviruses are discussed. PMID:18606369

  10. Isolation and characterization of a herpesvirus from feral pigeons in China.

    PubMed

    Zhao, Panpan; Ma, Jian; Guo, Ying; Tian, Li; Guo, Guangyang; Zhang, Kexin; Xing, Mingwei

    2015-12-01

    A herpesvirus was isolated during a diagnostic investigation of severe cases of conjunctivitis in feral pigeons (Columba livia f. domestica). Isolates of the virus were recovered from throat swabs of the pigeons followed by inoculation of the swab samples in chicken embryo fibroblasts. Pigeons inoculated with the isolated virus had similar clinical signs to those observed in naturally infected birds. Transmission electron microscopy revealed viral structures with typical herpesvirus morphology. Polymerase chain reaction amplification, using herpesvirus-identifying primers resulted in an amplicon of the expected size for herpesvirus. Sequencing of these amplicons and database comparisons identified the herpesvirus UL30 homologue. Phylogenetic reconstructions suggested that the isolated herpesvirus belongs to the Mardivirus genus of Alphaherpesvirinae. Using the current herpesvirus nomenclature conventions, the authors propose that the herpesvirus be named Columbid herpesvirus-1 Heilongjiang. PMID:26542366

  11. Hsp90 Inhibitors Are Efficacious against Kaposi Sarcoma by Enhancing the Degradation of the Essential Viral Gene LANA, of the Viral Co-Receptor EphA2 as well as Other Client Proteins

    PubMed Central

    Chen, Wuguo; Sin, Sang-Hoon; Wen, Kwun Wah; Damania, Blossom; Dittmer, Dirk P.

    2012-01-01

    Heat-shock protein 90 (Hsp90) inhibitors exhibit activity against human cancers. We evaluated a series of new, oral bioavailable, chemically diverse Hsp90 inhibitors (PU-H71, AUY922, BIIB021, NVP-BEP800) against Kaposi sarcoma (KS). All Hsp90 inhibitors exhibited nanomolar EC50 in culture and AUY922 reduced tumor burden in a xenograft model of KS. KS is associated with KS-associated herpesvirus (KSHV). We identified the viral latency associated nuclear antigen (LANA) as a novel client protein of Hsp90 and demonstrate that the Hsp90 inhibitors diminish the level of LANA through proteasomal degradation. These Hsp90 inhibitors also downregulated EphA2 and ephrin-B2 protein levels. LANA is essential for viral maintenance and EphA2 has recently been shown to facilitate KSHV infection; which in turn feeds latent persistence. Further, both molecules are required for KS tumor formation and both were downregulated in response to Hsp90 inhibitors. This provides a rationale for clinical testing of Hsp90 inhibitors in KSHV-associated cancers and in the eradication of latent KSHV reservoirs. PMID:23209418

  12. Convergent capture of retroviral superantigens by mammalian herpesviruses

    PubMed Central

    Aswad, Amr; Katzourakis, Aris

    2015-01-01

    Horizontal gene transfer from retroviruses to mammals is well documented and extensive, but is rare between unrelated viruses with distinct genome types. Three herpesviruses encode a gene with similarity to a retroviral superantigen gene (sag) of the unrelated mouse mammary tumour virus (MMTV). We uncover ancient retroviral sags in over 20 mammals to reconstruct their shared history with herpesviral sags, revealing that the acquisition is a convergent evolutionary event. A retrovirus circulating in South American primates over 10 million years ago was the source of sag in two monkey herpesviruses, and a different retrovirus was the source of sag in a Peruvian rodent herpesvirus. We further show through a timescaled phylogenetic analysis that a cross-species transmission of monkey herpesviruses occurred after the acquisition of sag. These results reveal that a diverse range of ancient sag-containing retroviruses independently donated sag twice from two separate lineages that are distinct from MMTV. PMID:26400439

  13. Convergent capture of retroviral superantigens by mammalian herpesviruses.

    PubMed

    Aswad, Amr; Katzourakis, Aris

    2015-01-01

    Horizontal gene transfer from retroviruses to mammals is well documented and extensive, but is rare between unrelated viruses with distinct genome types. Three herpesviruses encode a gene with similarity to a retroviral superantigen gene (sag) of the unrelated mouse mammary tumour virus (MMTV). We uncover ancient retroviral sags in over 20 mammals to reconstruct their shared history with herpesviral sags, revealing that the acquisition is a convergent evolutionary event. A retrovirus circulating in South American primates over 10 million years ago was the source of sag in two monkey herpesviruses, and a different retrovirus was the source of sag in a Peruvian rodent herpesvirus. We further show through a timescaled phylogenetic analysis that a cross-species transmission of monkey herpesviruses occurred after the acquisition of sag. These results reveal that a diverse range of ancient sag-containing retroviruses independently donated sag twice from two separate lineages that are distinct from MMTV. PMID:26400439

  14. The protective antigens of equine herpesvirus type 1.

    PubMed

    Papp-Vid, G; Derbyshire, J B

    1978-04-01

    Equine herpesvirus type 1 was cultivated in swine testis cell cultures and partially purified by differential centrifugation and centrifugation in a linear sucrose density gradient. The viral envelope was separated from the nucleocapsid by treatment with Rexol 25J followed by sucrose gradient centrifugation. The envelope and nucleocapsid preparations were then electrophoresed in polyacrylamide gel after solubilization with sodium dodecyl sulphate. Hamsters were immunized with various preparations of the partially purified virus, including live or inactivated equine herpesvirus type 1 and viral envelope and nucleocapsid, all derived from the Kentucky D strain of the virus. Challenge of the immunized hamsters, with a hamster-adapted strain of equine herpesvirus type 1 demonstrated protection only in those animals which had been vaccinated with envelope-containing materials. When vaccination was carried out with fractions of electrophoresed envelope or nucleocapsid, protection was induced only by polypeptides of high molecular weight containing a glycoprotein component of the envelope of equine herpesvirus type 1. PMID:208736

  15. Recurrent Classical Type of Kaposi's Sarcoma Treated by Interferon-alpha

    PubMed Central

    Kang, Min Ju

    2008-01-01

    Kaposi's sarcoma (KS) is a lympho-angioproliferative disease, with four variants; one of which is classical KS (CKS). Classical KS is clinically characterized by single or multiple pea-sized bluish-red macules on the distal portions of the lower extremities. A 60-year-old man presented with an asymptomatic, solitary patch on the left sole. He had been successfully treated for the classical type of Kaposi sarcoma on the right sole with interferon-alpha 3 years before. The patient was treated with six million units of interferon-alpha three times per week for 6 months. The lesion showed complete resolution and there has been no report of recurrence for 1 year after treatment. PMID:27303184

  16. Descriptive epidemiology of Kaposi sarcoma in Europe. Report from the RARECARE project.

    PubMed

    Stiller, C A; Trama, A; Brewster, D H; Verne, J; Bouchardy, C; Navarro, C; Chirlaque, M D; Marcos-Gragera, R; Visser, O; Serraino, D; Weiderpass, E; Dei Tos, A P; Ascoli, V

    2014-12-01

    Kaposi sarcoma (KS) is a virus-related malignancy which most frequently arises in skin, though visceral sites can also be involved. Infection with Kaposi sarcoma herpes virus (KSHV or HHV-8) is required for development of KS. Nowadays, most cases worldwide occur in persons who are immunosuppressed, usually because of HIV infection or as a result of therapy to combat rejection of a transplanted organ, but classic Kaposi sarcoma is predominantly a disease of the elderly without apparent immunosuppression. We analyzed 2667 KS incident cases diagnosed during 1995-2002 and registered by 75 population-based European cancer registries contributing to the RARECARE project. Total crude and age-standardized incidence rate was 0.3 per 100,000 per year with an estimated 1642 new cases per year in the EU27 countries. Age-standardized incidence rate was 0.8 per 100,000 in Southern Europe but below 0.3 per 100,000 in all other regions. The elevated rate in southern Europe was attributable to a combination of classic Kaposi sarcoma in some Mediterranean countries and the relatively high incidence of AIDS in several countries. Five-year relative survival for 2000-2002 by the period method was 75%. More than 10,000 persons were estimated to be alive in Europe at the beginning of 2008 with a past diagnosis of KS. The aetiological link with suppressed immunity means that many people alive following diagnosis of KS suffer comorbidity from a pre-existing condition. While KS is a rare cancer, it has a relatively good prognosis and so the number of people affected by it is quite large. Thus it provides a notable example of the importance of networking in diagnosis, therapy and research for rare cancers. PMID:25454979

  17. Intralesional vinblastine injections for treatment of classic Kaposi sarcoma in diabetic patients.

    PubMed

    Vassallo, Camilla; Carugno, Andrea; Derlino, Federica; Ciocca, Olga; Brazzelli, Valeria; Borroni, Giovanni

    2015-05-01

    Classic Kaposi sarcoma (KS) usually is a localized and slowly progressing disease that mainly affects elderly patients; therefore, local treatment generally is recommended. In this study, we evaluated the clinical efficacy of intralesional vinblastine (VNB) for the treatment of classic KS in 6 participants with type 2 diabetes mellitus. Results indicated that intralesional VNB injections may be an effective alternative treatment of classic KS in diabetic patients. PMID:26057517

  18. CD40 antigen is expressed by endothelial cells and tumor cells in Kaposi's sarcoma.

    PubMed Central

    Pammer, J.; Plettenberg, A.; Weninger, W.; Diller, B.; Mildner, M.; Uthman, A.; Issing, W.; Stürzl, M.; Tschachler, E.

    1996-01-01

    The CD40 antigen is a member of the tumor necrosis factor receptor/nerve growth factor receptor superfamily and is involved in cell proliferation, differentiation, and survival. Using different monoclonal antibodies, we found CD40 expression by immunohistochemistry on CD31- and CD34-positive Kaposi's sarcoma spindle cells in all tumors of 18 HIV-1 seropositive and 4 HIV-1 seronegative patients. Western blot analysis of tumor lysates detected a 48- to 50-kd glycoprotein corresponding to the CD40 antigen expressed by B lymphocytes. CD40 expression was also detectable in one of four cultures of spindle cells derived from Kaposi sarcoma tissue. Treatment of the CD40-positive spindle cells but not of the CD40-negative ones with interferon-gamma up-regulated CD40 surface expression. Besides on Kaposi sarcoma tumor cells, CD40 was distinctly present on vascular endothelial cells in areas within and adjacent to the tumors and in benign inflammatory lesions such as granulation tissue of HIV-1-negative patients. In contrast, CD34-negative endothelia of thin walled vessels, most likely lymphatics, were predominantly CD40 negative. Only faint or no CD40 expression was found on endothelial cells in normal skin. We conclude from our data that expression of the CD40 antigen by endothelial cells is up-regulated during tissue inflammation. As signaling through CD40 is able to increase cell survival, expression of CD40 by Kaposi sarcoma tumor cells might play an important role in the pathogenesis of this neoplasm. Images Figure 1 Figure 2 Figure 3 Figure 5 PMID:8623911

  19. (18)F-FDG PET/CT findings in a case with HIV (-) Kaposi sarcoma.

    PubMed

    Ozdemir, E; Poyraz, N Y; Keskin, M; Kandemir, Z; Turkolmez, S

    2014-01-01

    Although mucocutaneous sites are the most frequently encountered sites of involvement, Kaposi Sarcoma (KS) may also occasionally involve the breast and the skeletal, endocrine, urinary and nervous systems.. Various imaging modalities may be used to delineate the extent of the disease by detecting unexpected sites of involvement. Herein, we report a case of classical type KS, in whom staging with (18)F-FDG PET/CT imaging disclosed widespread disease and unexpected findings of bone and salivary gland involvement. PMID:24119549

  20. Bilateral Chest X-Ray Shadowing and Bilateral leg lesions - A case of Pulmonary Kaposi Sarcoma

    PubMed Central

    Khattak, M

    2016-01-01

    We report a case of a 30 year old gentleman seen on the respiratory ward with no significant past medical history presenting with a three week history of worsening dyspnoea, productive cough, fever, bilateral leg swelling and bilateral leg swelling. Initial differential diagnosis included community-acquired pneumonia, cellulitis and deep vein thrombosis. After much investigation a diagnosis of AIDS-related kaposi's sarcoma with visceral manifestations was made. PMID:27239297

  1. PCR detection of bovine herpesviruses from nonbovine ruminants in Hungary.

    PubMed

    Kálmán, Dóra; Egyed, László

    2005-07-01

    Polymerase chain reaction (PCR) was used to test six different nonbovine ruminant species for five bovine herpesviruses including infectious bovine rhinotracheitis virus (BoHV-1), bovine herpes mammillitis virus (BoHV-2), Movar-type herpesvirus (BoHV-4), bovine herpesvirus type 5 (BoHV-5), and alcelaphine herpesvirus 1 (AlHV-1). Species tested included 56 roe deer (Capreolus capreolus), 66 red deer (Cervus elaphus), 20 fallow deer (Dama dama), 16 mouflon (Ovis musimon), 34 domestic sheep, and 44 domestic goats, which were sampled in Hungary in 2003. Tracheal and popliteal lymph nodes collected from these animals were tested for the presence of the five bovine herpesviruses using three nested (two of which were duplex) PCR assays. Three bovine herpesviruses (BoHV-1, -2, and -4) were detected, whereas no evidence of AlHV-1 or BoHV-5 was observed. Prevalence of BoHV-1 ranged from 12% to 47%, and PCR-positive results were observed in all species tested. BoHV-2 was detected from roe deer, red deer, fallow deer, mouflon, and domestic sheep, and the prevalence in these species ranged from 3% to 50%. BoHV-4 was detected in all species, with prevalence ranging from 12% to 69%. Sequenced PCR products were 99-100% identical to bovine herpesviral sequences deposited in the GenBank. PMID:16244057

  2. Herpesviruses and Newcastle disease viruses in white storks (Ciconia ciconia).

    PubMed

    Kaleta, E F; Kummerfeld, N

    1983-01-01

    Three herpesviruses were isolated from white storks (Ciconia ciconia). All isolates reacted in cross-neutralisation tests with homologous antisera and with sera prepared against a herpesvirus from a black stork (Ciconia nigra). These data indicate serologic relatedness of the herpesviruses from both stork species. Antisera prepared against herpesviruses from the domestic chicken (viruses of Marek's disease and infectious laryngotracheitis), turkey, duck and pigeon as well as from the blue-fronted amazon (Amazona aestiva), prairie falcon (Falco mexicanus), eagle owl (Bubo bubo), Lake Victoria cormorant (Phalacrocorax melanoleucos), bobwhite quail (Colinus virginianus) and desmoiselle crane (Anthropoides virgo) did not react with the stork herpesviruses. Neutralising antibodies against stork herpesvirus were detected in the majority of 72 blood samples from white and black storks. In addition, three Newcastle disease viruses (NDV) could be isolated from white storks. One isolate was highly virulent the two others were avirulent for the chicken. Haemagglutination inhibition tests have shown that some storks have antibodies against Paramyxovirus- (PMV)-1 (NDV), PMV-2 and PMV-3. No antibodies could be detected in stork sera against PMV-4, -6 and -7. PMID:18766791

  3. Photodynamic therapy for treatment of AIDS-related mucocutaneous Kaposi's sarcoma (Invited Paper)

    NASA Astrophysics Data System (ADS)

    Schweitzer, Vanessa G.

    1992-06-01

    Since 1975, Phase I/II studies have demonstrated the successfulness of hematoporphyrin derivative photodynamic therapy (PDT) in the treatment of various malignancies of the skin, eye, bladder, lung, and head and neck. Moreover, in 1981 two cases of traditional Western cutaneous Kaposi's sarcoma (TKS) have been treated with photodynamic therapy with both early and late complete response. To date, attempts to cure and palliation of the more aggressive AIDS-related oral Kaposi's sarcoma with conventional radiation, chemotherapy or immunotherapy, or surgical excision have been limited and often associated with debilitating mucositis and further immunosuppression. Certain aspects of photodynamic therapy may be efficacious for treatment of mucocutaneous Kaposi's sarcoma: (1) the selective retention of hematoporphyrin derivative by neoplastic lesions (endothelial cell tumors); (2) a tumor- specific cytotoxic agent (i.e., free oxygen radical); (3) absence of systemic toxicity from immunosuppression; (4) the potential for retreatment without increasing side effects; and (5) porphyrin-mediated photoinactivation of enveloped viruses. Herein presented are seven cases of AIDS-related KS (EKS) with diffuse, superficial, and nodular mucocutaneous lesions treated with dihematoporphyrin derivative and photodynamic therapy with subsequent dramatic early partial and complete responses.

  4. Fluorescent Protein Approaches in Alpha Herpesvirus Research.

    PubMed

    Hogue, Ian B; Bosse, Jens B; Engel, Esteban A; Scherer, Julian; Hu, Jiun-Ruey; Del Rio, Tony; Enquist, Lynn W

    2015-11-01

    In the nearly two decades since the popularization of green fluorescent protein (GFP), fluorescent protein-based methodologies have revolutionized molecular and cell biology, allowing us to literally see biological processes as never before. Naturally, this revolution has extended to virology in general, and to the study of alpha herpesviruses in particular. In this review, we provide a compendium of reported fluorescent protein fusions to herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) structural proteins, discuss the underappreciated challenges of fluorescent protein-based approaches in the context of a replicating virus, and describe general strategies and best practices for creating new fluorescent fusions. We compare fluorescent protein methods to alternative approaches, and review two instructive examples of the caveats associated with fluorescent protein fusions, including describing several improved fluorescent capsid fusions in PRV. Finally, we present our future perspectives on the types of powerful experiments these tools now offer. PMID:26610544

  5. Fluorescent Protein Approaches in Alpha Herpesvirus Research

    PubMed Central

    Hogue, Ian B.; Bosse, Jens B.; Engel, Esteban A.; Scherer, Julian; Hu, Jiun-Ruey; del Rio, Tony; Enquist, Lynn W.

    2015-01-01

    In the nearly two decades since the popularization of green fluorescent protein (GFP), fluorescent protein-based methodologies have revolutionized molecular and cell biology, allowing us to literally see biological processes as never before. Naturally, this revolution has extended to virology in general, and to the study of alpha herpesviruses in particular. In this review, we provide a compendium of reported fluorescent protein fusions to herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) structural proteins, discuss the underappreciated challenges of fluorescent protein-based approaches in the context of a replicating virus, and describe general strategies and best practices for creating new fluorescent fusions. We compare fluorescent protein methods to alternative approaches, and review two instructive examples of the caveats associated with fluorescent protein fusions, including describing several improved fluorescent capsid fusions in PRV. Finally, we present our future perspectives on the types of powerful experiments these tools now offer. PMID:26610544

  6. Phase-Dependent Immune Evasion of Herpesviruses▿ †

    PubMed Central

    Vider-Shalit, Tal; Fishbain, Vered; Raffaeli, Shai; Louzoun, Yoram

    2007-01-01

    Viruses employ various modes to evade immune detection. Two possible evasion modes are a reduction of the number of epitopes presented and the mimicry of host epitopes. The immune evasion efforts are not uniform among viral proteins. The number of epitopes in a given viral protein and the similarity of the epitopes to host peptides can be used as a measure of the viral attempts to hide this protein. Using bioinformatics tools, we here present a genomic analysis of the attempts of four human herpesviruses (herpes simplex virus type 1-human herpesvirus 1, Epstein-Barr virus-human herpesvirus 4, human cytomegalovirus-human herpesvirus 5, and Kaposi's sarcoma-associated herpesvirus-human herpesvirus 8) and one murine herpesvirus (murine herpesvirus 68) to escape from immune detection. We determined the full repertoire of CD8 T-lymphocyte epitopes presented by each viral protein and show that herpesvirus proteins present many fewer epitopes than expected. Furthermore, the epitopes that are presented are more similar to host epitopes than are random viral epitopes, minimizing the immune response. We defined a score for the size of the immune repertoire (the SIR score) based on the number of epitopes in a protein. The numbers of epitopes in proteins expressed in the latent and early phases of infection were significantly smaller than those in proteins expressed in the lytic phase in all tested viruses. The latent and immediate-early epitopes were also more similar to host epitopes than were lytic epitopes. A clear trend emerged from the analysis. In general, herpesviruses demonstrated an effort to evade immune detection. However, within a given herpesvirus, proteins expressed in phases critical to the fate of infection (e.g., early lytic and latent) evaded immune detection more than all others. The application of the SIR score to specific proteins allows us to quantify the importance of immune evasion and to detect optimal targets for immunotherapy and vaccine development

  7. Identification of a novel herpesvirus in captive Eastern box turtles (Terrapene carolina carolina).

    PubMed

    Sim, Richard R; Norton, Terry M; Bronson, Ellen; Allender, Matthew C; Stedman, Nancy; Childress, April L; Wellehan, James F X

    2015-02-25

    Herpesviruses are significant pathogens of chelonians which most commonly cause upper respiratory tract disease and necrotizing stomatitis. Herpesvirus infection was identified in two populations of captive Eastern box turtles (Terrapene carolina carolina) using histopathology and polymerase chain reaction (PCR) with DNA sequencing. Necrotizing lesions with eosinophilic to amphophilic intranuclear inclusion bodies were identified in the tissues of one hatch-year individual in January 2013, which was herpesvirus positive by PCR. A separate captive group of adults had an observed herpesvirus prevalence of 58% using PCR in July 2011. In these cases, a novel herpesvirus, Terrapene herpesvirus 1 (TerHV1), was identified and serves as the first herpesvirus sequenced in the genus Terrapene. Similar to the other herpesviruses of the Order Testudines, TerHV1 clusters with the genus Scutavirus of the subfamily Alphaherpesvirinae. PMID:25575878

  8. Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination

    PubMed Central

    Frederico, Bruno; Chao, Brittany; Lawler, Clara; May, Janet S.

    2015-01-01

    Lymphocyte proliferation, mobility and longevity make them prime targets for virus infection. Myeloid cells that process and present environmental antigens to lymphocytes are consequently an important line of defence. Subcapsular sinus macrophages (SSMs) filter the afferent lymph and communicate with B-cells. How they interact with B-cell-tropic viruses is unknown. We analysed their encounter with murid herpesvirus-4 (MuHV-4), an experimentally accessible gammaherpesvirus related to Kaposi's sarcoma-associated herpesvirus. MuHV-4 disseminated via lymph nodes, and intranasally or subcutaneously inoculated virions readily infected SSMs. However, this infection was poorly productive. SSM depletion with clodronate-loaded liposomes or with diphtheria toxin in CD169–diphtheria toxin receptor transgenic mice increased B-cell infection and hastened virus spread to the spleen. Dendritic cells provided the main route to B-cells, and SSMs slowed host colonization, apparently by absorbing virions non-productively from the afferent lymph. PMID:25872742

  9. Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination.

    PubMed

    Frederico, Bruno; Chao, Brittany; Lawler, Clara; May, Janet S; Stevenson, Philip G

    2015-08-01

    Lymphocyte proliferation, mobility and longevity make them prime targets for virus infection. Myeloid cells that process and present environmental antigens to lymphocytes are consequently an important line of defence. Subcapsular sinus macrophages (SSMs) filter the afferent lymph and communicate with B-cells. How they interact with B-cell-tropic viruses is unknown. We analysed their encounter with murid herpesvirus-4 (MuHV-4), an experimentally accessible gammaherpesvirus related to Kaposi's sarcoma-associated herpesvirus. MuHV-4 disseminated via lymph nodes, and intranasally or subcutaneously inoculated virions readily infected SSMs. However, this infection was poorly productive. SSM depletion with clodronate-loaded liposomes or with diphtheria toxin in CD169-diphtheria toxin receptor transgenic mice increased B-cell infection and hastened virus spread to the spleen. Dendritic cells provided the main route to B-cells, and SSMs slowed host colonization, apparently by absorbing virions non-productively from the afferent lymph. PMID:25872742

  10. HERPESVIRUSES INCLUDING NOVEL GAMMAHERPESVIRUSES ARE WIDESPREAD AMONG PHOCID SEAL SPECIES IN CANADA.

    PubMed

    Bellehumeur, Christian; Nielsen, Ole; Measures, Lena; Harwood, Lois; Goldstein, Tracey; Boyle, Brian; Gagnon, Carl A

    2016-01-01

    Little is known about herpesviruses in Canadian pinnipeds. We measured prevalence of antibodies to herpesviruses in the sera from Canadian phocid seals by an indirect enzyme-linked immunosorbent assay. Wild harbor seals (Phoca vitulina) and captive harbor seals were positive for antibodies to Phocid herpesvirus 1 (PhoHV-1) at prevalences of 91% and 100%, respectively. Sera from wild hooded seals (Cystophora cristata), harp seals (Pagophilus groenlandica), and grey seals (Halichoerus grypus) were positive for antibodies to PhoHV-1 antigenically related herpesvirus antigens at 73%, 79%, and 96%, respectively. We isolated new herpesviruses in cell culture from two hunter-harvested ringed seals (Pusa hispida) in poor body condition from Ulukhaktok, Northwest Territories, Canada; one lethargic hooded seal from the St. Lawrence Estuary, Québec, Canada; and one captive, asymptomatic harp seal from the Magdalen Islands, Québec. Partial sequencing of the herpesvirus DNA polymerase gene revealed that all four virus isolates were closely related to PhoHV-2, a member of the Gammaherpesvirinae subfamily, with nucleotide similarity ranging between 92.8% and 95.3%. The new seal herpesviruses were genetically related to other known pinniped herpesviruses, such as PhoHV-1, Otariid herpesvirus 3, Hawaiian monk (Monachus schauinslandi) seal herpesvirus, and Phocid herpesvirus 5 with 47-48%, 55%, 77%, and 70-77% nucleotide similarities, respectively. The harp seal herpesvirus and both ringed seal herpesviruses were almost identical to each other, whereas the hooded seal herpesvirus was genetically different from the three others (92.8% nucleotide similarity), indicating detection of at least two novel seal herpesviruses. These findings are the first isolation, partial genome sequencing, and identification of seal gammaherpesviruses in three species of Canadian phocid seals; two species of which were suspected of exposure to one or more antigenically related herpesviruses based on

  11. Initial Detection and Molecular Characterization of Namaycush Herpesvirus (Salmonid Herpesvirus 5) in Lake Trout.

    PubMed

    Glenney, Gavin W; Barbash, Patricia A; Coll, John A

    2016-03-01

    A novel herpesvirus was found by molecular methods in samples of Lake Trout Salvelinus namaycush from Lake Erie, Pennsylvania, and Lake Ontario, Keuka Lake, and Lake Otsego, New York. Based on PCR amplification and partial sequencing of polymerase, terminase, and glycoprotein genes, a number of isolates were identified as a novel virus, which we have named Namaycush herpesvirus (NamHV) salmonid herpesvirus 5 (SalHV5). Phylogenetic analyses of three NamHV genes indicated strong clustering with other members of the genus Salmonivirus, placing these isolates into family Alloherpesviridae. The NamHV isolates were identical in the three partially sequenced genes; however, they varied from other salmonid herpesviruses in nucleotide sequence identity. In all three of the genes sequenced, NamHV shared the highest sequence identity with Atlantic Salmon papillomatosis virus (ASPV; SalHV4) isolated from Atlantic Salmon Salmo salar in northern Europe, including northwestern Russia. These results lead one to believe that NamHV and ASPV have a common ancestor that may have made a relatively recent host jump from Atlantic Salmon to Lake Trout or vice versa. Partial nucleotide sequence comparisons between NamHV and ASPV for the polymerase and glycoprotein genes differ by >5% and >10%, respectively. Additional nucleotide sequence comparisons between NamHV and epizootic epitheliotropic disease virus (EEDV/SalHV3) in the terminase, glycoprotein, and polymerase genes differ by >5%, >20%, and >10%, respectively. Thus, NamHV and EEDV may be occupying discrete ecological niches in Lake Trout. Even though NamHV shared the highest genetic identity with ASPV, each of these viruses has a separate host species, which also implies speciation. Additionally, NamHV has been detected over the last 4 years in four separate water bodies across two states, which suggests that NamHV is a distinct, naturally replicating lineage. This, in combination with a divergence in nucleotide sequence from EEDV

  12. Is human herpesvirus 8 infection more common in men than in women? Systematic review and meta-analysis.

    PubMed

    Begré, Lorin; Rohner, Eliane; Mbulaiteye, Sam M; Egger, Matthias; Bohlius, Julia

    2016-08-15

    All forms of Kaposi sarcoma (KS) are more common in men than in women. It is unknown if this is due to a higher prevalence of human herpesvirus 8 (HHV-8), the underlying cause of KS, in men compared to women. We did a systematic review and meta-analysis to examine the association between HHV-8 seropositivity and gender in the general population. Studies in selected populations like for example, blood donors, hospital patients and men who have sex with men were excluded. We searched Medline and Embase from January 1994 to February 2015. We included observational studies that recruited participants from the general population and reported HHV-8 seroprevalence for men and women or boys and girls. We used random-effects meta-analysis to pool odds ratios (OR) of the association between HHV-8 and gender. We used meta-regression to identify effect modifiers, including age, geographical region and type of HHV-8 antibody test. We included 22 studies, with 36,175 participants. Men from sub-Saharan Africa (SSA) [OR 1.21, 95% confidence interval (CI) 1.09-1.34], but not men from elsewhere (OR 0.94, 95% CI 0.83-1.06), were more likely to be HHV-8 seropositive than women (p value for interaction = 0.010). There was no difference in HHV-8 seroprevalence between boys and girls from SSA (OR 0.90, 95% CI 0.72-1.13). The type of HHV-8 assay did not affect the overall results. A higher HHV-8 seroprevalence in men than women in SSA may partially explain why men have a higher KS risk in this region. PMID:27062038

  13. HIV and human herpesvirus 8 co-infection across the globe: Systematic review and meta-analysis.

    PubMed

    Rohner, Eliane; Wyss, Natascha; Heg, Zina; Faralli, Zully; Mbulaiteye, Sam M; Novak, Urban; Zwahlen, Marcel; Egger, Matthias; Bohlius, Julia

    2016-01-01

    HIV-infection is an important risk factor for developing Kaposi sarcoma (KS), but it is unclear whether HIV-positive persons are also at increased risk of co-infection with human herpesvirus 8 (HHV-8), the infectious cause of KS. We systematically searched literature up to December 2012 and included studies reporting HHV-8 seroprevalence for HIV-positive and HIV-negative persons. We used random-effects meta-analysis to combine odds ratios (ORs) of the association between HIV and HHV-8 seropositivity and conducted random-effects meta-regression to identify sources of heterogeneity. We included 93 studies with 58,357 participants from 32 countries in sub-Saharan Africa, North and South America, Europe, Asia, and Australia. Overall, HIV-positive persons were more likely to be HHV-8 seropositive than HIV-negative persons (OR 1.99, 95% confidence interval [CI] 1.70-2.34) with considerable heterogeneity among studies (I(2) 84%). The association was strongest in men who have sex with men (MSM, OR 3.95, 95% CI 2.92-5.35), patients with hemophilia (OR 3.11, 95% CI 1.19-8.11), and children (OR 2.45, 95% CI 1.58-3.81), but weaker in heterosexuals who engage in low-risk (OR 1.42, 95% CI 1.16-1.74) or high-risk sexual behavior (OR 1.66, 95% CI 1.27-2.17), persons who inject drugs (OR 1.66, 95% CI 1.28-2.14), and pregnant women (OR 1.68, 95% CI 1.15-2.47), p value for interaction <0.001. In conclusion, HIV-infection was associated with an increased HHV-8 seroprevalence in all population groups examined. A better understanding of HHV-8 transmission in different age and behavioral groups is needed to develop strategies to prevent HHV-8 transmission. PMID:26175054

  14. Herpesvirus infections of the central nervous system in immunocompromised patients

    PubMed Central

    Strank, Cornelia

    2012-01-01

    Human herpesviruses may cause infections of the central nervous system during primary infection or following reactivation from a latent state. Especially in immunosuppressed patients the infection can take a life-threatening course, and therefore early diagnosis of herpesvirus-associated neurological diseases should have high priority. Clinical presentation in these patients is usually without typical features, making diagnosis even more challenging. Therefore general broad testing for different herpesviruses in cerebrospinal fluid samples is highly recommended. In addition, determination of the virus DNA level in the cerebrospinal fluid by quantitative assays seems to be of high importance to determine prognosis. Moreover, it might help to differentiate between specific virus-associated disease and unspecific presence of virus in the cerebrospinal fluid, especially in immunocompromised patients. Polymerase chain reaction analysis of cerebrospinal fluid has revolutionized the diagnosis of nervous system viral infections, particularly those caused by human herpesviruses. This review summarizes the role human herpesviruses play in central nervous system infections in immunocompromised patients, with a focus on the clinical manifestation of encephalitis. PMID:22973424

  15. Recent developments in anti-herpesvirus drugs.

    PubMed

    Field, Hugh J; Vere Hodge, R Anthony

    2013-01-01

    Background Herpesviruses notably establish lifelong infections, with latency and reactivation. Many of the known human herpesviruses infect large proportions of the population worldwide. Treatment or prevention of herpes infections and recurrent disease still pose a challenge in the 21st century. Sources of data Original papers and review articles, meeting abstracts, a book (Clinical Virology; DD Richman, RJ Whitley & FG Hayden eds) and company web sites. Areas of agreement For herpes simplex types 1 and 2 and for varicella zoster, acyclovir (ACV; now increasingly replaced by its prodrug valacyclovir, VACV) and famciclovir (FCV) have greatly reduced the burden of disease and have established a remarkable safety record. Drug-resistance, in the otherwise healthy population, has remained below 0.5% after more that 20 years of antiviral use. In immunocompromised patients, drug resistance is more common and alternative drugs with good safety profiles are desirable. For human cytomegalovirus disease, which occurs in immunocompromised patients, ganciclovir and increasingly its prodrug valganciclovir are the drugs of choice. However, alternative drugs, with better safety, are much needed. Areas of controversy Various questions are highlighted. Should the new 1-day therapies for recurrent herpes labialis and genital herpes replace the current standard multi-day therapies? The marked differences between VACV and FCV (e.g. triphosphate stability, effect on latency) may not yet be fully exploited? Do current antivirals reduce post-herpetic neuralgia (PHN)? For immunocompromised patients with varicella zoster virus (VZV) disease, should the first-line treatment be FCV, not ACV or VACV? Should there be more support to explore new avenues for current antivirals, for example in possibly reducing herpes latency or Alzheimer's disease (AD)? Should primary Epstein-Barr virus (EBV) disease in adolescents be treated with antivirals? How can new compounds be progressed when the

  16. Serological comparisons of antigenically related herpesviruses in cattle, red deer and goats.

    PubMed

    Nixon, P; Edwards, S; White, H

    1988-01-01

    Serological comparisons were made using related herpesviruses from cattle (bovid herpesvirus 1), red deer (herpesvirus of cervidae 1) and goats (bovid herpesvirus 6) by virus neutralization and enzyme-linked immunosorbent assays. The test samples comprised field sera from British cattle, red deer and goats and sera from experimentally infected or immunized animals. Both the cervine and caprine viruses appeared to be more closely related to bovid herpesvirus 1 than they were to each other. Cattle sera reacted most strongly with the bovine virus and deer sera with the cervine virus. Antibodies to the caprine virus were not detected in the samples from British goats. PMID:2848356

  17. Analysis of herpesvirus host specificity determinants using herpesvirus genomes as bacterial artificial chromosomes.

    PubMed

    Arii, Jun; Kato, Kentaro; Kawaguchi, Yasushi; Tohya, Yukinobu; Akashi, Hiroomi

    2009-08-01

    Almost all mammalian alphaherpesviruses can grow in cells derived from several types of animals in vitro. However, FHV-1 can only infect feline cell lines. For this reason, FHV-1 should be a good model to investigate species barriers to herpesviruses in vivo. To apply bacterial mutagenesis of FHV-1, we cloned the FHV-1 genome as a BAC. Using lambda and flp recombinations, we introduced a monomeric red fluorescence protein into the C-terminus of glycoprotein D. Although GFP in the constructed recombinant FHV-1, a transfectant of the bacmid of FHV-1 that possessed the GFP, acted in non-feline cell lines, the virus could not enter non-feline cell lines, demonstrating that the host specificity of FHV-1 was restricted in an early step of infection. The host range of canine herpesvirus is limited to dogs in vitro and in vivo; it cannot enter non-canine cell lines as a result of infection but the GFP is active by transfection, revealing the same result that the restriction step is at an early stage of infection. These results suggest the possibility of breaking species barriers of FHV-1 and CHV by modifying the gene(s) that act at the early stage of infection. PMID:19659927

  18. Investigation of Koi Herpesvirus Latency in Koi▿

    PubMed Central

    Eide, Kathleen E.; Miller-Morgan, Tim; Heidel, Jerry R.; Kent, Michael L.; Bildfell, Rob J.; LaPatra, Scott; Watson, Gregory; Jin, Ling

    2011-01-01

    Koi herpesvirus (KHV) has recently been classified as a member of the family of Alloherpesviridae within the order of Herpesvirales. One of the unique features of Herpesviridae is latent infection following a primary infection. However, KHV latency has not been recognized. To determine if latency occurs in clinically normal fish from facilities with a history of KHV infection or exposure, the presence of the KHV genome was investigated in healthy koi by PCR and Southern blotting. KHV DNA, but not infectious virus or mRNAs from lytic infection, was detected in white blood cells from investigated koi. Virus shedding was examined via tissue culture and reverse transcription-PCR (RT-PCR) testing of gill mucus and feces from six koi every other day for 1 month. No infectious virus or KHV DNA was detected in fecal secretion or gill swabs, suggesting that neither acute nor persistent infection was present. To determine if KHV latent infections can be reactivated, six koi were subjected to a temperature stress regime. KHV DNA and infectious virus were detected in both gill and fecal swabs by day 8 following temperature stress. KHV DNA was also detectable in brain, spleen, gills, heart, eye, intestine, kidney, liver, and pancreas in euthanized koi 1 month post-temperature stress. Our study suggests that KHV may become latent in leukocytes and other tissues, that it can be reactivated from latency by temperature stress, and that it may be more widespread in the koi population than previously suspected. PMID:21389134

  19. Human herpesvirus 6 and chronic fatigue syndrome

    PubMed Central

    Eymard, Daniel; Lebel, François; Miller, Mark; Turgeon, François

    1993-01-01

    The cause of chronic fatigue syndrome (CFS) is still enigmatic. Using indirect immunofluorescence testing for measuring antibody against human herpesvirus 6 (HHV-6), this study investigated the association of CFS with infection by HHV-6. Seventeen patients (group A) fulfilling the Centers for Disease Control (CDC) definition for CFS were compared with eight patients (group B) with chronic fatigue but not meeting the CDC criteria. No significant difference was found between the two groups for 30 parameters including sex, age, exposure to children and serology for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and toxoplasma. Univariate analysis showed that patients in group A complained more frequently of a sore throat, headache and of recurrent type of fatigue. These three parameters are discriminant in identifying patients who will meet the CDC case definition of CFS. The titre of antibody against HHV-6 in group A (1:99) was significantly higher than in group B (1:15) (P=0.007). Elevated HHV-6 titres suggests that this virus could be a cofactor in the pathogenesis of CFS. PMID:22346448

  20. Molecular gymnastics at the herpesvirus surface

    PubMed Central

    Rey, Félix A

    2006-01-01

    This review analyses recent structural results that provide clues about a possible molecular mechanism for the transmission of a fusogenic signal among the envelope glycoproteins of the herpes simplex virus on receptor binding by glycoprotein gD. This signal triggers the membrane-fusion machinery of the virus—contained in glycoproteins gB, gH and gL—to induce the merging of viral and cellular membranes, and to allow virus entry into target cells. This activating process parallels that of γ-retroviruses, in which receptor binding by the amino-terminal domain of the envelope protein activates the fusogenic potential of the virion in a similar way, despite the different organization of the envelope complexes of these two types of viruses. Therefore, the new structural results on the interaction of gD with its receptors might also provide insights into the mechanism of fusogenic signal transmission in γ-retroviruses. Furthermore, the fusion activation parallels with retroviruses, together with the recently reported structural homology of gB with the rhabdovirus envelope glycoprotein indicate that the complex entry apparatus of herpesviruses appears to be functionally related to that of simpler enveloped viruses. PMID:17016458

  1. Cross-regulation between herpesviruses and the TNF superfamily members

    PubMed Central

    Šedý, John R.; Spear, Patricia G.

    2008-01-01

    Herpesviruses have evolved numerous strategies to subvert host immune responses so they can coexist with their host species. These viruses ‘co-opt’ host genes for entry into host cells and then express immunomodulatory genes, including mimics of members of the tumour-necrosis factor (TNF) superfamily, that initiate and alter host-cell signalling pathways. TNF superfamily members have crucial roles in controlling herpesvirus infection by mediating the direct killing of infected cells and by enhancing immune responses. Despite these strong immune responses, herpesviruses persist in a latent form, which suggests a dynamic relationship between the host immune system and the virus that results in a balance between host survival and viral control. PMID:18949019

  2. Herpesvirus gB: A Finely Tuned Fusion Machine

    PubMed Central

    Cooper, Rebecca S.; Heldwein, Ekaterina E.

    2015-01-01

    Enveloped viruses employ a class of proteins known as fusogens to orchestrate the merger of their surrounding envelope and a target cell membrane. Most fusogens accomplish this task alone, by binding cellular receptors and subsequently catalyzing the membrane fusion process. Surprisingly, in herpesviruses, these functions are distributed among multiple proteins: the conserved fusogen gB, the conserved gH/gL heterodimer of poorly defined function, and various non-conserved receptor-binding proteins. We summarize what is currently known about gB from two closely related herpesviruses, HSV-1 and HSV-2, with emphasis on the structure of the largely uncharted membrane interacting regions of this fusogen. We propose that the unusual mechanism of herpesvirus fusion could be linked to the unique architecture of gB. PMID:26690469

  3. Directional transneuronal spread of α-herpesvirus infection

    PubMed Central

    Curanovic, D; Enquist, LW

    2010-01-01

    Most α-herpesviruses are pantropic, neuroinvasive pathogens that establish a reactivateable, latent infection in the PNS of their natural hosts. Various manifestations of herpes disease rely on extent and direction of the spread of infection between the surface epithelia and the nervous system components that innervate that surface. One aspect of such controlled spread of infection is the capacity for synaptically defined, transneuronal spread, a property that makes α-herpesviruses useful tools for determining the connectivity of neural circuits. The current understanding of intra-axonal transport and transneuronal spread of α-herpesviruses is reviewed, focusing on work with herpes simplex virus and pseudorabies virus, the available in vitro technology used to study viral transport and spread is evaluated and how certain viral mutants can be used to examine neural circuit architecture is described in this article. PMID:20161665

  4. Kaposi sarcoma in a fingolimod-treated patient with multiple sclerosis.

    PubMed

    Walker, Susan; Brew, Bruce

    2016-09-01

    Kaposi sarcoma (KS) is a vascular tumour of endothelial cell origin, associated with human herpes virus 8. It develops in one of four clinical settings, one of which is iatrogenic immunosuppression. We present the case of a 46year-old man with relapsing-remitting multiple sclerosis who developed KS in the context of fingolimod use. To our knowledge, this is the second reported case of KS in a fingolimod-treated individual. This case highlights potential risks associated with immunosuppression with this medicine and ongoing need for vigilance in assessing for such complications. PMID:27168454

  5. Maladie de kaposi classique botriomycome-like: un piège diagnostic

    PubMed Central

    Bouzidi, Hanae; Gallouj, Salim; Amraoui, Nissrine; Mernissi, Fatima Zahra; Harmouch, Taoufiq

    2014-01-01

    La maladie de kaposi (MK) botriomycome-like et une variante clinique et anatomopathologique rare de la MK, rapportée aussi bien dans la forme classique et épidémique de la MK. C'est une entité difficile à diagnostiquer car ses caractéristiques cliniques et histologiques englobent à la fois celles du botriomycome et de la MK. En plus du contexte clinique l’étude histologique et immunohistochimique restent primordiales pour établir son diagnostic. Nous rapportons un cas de MK botriomycome-like assez particulier pas sa localisation et son siège unique. PMID:25317231

  6. Kaposi Sarcoma of Childhood: Inborn or Acquired Immunodeficiency to Oncogenic HHV-8.

    PubMed

    Jackson, Carolyn C; Dickson, Mark A; Sadjadi, Mahan; Gessain, Antoine; Abel, Laurent; Jouanguy, Emmanuelle; Casanova, Jean-Laurent

    2016-03-01

    Kaposi sarcoma (KS) is an endothelial malignancy caused by human herpes virus-8 (HHV-8) infection. The epidemic and iatrogenic forms of childhood KS result from a profound and acquired T cell deficiency. Recent studies have shown that classic KS of childhood can result from rare single-gene inborn errors of immunity, with mutations in WAS, IFNGR1, STIM1, and TNFRSF4. The pathogenesis of the endemic form of childhood KS has remained elusive. We review childhood KS pathogenesis and its relationship to inherited and acquired immunodeficiency to oncogenic HHV-8. PMID:26469702

  7. Inclusion body disease (herpesvirus infection) of falcons (IBDF).

    PubMed

    Graham, D L; Mare, C J; Ward, F P; Peckham, M C

    1975-01-01

    Inclusion body disease of falcons (IBDF) is caused by a herpesvirus. The clinical course is short, 24 to 72 hours in duration, and is characterized by mild to severe depression and weakness often accompanied by anorexia. The disease is invariably fatal. The virus has a marked affinity for the reticuloendothelial system and hepatocytes,producing focal to diffuse necrosis of infected tissues accompanied by the formation of intranuclear inclusion bodies. The virus is pathogenic for American kestrels (Falco sparverius) and great horned owls (Bubo virginianus) in which typical lesions of IBDF are reproduced. The lesions of IBDF are similar to those produced by some herpesvirus infections in other avian species. PMID:163383

  8. Herpesvirus Respiratory Infections in Immunocompromised Patients: Epidemiology, Management, and Outcomes.

    PubMed

    Reid, Gail E; Lynch, Joseph P; Weigt, Samuel; Sayah, David; Belperio, John A; Grim, Shellee A; Clark, Nina M

    2016-08-01

    Among immunocompromised individuals, members of the human Herpesviridae family are frequently encountered pathogens. Cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus, Epstein-Barr virus, and human herpesvirus-6, -7, and -8 all establish latency after infection and can reactivate during periods of immunosuppression, leading to both direct and indirect adverse effects on the host including severe organ dysfunction as well as allograft rejection and loss after transplantation. While not all herpesviruses are primary respiratory pathogens, many of their manifestations include involvement of the respiratory tract. This article discusses the individual viruses, their epidemiology, and clinical manifestations as well as recommended treatment and preventive strategies. PMID:27486740

  9. Probable herpesvirus infection in an eastern cottontail (Sylvilagus floridanus).

    PubMed

    Schmidt, S P; Bates, G N; Lewandoski, P J

    1992-10-01

    One wild eastern cottontail (Sylvilagus floridanus) from Milwaukee County, Wisconsin was necropsied. The lungs contained numerous multifocal, circumscribed, tan foci; the spleen was markedly enlarged and had a mottled reddish tan color; and the brain had a red to tan friable tract in the left hemisphere. Microscopically, the lung had a severe bronchiolitis and pneumonia. The bronchiolitis was characterized by epithelial cells containing eosinophilic intranuclear inclusion bodies. The encephalomalacia of the left cerebral cortex featured tissue disruption and astrocytes or neurons containing intranuclear inclusion bodies. Herpesvirus particles were found within the bronchiolar epithelial cells. Based on histopathological and ultrastructural findings, a herpesvirus seemed the most likely etiologic agent. PMID:1335521

  10. Structure of the immediate early gene of canine herpesvirus.

    PubMed

    Miyoshi, M; Takiguchi, M; Yasuda, J; Hashimoto, A; Takada, A; Okazaki, K; Kida, H

    1999-01-01

    The nucleotide sequence of the immediate early (IE) gene of canine herpesvirus was determined. This gene was located in the inverted repeat regions, encoding a polypeptide of 1,383 amino acids. The predicted amino acid sequence was most closely related to that of the feline herpesvirus 1 IE protein among those of other alphaherpesviruses. DNA binding and transcriptional activation domains were found in the IE protein. A spliced region of the IE gene transcript was determined in its 5' non-coding region. PMID:10470264

  11. Molecular characterization and baculovirus expression of the glycoprotein B of a seal herpesvirus (phocid herpesvirus-1).

    PubMed

    Harder, T C; Osterhaus, A D

    1997-01-20

    A glycoprotein B (gB) gene homologue was identified in a 5.4-kb BamHl genomic fragment of the phocid herpesvirus type-1 (PhHV-1) which represents a widespread and important pathogen of pinnipeds. Sequence analysis revealed a gB-specific open-reading frame comprising 881 amino acids. Phylogenetic analysis gave evidence for a close evolutionary relationship between PhHV-1 and members of the Varicellovirus genus of the alpha-Herpesvirinae and canid herpesvirus in particular. In PhHV-1-infected Crandell feline kidney cells gB is expressed as a 113-kDa glycosylated molecule which is proteolytically cleaved into at least two fragments of 67 and 53-59 kDa apparently forming disulfide-linked heterodimers of 140 kDa. Cell surface expression of PhHV-1 gB was confirmed by FACS analysis. Thus, synthesis and processing of the gB protein of PhHV-1 follows a pattern also observed in other Varicelloviruses. Since the gB protein of herpesviruses, expressed in the baculovirus system, has been shown to be a suitable target for vaccine design, we used this system for expression of PhHV-1 gB. Recombinant (rec) baculovirus-expressed gB was identified as a 105-kDa glycosylated molecule. Proteolytic cleavage into fragments of 62 and 52 kDa was markedly delayed compared to wild-type (wt) gB. Wt and rec gB harbored endoglycosidase H (precursor)- as well as N-glycosidase F-sensitive N-glycans (proteolytic fragments). Baculovirus-expressed gB appeared to be antigenically authentic, since it was recognized in radioimmunoprecipitation and immune peroxidase monolayer assays by PhHV-1-neutralizing seal sera and by gB-specific neutralizing murine monoclonal antibodies. Furthermore, PhHV-1-neutralizing antibodies were induced in mice following immunization with baculovirus-expressed gB, indicating its suitability for incorporation in a candidate vaccine for seals. PMID:9018133

  12. Kaposi Sarcoma of the eyelid as an initial manifestation of AIDS.

    PubMed

    Teixeira, Ana Isabel; Neno, Miguel; Badura, Robert; Borges-Costa, João; Filipe, Paulo Leal

    2016-01-01

    Kaposi sarcoma (KS) is a multifocal systemic disease that originates in the vascular endothelium related to Human Herpes Virus 8 (HHV-8). In the early 1980s the first series of cases of disseminated Kaposi Sarcoma in HIV infected patients were reported. However, with the advent of highly active antiretroviral therapy (HAART) since 1997, these cases are less frequently observed by clinicians. We report the case of a 40-year-old woman, presenting with two asymptomatic purpuric nodules localized in the superior and inferior left eyelids, occluding the palpebral fissure, which were present for 4 months prior to presentation. The eyelid nodules were determined to represent KS, but there were no additional cutaneous lesions. Pulmonary and gastric KS involvement was documented. Antiretroviral therapy was initiated along with pegylated liposomal doxorubicin. The nodules gradually disappeared and her immune status eventually improved. Ocular and periorbital involvement of KS associated with HIV-1 infection as the initial clinical manifestations is a rare advent. This case is important as it illustrates that disseminated KS was not to be predicted by the number or the extension of cutaneous lesions. PMID:27617725

  13. Supraglottic Kaposi's Sarcoma in HIV-Negative Patients: Case Report and Literature Review

    PubMed Central

    Server, Ela A.; Durna, Yusuf M.; Yigit, Ozgur; Bozkurt, Erol R.

    2016-01-01

    This paper presents a case report of an HIV-negative, supraglottic Kaposi's sarcoma patient. The 80-year-old male patient was admitted with complaints of hoarseness, difficulty in swallowing, and a stinging sensation in his throat for approximately six months. The endoscopic larynx examination revealed a lesion which had completely infiltrated the epiglottis, reached right aryepiglottic fold, was vegetating, pink and purple in color, multilobular, fragile, and shaped like a bunch of grapes, and partially blocked the bleeding airway passage. The case was discussed by the hospital's head-neck cancer committee and a surgery decision was made. A tracheotomy was performed under local anesthesia before the operation due to respiratory distress and endotracheal intubation difficulty. Direct laryngoscopy showed that the mass was limited in the supraglottic area, had invaded the entire left aryepiglottic fold and one-third of the front right aryepiglottic fold, and completely covered epiglottis. It should be remembered that although rare, Kaposi's sarcoma may be encountered in larynx malignancy cases. Disease-free survival may be achieved through local excision and postoperative radiotherapy. PMID:27375914

  14. DISTANCE TRANSMISSION OF OVINE HERPESVIRUS 2 FROM SHEEP TO BISON

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Malignant catarrhal fever (MCF) is potentially devastating to American bison. Virtually all bison MCF cases in North America are caused by ovine herpesvirus 2 (OvHV-2), a member of the gammaherpesvirus subfamily, which is carried almost exclusively by sheep. In this communication, we report transm...

  15. The biology of bovine herpesvirus-4 infection of cattle.

    PubMed

    Thiry, E; Dubuisson, J; Bublot, M; Van Bressem, M F; Pastoret, P P

    1990-02-01

    The biology of bovine herpesvirus-4 (BHV-4) infection of cattle is reviewed. The infection is distributed worldwide. Most of isolated viruses are non-pathogenic in cattle; some of them are able to produce a genital disease. Twenty-nine structural polypeptides were described; ten of them are glycosylated. Two major glycoproteins were characterized by monoclonal antibodies. Restriction maps of BHV-4 DNA are available for the enzymes EcoRI, BamHi and HindIII. The strain variations studied by restriction analysis are very weak. The virus is able to persist in a latent state after primary infection. The identified sites of latency are nervous ganglia and mononuclear blood cells. The immune response of cattle after BHV-4 infection is characterized by low or undetectable levels of neutralizing antibodies. Four envelope proteins are recognized by convalescent sera and are the main antigenic components. Skin test remains negative in immunized cattle. Bovine herpesvirus-4 is not strictly species-specific: infection was proved in American bison (Bison bison), African buffalo (Syncerus caffer), sheep and probably cat, because feline herpesvirus-2 is in fact a BHV-4 strain. Finally BHV-4 shares antigenic and genomic relationships with alcelaphine herpesvirus-1, the causal agent of the African form of malignant catarrhal fever. PMID:2155770

  16. Tegument protein control of latent herpesvirus establishment and animation.

    PubMed

    Penkert, Rhiannon R; Kalejta, Robert F

    2011-01-01

    Herpesviruses are successful pathogens that infect most vertebrates as well as at least one invertebrate species. Six of the eight human herpesviruses are widely distributed in the population. Herpesviral infections persist for the life of the infected host due in large part to the ability of these viruses to enter a non-productive, latent state in which viral gene expression is limited and immune detection and clearance is avoided. Periodically, the virus will reactivate and enter the lytic cycle, producing progeny virus that can spread within or to new hosts. Latency has been classically divided into establishment, maintenance, and reactivation phases. Here we focus on demonstrated and postulated molecular mechanisms leading to the establishment of latency for representative members of each human herpesvirus family. Maintenance and reactivation are also briefly discussed. In particular, the roles that tegument proteins may play during latency are highlighted. Finally, we introduce the term animation to describe the initiation of lytic phase gene expression from a latent herpesvirus genome, and discuss why this step should be separated, both molecularly and theoretically, from reactivation. PMID:21429246

  17. Evolutionarily Conserved Herpesviral Protein Interaction Networks

    PubMed Central

    Fossum, Even; Friedel, Caroline C.; Rajagopala, Seesandra V.; Titz, Björn; Baiker, Armin; Schmidt, Tina; Kraus, Theo; Stellberger, Thorsten; Rutenberg, Christiane; Suthram, Silpa; Bandyopadhyay, Sourav; Rose, Dietlind; von Brunn, Albrecht; Uhlmann, Mareike; Zeretzke, Christine; Dong, Yu-An; Boulet, Hélène; Koegl, Manfred; Bailer, Susanne M.; Koszinowski, Ulrich; Ideker, Trey; Uetz, Peter; Zimmer, Ralf; Haas, Jürgen

    2009-01-01

    Herpesviruses constitute a family of large DNA viruses widely spread in vertebrates and causing a variety of different diseases. They possess dsDNA genomes ranging from 120 to 240 kbp encoding between 70 to 170 open reading frames. We previously reported the protein interaction networks of two herpesviruses, varicella-zoster virus (VZV) and Kaposi's sarcoma-associated herpesvirus (KSHV). In this study, we systematically tested three additional herpesvirus species, herpes simplex virus 1 (HSV-1), murine cytomegalovirus and Epstein-Barr virus, for protein interactions in order to be able to perform a comparative analysis of all three herpesvirus subfamilies. We identified 735 interactions by genome-wide yeast-two-hybrid screens (Y2H), and, together with the interactomes of VZV and KSHV, included a total of 1,007 intraviral protein interactions in the analysis. Whereas a large number of interactions have not been reported previously, we were able to identify a core set of highly conserved protein interactions, like the interaction between HSV-1 UL33 with the nuclear egress proteins UL31/UL34. Interactions were conserved between orthologous proteins despite generally low sequence similarity, suggesting that function may be more conserved than sequence. By combining interactomes of different species we were able to systematically address the low coverage of the Y2H system and to extract biologically relevant interactions which were not evident from single species. PMID:19730696

  18. Equid herpesvirus type 1 activates platelets.

    PubMed

    Stokol, Tracy; Yeo, Wee Ming; Burnett, Deborah; DeAngelis, Nicole; Huang, Teng; Osterrieder, Nikolaus; Catalfamo, James

    2015-01-01

    Equid herpesvirus type 1 (EHV-1) causes outbreaks of abortion and neurological disease in horses. One of the main causes of these clinical syndromes is thrombosis in placental and spinal cord vessels, however the mechanism for thrombus formation is unknown. Platelets form part of the thrombus and amplify and propagate thrombin generation. Here, we tested the hypothesis that EHV-1 activates platelets. We found that two EHV-1 strains, RacL11 and Ab4 at 0.5 or higher plaque forming unit/cell, activate platelets within 10 minutes, causing α-granule secretion (surface P-selectin expression) and platelet microvesiculation (increased small events double positive for CD41 and Annexin V). Microvesiculation was more pronounced with the RacL11 strain. Virus-induced P-selectin expression required plasma and 1.0 mM exogenous calcium. P-selectin expression was abolished and microvesiculation was significantly reduced in factor VII- or X-deficient human plasma. Both P-selectin expression and microvesiculation were re-established in factor VII-deficient human plasma with added purified human factor VIIa (1 nM). A glycoprotein C-deficient mutant of the Ab4 strain activated platelets as effectively as non-mutated Ab4. P-selectin expression was abolished and microvesiculation was significantly reduced by preincubation of virus with a goat polyclonal anti-rabbit tissue factor antibody. Infectious virus could be retrieved from washed EHV-1-exposed platelets, suggesting a direct platelet-virus interaction. Our results indicate that EHV-1 activates equine platelets and that α-granule secretion is a consequence of virus-associated tissue factor triggering factor X activation and thrombin generation. Microvesiculation was only partly tissue factor and thrombin-dependent, suggesting the virus causes microvesiculation through other mechanisms, potentially through direct binding. These findings suggest that EHV-1-induced platelet activation could contribute to the thrombosis that occurs in

  19. Columbid herpesvirus-1 mortality in great horned owls (Bubo virginianus) from Calgary, Alberta.

    PubMed

    Rose, Nicole; Warren, Amy L; Whiteside, Douglas; Bidulka, Julie; Robinson, John H; Illanes, Oscar; Brookfield, Caroline

    2012-03-01

    Four cases of Columbid herpesvirus-1 infection in great horned owls (Bubo virginianus) were identified in Calgary, Alberta. Necropsy findings included severe multifocal hepatic and splenic necrosis, pharyngeal ulceration and necrosis, and gastrointestinal necrosis. Occasional eosinophilic intranuclear viral inclusion bodies were associated with the foci of necrosis and polymerase chain reaction (PCR) testing confirmed a diagnosis of herpesvirus-induced disease. The sequence of a PCR amplicon had 99.7% homology to Columbid herpesvirus-1. PMID:22942441

  20. Columbid herpesvirus-1 mortality in great horned owls (Bubo virginianus) from Calgary, Alberta

    PubMed Central

    Rose, Nicole; Warren, Amy L.; Whiteside, Douglas; Bidulka, Julie; Robinson, John H.; Illanes, Oscar; Brookfield, Caroline

    2012-01-01

    Four cases of Columbid herpesvirus-1 infection in great horned owls (Bubo virginianus) were identified in Calgary, Alberta. Necropsy findings included severe multifocal hepatic and splenic necrosis, pharyngeal ulceration and necrosis, and gastrointestinal necrosis. Occasional eosinophilic intranuclear viral inclusion bodies were associated with the foci of necrosis and polymerase chain reaction (PCR) testing confirmed a diagnosis of herpesvirus-induced disease. The sequence of a PCR amplicon had 99.7% homology to Columbid herpesvirus-1. PMID:22942441

  1. [Antiviral action and pathogenetic targets for seaweed sulfated polysaccharides in herpesvirus infections].

    PubMed

    Besednova, N N; Makarenkova, I D; Zvyagintseva, T N; Imbs, T I; Somova, L M; Zaporozhets, T S

    2016-03-01

    The review summarizes results of studies of effects of sulfated polysaccharides from seaweed on herpesviruses and the course of herpesvirus infections. Importance of this problem is determined by the prevalence of herpesviruses that can persist in the human body and demonstrate a high degree of immune mimicry and resistance to antiviral agents. A wide range of physiological action of sulfated polysaccharides, receptor agonists of innate and adaptive immune cells, which possess potent antiviral, antioxidant and anti-inflammatory activities, open the possibility of their use for creation of new generation pharmacological substances and agents with associated activity for the treatment of herpesvirus infections. PMID:27420612

  2. Herpesvirus Telomerase RNA (vTR) with a Mutated Template Sequence Abrogates Herpesvirus-Induced Lymphomagenesis

    PubMed Central

    Kaufer, Benedikt B.; Arndt, Sina; Trapp, Sascha; Osterrieder, Nikolaus; Jarosinski, Keith W.

    2011-01-01

    Telomerase reverse transcriptase (TERT) and telomerase RNA (TR) represent the enzymatically active components of telomerase. In the complex, TR provides the template for the addition of telomeric repeats to telomeres, a protective structure at the end of linear chromosomes. Human TR with a mutation in the template region has been previously shown to inhibit proliferation of cancer cells in vitro. In this report, we examined the effects of a mutation in the template of a virus encoded TR (vTR) on herpesvirus-induced tumorigenesis in vivo. For this purpose, we used the oncogenic avian herpesvirus Marek's disease virus (MDV) as a natural virus-host model for lymphomagenesis. We generated recombinant MDV in which the vTR template sequence was mutated from AATCCCAATC to ATATATATAT (vAU5) by two-step Red-mediated mutagenesis. Recombinant viruses harboring the template mutation replicated with kinetics comparable to parental and revertant viruses in vitro. However, mutation of the vTR template sequence completely abrogated virus-induced tumor formation in vivo, although the virus was able to undergo low-level lytic replication. To confirm that the absence of tumors was dependent on the presence of mutant vTR in the telomerase complex, a second mutation was introduced in vAU5 that targeted the P6.1 stem loop, a conserved region essential for vTR-TERT interaction. Absence of vTR-AU5 from the telomerase complex restored virus-induced lymphoma formation. To test if the attenuated vAU5 could be used as an effective vaccine against MDV, we performed vaccination-challenge studies and determined that vaccination with vAU5 completely protected chickens from lethal challenge with highly virulent MDV. Taken together, our results demonstrate 1) that mutation of the vTR template sequence can completely abrogate virus-induced tumorigenesis, likely by the inhibition of cancer cell proliferation, and 2) that this strategy could be used to generate novel vaccine candidates against virus

  3. Disseminated Kaposi's Sarcoma in an HIV-Positive Patient: A Rare Entity in an Indian Patient

    PubMed Central

    Behera, Biswanath; Chandrashekar, Laxmisha; Thappa, Devinder Mohan; Toi, Pampa Ch; Vinod, Kolar Vishwanath

    2016-01-01

    AIDS-associated disseminated Kaposi sarcoma (KS) is a rare entity, especially in India due to the low prevalence of human herpes virus-8 infections in Indian population. Due to its rapid and progressive nature, early diagnosis and institution of highly active antiretroviral therapy is crucial in AIDS-associated KS, with a view to achieving favorable prognosis. We report a case of disseminated KS in an HIV-1 positive patient, who presented with two months history of multiple violaceous patches and plaques over the trunk, bilateral upper limbs, lower limbs, and hard palate. The patient died of recurrent massive pleural effusion before starting antiretroviral therapy. This case is being reported due to the paucity of KS in the Indian literature, especially the disseminated type and to highlight its rapidly progressive course which can be fatal. PMID:27293276

  4. A Challenging Case of Rapid Progressive Kaposi Sarcoma After Renal Transplantation

    PubMed Central

    Reuter, Stefan; Vrachimis, Alexis; Huss, Sebastian; Wardelmann, Eva; Weckesser, Mathias; Pavenstädt, Hermann

    2014-01-01

    Abstract De-novo malignancy is a serious posttransplant complication. While the incidence of Kaposi sarcoma (KS) is low, the time for its diagnosis is early after renal transplantation. Typically, it can be identified because of the classical skin lesion. We herein report an unusual case of rapid progressive KS without skin lesions in a 52-year-old patient leading to death within 8 months after kidney transplantation. This striking case illustrates the usefulness of [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography for demonstrating the cause of unexplained deterioration of patient’s condition. Early identification of KS is critical because early (modification of) therapy can substantially improve patient’s prognosis. PMID:25192485

  5. Kaposi sarcoma and lymphadenopathy syndrome: limitations of abdominal CT in acquired immunodeficiency syndrome

    SciTech Connect

    Moon, K.L. Jr.; Federle, M.P.; Abrams, D.I.; Volberding, P.; Lewis, B.J.

    1984-02-01

    Abdominal computed tomography (CT) was performed in 31 patients with Kaposi sarcoma (KS) related to acquired immunodeficiency syndrome (AIDS), three patients with classic KS, and 12 patients with the newly described lymphadenopathy syndrome (LNS). The frequency, distribution, and appearance of lymphadenopathy and splenomegaly were similar in the AIDS-related KS and LNS groups. Rectal and perirectal disease was identified in 86% of homosexual men studied; rectal KS could not be distinguished from proctitis on CT criteria alone. No CT abnormalities were seen in patients with classic KS. The CT demonstration of retroperitoneal, mesenteric, or pelvic adenopathy or of rectal or perirectal disease in patients with AIDS-related KS is not necessarily indicative of widespread involvement with the disease.

  6. Atypical Kaposi Sarcoma of the Tongue in HIV Positive Tanzanian Female

    PubMed Central

    Shao, Elichilia; Ruhangisa, Flora; Minja, Neema; Nnko, Kanankira; Katundu, Denis; Semango, George; Mbwilo, Eva; Mwasamwaja, Amos; Kilonzo, Kajiru; Lyaruu, Isaack

    2015-01-01

    We report atypical case of Kaposi Sarcoma (KS) in a 32-year-old human immunodeficiency virus- (HIV-) infected female, involving only the tongue. Viral loads and CD4 T cells were measured and were 65,000 cps/mL and 10 cells/mL, respectively. This patient was newly diagnosed and had no history of antiretroviral therapy (ART), radiotherapy, or immunosuppressive drugs prior to this admission. Clinically, there were no dermatological features of KS lesions which are purple, red, or brown and which may be flat, raised (plaques), or bumpy (nodules) except for fungating and protruding enlarged tongue which was necrotic. Histologically, it was proven to be the most common type of KS “epidemic” or AIDS-related KS. PMID:26664777

  7. Stable growth transformation of human T lymphocytes by herpesvirus saimiri.

    PubMed Central

    Biesinger, B; Müller-Fleckenstein, I; Simmer, B; Lang, G; Wittmann, S; Platzer, E; Desrosiers, R C; Fleckenstein, B

    1992-01-01

    Herpesvirus saimiri induces T-cell lymphomas in various species of New World monkeys and in rabbits, and it is able to immortalize monkey T lymphocytes in vitro. Sequences responsible for these effects have been localized to a region of the genome that varies significantly among the virus subgroups A, B, and C. We now report that infection of human blood lymphocytes and thymocytes with strains of subgroup C, in contrast to viruses of the other subgroups, yields continuously proliferating T-cell lines with the phenotype of mature CD4- or CD8-positive cells. Infection with strains of Herpes-virus saimiri subgroup C can thus be used to generate human T-cell lines for a variety of immunological and developmental studies. Images PMID:1313581

  8. Restriction enzyme maps of the macropodid herpesvirus 2 genome.

    PubMed

    Johnson, M A; Whalley, J M

    1987-01-01

    The DNA of macropodid herpesvirus 2 (dorcopsis wallaby herpesvirus) was analysed using restriction enzymes and molecular cloning techniques. Sets of EcoRI and SalI clones were prepared which represented approximately 85 per cent of the genome, and these clones were used to map the DNA by double-digestion and hybridization experiments. Data on uncloned regions were obtained by analysing fragments excised from agarose gels, and terminal fragments were identified by exonuclease III digestion. The genome was shown to be approximately 135 kilobases (kb) long. It has a long unique sequence (95 kb) bounded by repeat sequences (5.5 kb) and joined at one end to a short unique sequence (15 kb) also bounded by repeat sequences (7.0 kb) in a manner similar to that of herpes simplex viruses 1 and 2. PMID:2889444

  9. The haemagglutination activity of equine herpesvirus type 1 glycoprotein C.

    PubMed

    Andoh, Kiyohiko; Hattori, Shiho; Mahmoud, Hassan Y A H; Takasugi, Maaya; Shimoda, Hiroshi; Bannai, Hiroshi; Tsujimura, Koji; Matsumura, Tomio; Kondo, Takashi; Kirisawa, Rikio; Mochizuki, Masami; Maeda, Ken

    2015-01-01

    Equine herpesvirus type 1 (EHV-1) has haemagglutination (HA) activity toward equine red blood cells (RBCs), but the identity of its haemagglutinin is unknown. To identify the haemagglutinin of EHV-1, the major glycoproteins of EHV-1 were expressed in 293T cells, and the cells or cell lysates were mixed with equine RBCs. The results showed that only EHV-1 glycoprotein C (gC)-producing cells adsorbed equine RBCs, and that the lysate of EHV-1 gC-expressing cells agglutinated equine RBCs. EHV-1 lacking gC did not show HA activity. HA activity was inhibited by monoclonal antibodies (MAbs) specific for gC, but not by antibodies directed against other glycoproteins. In addition, HA activity was not inhibited by the addition of heparin. These results indicate that EHV-1 gC can bind equine RBCs irrespective of heparin, in contrast to other herpesvirus gC proteins. PMID:25456403

  10. Dyscoria associated with herpesvirus infection in owl monkeys (Aotus nancymae)

    SciTech Connect

    Gozalo, Alfonso S.; Montoya, Enrique J.; Weller, Richard E.

    2008-08-16

    Abstract Dyscoria was observed in a female owl monkey and her two offspring. A third offspring was found dead with necrohemorrhagic encephalitis. Two males paired with the female died, one of which showed oral ulcers at necropsy. Histologic examination of the oral ulcers revealed syncytia and eosinophilic intranuclear inclusion bodies in epithelial cells. Ocular examination revealed posterior synechia associated with the dyscoria in all three animals. Serum samples from the female and her offspring were positive for Herpesvirus simplex antibodies by enzyme-linked immunosorbent assay. The clinical history, gross and microscopic lesions, and serology results suggests a herpesviral etiology, possibly, H. simplex or H. saimiri-1. This report underscores the risks associated with introducing animals into breeding or research colonies that were previously kept as pets or those from unknown origin that could carry asymptomatic pathogenic Herpesvirus infections. In addition, herpesviral infection should be considered among the differential diagnoses if dyscoria is observed in nonhuman primates.

  11. Human herpesvirus-8 and other viral infections, Papua New Guinea.

    PubMed Central

    Rezza, G.; Danaya, R. T.; Wagner, T. M.; Sarmati, L.; Owen, I. L.; Monini, P.; Andreoni, M.; Suligoi, B.; Ensoli, B.; Pozio, E.

    2001-01-01

    We studied residents of remote villages and the capital (Port Moresby) of Papua New Guinea to determine the distribution of human herpesvirus-8 (HHV-8) infection. Our data suggest that HHV-8 has been endemic on the island for a long time and that the epidemiologic pattern of HHV-8 is more similar to that of herpes simplex virus-2 than hepatitis C virus. PMID:11747707

  12. Prevalence and Clinical Significance of Herpesvirus Infection in Populations of Australian Marsupials

    PubMed Central

    Stalder, Kathryn; Vaz, Paola K.; Gilkerson, James R.; Baker, Rupert; Whiteley, Pam; Ficorilli, Nino; Tatarczuch, Liliana; Portas, Timothy; Skogvold, Kim; Anderson, Garry A.; Devlin, Joanne M.

    2015-01-01

    Herpesviruses have been reported in several marsupial species, but molecular classification has been limited to four herpesviruses in macropodids, a gammaherpesvirus in two antechinus species (Antechinus flavipes and Antechinus agilis), a gammaherpesvirus in a potoroid, the eastern bettong (Bettongia gaimardi) and two gammaherpesviruses in koalas (Phascolarctos cinereus). In this study we examined a range of Australian marsupials for the presence of herpesviruses using molecular and serological techniques, and also assessed risk factors associated with herpesvirus infection. Our study population included 99 koalas (Phascolarctos cinereus), 96 eastern grey kangaroos (Macropus giganteus), 50 Tasmanian devils (Sarcophilus harrisii) and 33 common wombats (Vombatus ursinius). In total, six novel herpesviruses (one alphaherpesvirus and five gammaherpesviruses) were identified in various host species. The overall prevalence of detection of herpesvirus DNA in our study population was 27.2% (95% confidence interval (CI) of 22.6–32.2%), but this varied between species and reached as high as 45.4% (95% CI 28.1–63.7%) in common wombats. Serum antibodies to two closely related macropodid herpesviruses (macropodid herpesvirus 1 and 2) were detected in 44.3% (95% CI 33.1–55.9%) of animals tested. This also varied between species and was as high as 92% (95% CI 74.0–99.0%) in eastern grey kangaroos. A number of epidemiological variables were identified as positive predictors for the presence of herpesvirus DNA in the marsupial samples evaluated. The most striking association was observed in koalas, where the presence of Chlamydia pecorum DNA was strongly associated with the presence of herpesvirus DNA (Odds Ratio = 60, 95% CI 12.1–297.8). Our results demonstrate the common presence of herpesviruses in Australian marsupials and provide directions for future research. PMID:26222660

  13. Fifth (human parvovirus) and sixth (herpesvirus 6) diseases.

    PubMed

    Koch, W C

    2001-06-01

    Fifth (erythema infectiosum) and sixth (roseola infantum) diseases are common rash illnesses of childhood that have long been recognized in clinical medicine. The discovery of the viruses that cause these illnesses has revealed relationships with other syndromes. Primary infection with the agent of erythema infectiosum, human parvovirus B19, is associated with transient aplastic crisis in hemolytic anemia, arthropathy in adults, chronic anemia in immunocompromised patients, and nonimmune fetal hydrops in pregnant women. The only documented illness associated with primary infection with human herpesvirus 6 is roseola or exanthema subitum in young children. However, reactivated infections in adults and immunocompromised patients may be associated with serious illness such as encephalitis/encephalopathy, and bone marrow suppression leading to transplant failure or graft-versus-host disease. Diagnostic studies for both viruses have been limited, although reliable serologic tests for human parvovirus B19 have recently become available. Diagnosis of human herpesvirus 6 remains problematic, because current tests cannot differentiate primary from reactivated disease. This is more of an issue for the putative relationship of these viruses to more chronic conditions, such as rheumatologic disease for human parvovirus B19 and multiple sclerosis for human herpesvirus 6. The relationship between the viruses and these conditions remains controversial, and better diagnostic tests and further information on viral pathogenesis for both viruses are required in order to make a reliable judgment in this regard. PMID:11964854

  14. Detection and Heterogeneity of Herpesviruses Causing Pacheco's Disease in Parrots

    PubMed Central

    Tomaszewski, Elizabeth; Wilson, Van G.; Wigle, William L.; Phalen, David N.

    2001-01-01

    Pacheco's disease (PD) is a common, often fatal, disease of parrots. We cloned a virus isolate from a parrot that had characteristic lesions of PD. Three viral clones were partially sequenced, demonstrating that this virus was an alphaherpesvirus most closely related to the gallid herpesvirus 1. Five primer sets were developed from these sequences. The primer sets were used with PCR to screen tissues or tissue culture media suspected to contain viruses from 54 outbreaks of PD. The primer sets amplified DNA from all but one sample. Ten amplification patterns were detected, indicating that PD is caused by a genetically heterogeneous population of viruses. A single genetic variant (psittacid herpesvirus variant 1) amplified with all primer sets and was the most common virus variant (62.7%). A single primer set (23F) amplified DNA from all of the positive samples, suggesting that PCR could be used as a rapid postmortem assay for these viruses. PCR was found to be significantly more sensitive than tissue culture for the detection of psittacid herpesviruses. PMID:11158102

  15. Toward a Comprehensive Phylogeny for Mammalian and Avian Herpesviruses

    PubMed Central

    McGeoch, Duncan J.; Dolan, Aidan; Ralph, Adam C.

    2000-01-01

    With the aim of deriving a definitive phylogenetic tree for as many mammalian and avian herpesvirus species as possible, alignments were made of amino acid sequences from eight conserved and ubiquitously present genes of herpesviruses, with 48 virus species each represented by at least one gene. Phylogenetic trees for both single-gene and concatenated alignments were evaluated thoroughly by maximum-likelihood methods, with each of the three herpesvirus subfamilies (the Alpha-, Beta-, and Gammaherpesvirinae) examined independently. Composite trees were constructed starting with the top-scoring tree based on the broadest set of genes and supplemented by addition of virus species from trees based on narrower gene sets, to give finally a 46-species tree; branching order for three regions within the tree remained unresolved. Sublineages of the Alpha- and Betaherpesvirinae showed extensive cospeciation with host lineages by criteria of congruence in branching patterns and consistency in extent of divergence. The Gammaherpesvirinae presented a more complex picture, with both higher and lower substitution rates in different sublineages. The final tree obtained represents the most detailed view to date of phylogenetic relationships in any family of large-genome viruses. PMID:11044084

  16. Kaposi's Sarcoma

    MedlinePlus

    ... are nodular and infiltrating. While it can have aggressive skin involvement the internal involvement is usually mild. ... the age of 10 years. It has an aggressive nature and its victims usually die within 2 ...

  17. [Investigation of human herpesvirus-8 seroprevalence in blood donors and HIV-positive patients admitted to Ege University Medical School Hospital, Turkey].

    PubMed

    Altuğlu, İmre; Yolcu, Ayfer; Öcek, Zeliha Aslı; Yazan Sertöz, Rüçhan; Gökengin, Deniz

    2016-01-01

    Human herpesvirus 8 (HHV-8), classified in Herpesviridae family, is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma and multicentric Castleman's disease. In contrast to the other herpesviruses, HHV-8 seroprevalence is low in general populations; however, the higher prevalence observed in individuals with immunodeficiencies such as AIDS poses an increased risk for KS. The global distribution of HHV-8 shows great variations, with the highest seroprevalence seen in Africa. The number of studies on the seroprevalence of HHV-8 in Turkey are limited. The aim of this study was to determine the HHV-8 seroprevalences in healthy blood donors and HIV-positive patients, that will contribute HHV-8 seroepidemiological data in our country. This study was designed as a cross-sectional study. A total of 551 healthy donors (76 female, 475 male; age range: 18-65 years) admitted to Ege University Medical School Hospital, Blood Center for blood donation between December 2013-January 2014, and 173 HIV-positive patients (30 female, 143 male; age range: 18-65 years) admitted to infectious diseases outpatient clinic between October 2013-January 2014, were included in the study. A commercial ELISA method (KSHV/HHV-8 IgG ELISA Kit, Advanced Biotechnologies Inc, USA) was used for the detection of IgG antibodies that were structured against HHV-8 lytic antigens. In the study, 29 (29/551, 5.3%) of blood donors and 44 (44/173, 25.4%) of HIV-positive patients, with a total of 73 (73/724, 10.1%) cases were found as HHV-8 seropositive. The difference between blood donors and HIV-positive patients in terms of HHV-8 seropositivity rates was statistically significant (5.3% versus 25.4%; p< 0.05). In both of the study groups, no statistically significant difference was detected between HHV-8 seropositivity with gender and age. When considering HIV-positive patients, no statistically significant difference was observed between HHV-8 seropositivity with the duration of anti

  18. Palatal Actinomycosis and Kaposi Sarcoma in an HIV-Infected Subject with Disseminated Mycobacterium avium-intracellulare Infection

    PubMed Central

    Ablanedo-Terrazas, Yuria; Ormsby, Christopher E.; Reyes-Terán, Gustavo

    2012-01-01

    Actinomyces and Mycobacterium avium-intracellulare are facultative intracellular organisms, members of the bacterial order actinomycetales. Although Actinomyces can behave as copathogen when anatomic barriers are compromised, its coinfection with Mycobacterium avium-intracellulare has not previously been reported. We present the first reported case of palatal actinomycosis co-infection with disseminated MAC, in an HIV-infected subject with Kaposi sarcoma and diabetes. We discuss the pathogenesis of the complex condition of this subject. PMID:22481952

  19. Substrate specificity of three viral thymidine kinases (TK): vaccinia virus TK, feline herpesvirus TK, and canine herpesvirus TK.

    PubMed

    Solaroli, N; Johansson, M; Balzarini, J; Karlsson, A

    2006-01-01

    In search of novel suicide gene candidates we have cloned and characterized thymidine kinases from three viruses; vaccinia virus TK (VVTK), feline herpesvirus TK (FHV-TK), and canine herpesvirus TK (CHV-TK). Our studies showed that VVTK primarily is a thymidine kinase, with a substrate specificity mainly restricted to dThd and only minor affinity for dCyd. VVTK also is related closely to mammalian thymidine kinase 1 (TK1), with 66% identity and 75% general homology. Although CHV-TK and FHV-TK are sequence related to herpes simplex virus types 1 thymidine kinase (HSV1-TK), with 31% and 35% identity and a general similarity of 54%, the substrate specificity of these enzymes was restricted to dThd and thymidine analogs. PMID:17065088

  20. Acute hemorrhagic and necrotizing pneumonia, splenitis, and dermatitis in a pet rabbit caused by a novel herpesvirus (leporid herpesvirus-4)

    PubMed Central

    Brash, Marina L.; Nagy, Éva; Pei, Yanlong; Carman, Susy; Emery, Susan; Smith, Alec E.; Turner, Patricia V.

    2010-01-01

    A 1.5-year-old female rabbit (doe) was presented with a 3-day history of lethargy, anorexia, and mild facial swelling. The animal died shortly after examination and severe, acute hemorrhagic pneumonia was noted grossly. An alphaherpesvirus consistent with leporid herpesvirus-4 was isolated and characterized from this animal. This is the first confirmed report of the disease in Canada. PMID:21358932

  1. Maladie de Kaposi à localisation broncho-pulmonaire révélant une infection VIH

    PubMed Central

    Sebbar, Amal; Zaghba, Nahid; Benjelloun, Hanane; Bakhatar, Abdelaziz; Yassine, Najiba

    2015-01-01

    La maladie de Kaposi (MK) associée au VIH, forme dite épidémique, a été décrite la 1ère fois en 1981 par Hymmes. C'est l'affection maligne la plus fréquente au cours du SIDA. La MK est à l'origine de 10% des atteintes pleuropulmonaires au cours de l'infection par le VIH et 40% des pneumopathies en cas de MK cutanéomuqueuse. Les localisations pulmonaires occupent la deuxième place des atteintes viscérales après la forme digestive. Le diagnostic repose sur des arguments épidémiologiques, cliniques, radiologiques, biologiques, endoscopiques et histologiques. Nous rapportons un cas de MK broncho-pulmonaire compliquant une infection VIH chez un patient présentant une maladie de Kaposi cutanée de découverte fortuite au cours de l'atteinte pulmonaire. Le diagnostic a été retenu après avoir éliminé les maladies opportunistes à tropisme pulmonaire. Le Kaposi pulmonaire constitue l'atteinte la plus grave de la MK-sida et la survie après le diagnostic est courte malgré les thérapeutiques agressives. PMID:26958142

  2. Characterization of ovine herpesvirus 2-induced malignant catarrhal fever in rabbits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Malignant catarrhal fever (MCF) is a frequently fatal lymphoproliferative disease syndrome primarily of ruminant species, caused by gammaherpesviruses in the genus Macavirus. Ovine herpesvirus 2 (OvHV-2),carried by sheep,causes sheep-associated MCF worldwide,while Alcelaphine herpesvirus 1 (AlHV-1)...

  3. Pneumonia and gastritis in a cat caused by feline herpesvirus-1.

    PubMed

    McGregor, Glenna F; Sheehan, Karen; Simko, Elemir

    2016-02-01

    We report a case of fatal respiratory and gastric herpesvirus infection in a vaccinated, adult cat with no known immunosuppression or debilitation. The disease was characterized by severe necrotizing bronchopneumonia, fibrinonecrotic laryngotracheitis, and multifocal necrotizing gastritis associated with eosinophilic intranuclear inclusion bodies and a large amount of feline herpesvirus-1 antigen detected with immunohistochemistry. PMID:26834264

  4. Research note: isolation of a herpesvirus from a bald eagle nestling

    USGS Publications Warehouse

    Docherty, D.E.; Romaine, R.I.; Knight, R.L.

    1983-01-01

    Cloacal swabs collected from wild bald eagle nestlings (Haliaeetus leucocephalus) were tested for viruses. A virus isolated from one of these samples had a lipid coat and contained DNA. Electron microscopy confirmed that it was a herpesvirus. This appears to be the first report of a herpesvirus isolation from a wild bald eagle.

  5. Identification and characterization of the genomic termini and cleavage/packaging signals of gallid herpesvirus 2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Herpesvirus replication within host cells produces concatameric genomic DNA which is cleaved into unit-length genomes and packaged into the capsid by a complex of proteins. The sites of cleavage have been identified for many herpesviruses and conserved signaling sequences involved in cleavage and p...

  6. Identification and characterization of the genomic termini and cleavage/packaging signals of gallid herpesvirus 2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Herpesvirus replication within infected host cells results in concatameric head-to-tail genomes which are cleaved at specific sites and packaged into the viral capsid by a complex of proteins. The sites of cleavage have been characterized for a number of herpesviruses and conserved signaling sequenc...

  7. [Simplified identification and differentiation of feline, canine and phocine herpesvirus isolates using monoclonal antibodies].

    PubMed

    Harder, T C; Lebich, M; Liess, B

    1994-10-01

    Infections by alpha-herpesviruses of dogs (canid herpesvirus, CHV) and cats (felid herpesvirus, FHV) are widespread in these species and are of significant clinical relevance. Immunologically closely related herpesviruses have been isolated from harbour seals (Phoca vitulina) showing respiratory disease, hepatitis and/or encephalitis. These isolates are currently referred to as phocid herpesviruses (PhHV). The host spectrum of CHV and FHV, respectively, appears to be restricted to members of the Canidae and Felidae families. Seal herpesviruses, in contrast, cross species barriers, at least in vitro where they productively replicate also in cells of felid origin. Whether cats are susceptible to natural PhHV-infections remains to be elucidated. A reliable etiological diagnosis of acute herpesvirus-associated infections should be desirable especially in breeding kennels and zoos where hosts susceptible for FHV, CHV oder PhHV are reared. For a rapid and unambiguous identification and differentiation of herpesvirus isolates derived from felids, canids and pinnipedia a simple enzyme immunoassay employing monoclonal antibodies is presented. PMID:7855845

  8. Coinfection with Human Herpesvirus 8 Is Associated with Persistent Inflammation and Immune Activation in Virologically Suppressed HIV-Infected Patients

    PubMed Central

    Masiá, Mar; Robledano, Catalina; Ortiz de la Tabla, Victoria; Antequera, Pedro; Lumbreras, Blanca; Hernández, Ildefonso; Gutiérrez, Félix

    2014-01-01

    Objectives Infection with co-pathogens is one of the postulated factors contributing to persistent inflammation and non-AIDS events in virologically-suppressed HIV-infected patients. We aimed to investigate the relationship of human herpesvirus-8 (HHV-8), a vasculotropic virus implicated in the pathogenesis of Kaposi's sarcoma, with inflammation and subclinical atherosclerosis in HIV-infected patients. Methods Prospective study including virologically suppressed HIV-infected patients. Several blood biomarkers (highly-sensitive C-reactive protein [hsCRP], tumour necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, malondialdehyde, plasminogen activator inhibitor [PAI-1], D-dimer, sCD14, sCD163, CD4/CD38/HLA-DR, and CD8/CD38/HLA-DR), serological tests for HHV-8 and the majority of herpesviruses, carotid intima-media thickness, and endothelial function through flow-mediated dilatation of the brachial artery were measured. Results A total of 136 patients were included, 34.6% of them infected with HHV-8. HHV-8-infected patients were more frequently co-infected with herpes simplex virus type 2 (HSV-2) (P<0.001), and less frequently with hepatitis C virus (HCV) (P = 0.045), and tended to be older (P = 0.086). HHV-8-infected patients had higher levels of hsCRP (median [interquartile range], 3.63 [1.32–7.54] vs 2.08 [0.89–4.11] mg/L, P = 0.009), CD4/CD38/HLA-DR (7.67% [4.10–11.86]% vs 3.86% [2.51–7.42]%, P = 0.035) and CD8/CD38/HLA-DR (8.02% [4.98–14.09]% vs 5.02% [3.66–6.96]%, P = 0.018). After adjustment for the traditional cardiovascular risk factors, HCV and HSV-2 infection, the associations remained significant: adjusted difference between HHV-8 positive and negative patients (95% confidence interval) for hsCRP, 74.19% (16.65–160.13)%; for CD4/CD38/HLA-DR, 89.65% (14.34–214.87)%; and for CD8/CD38/HLA-DR, 58.41% (12.30–123.22)%. Flow

  9. Herpesvirus in bottlenose dolphins (Tursiops truncatus): cultivation, epidemiology, and associated pathology.

    PubMed

    van Elk, Cornelis E; van de Bildt, Marco W G; de Jong, Antonius A W; Osterhaus, Albert D M E; Kuiken, Thijs

    2009-10-01

    We studied the pathology, epidemiology, and clinical significance of genital herpesvirus infection in a zoo collection of bottlenose dolphins (Tursiops truncatus). Samples from the genital mucosa of male (n=21) and female (n=15) dolphins were tested by nested polymerase chain reaction (PCR) targeting the DNA polymerase of herpesvirus. Herpesvirus infection was significantly associated with the occurrence of mucosal plaques on penis (n=3) or vulva (n=4). Biopsies from a penile plaque showed epithelial hyperplasia by histology, contained herpesvirus-like particles by electron microscopy, and tested positive for herpesvirus by PCR. Herpesvirus was successfully cultivated from penile plaque samples and identified as a member of the Gammaherpesvirinae by DNA sequencing and phylogenetic analysis. We used the newly cultivated bottlenose dolphin herpesvirus (TTHV) to develop a direct enzyme-linked immunosorbent assay for anti-TTHV antibodies in banked sera of these dolphins. The percentage of positive samples was higher in adults (20/21, 95%) than in juveniles (7/15, 47%). Seroconversion occurred around the age of onset of sexual behavior. Although herpesvirus infection has been associated with abortion, perinatal mortality, and urogenital neoplasia in other species, we found no evidence of herpesvirus infection by PCR in tissues from six cases of abortion and perinatal mortality, and no diagnoses of urogenital tumors in 24 bottlenose dolphins from this zoo collection that died since 1990. Together, we here report the first successful cultivation from bottlenose dolphins of a herpesvirus that probably causes benign genital plaques, is endemic in this group of dolphins, and is likely transmitted by sexual contact. PMID:19901366

  10. Infectious agents in human cancers: lessons in immunity and immunomodulation from gammaherpesviruses EBV and KSHV.

    PubMed

    Taylor, Graham S; Blackbourn, David J

    2011-06-28

    Members of the herpesvirus family have evolved the ability to persist in their hosts by establishing a reservoir of latently infected cells each carrying the viral genome with reduced levels of viral protein synthesis. In order to spread within and between hosts, in some cells, the quiescent virus will reactivate and enter lytic cycle replication to generate and release new infectious virus particles. To allow the efficient generation of progeny viruses, all herpesviruses have evolved a wide variety of immunomodulatory mechanisms to limit the exposure of cells undergoing lytic cycle replication to the immune system. Here we have focused on the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) that, uniquely among the eight human herpesviruses identified to date, have growth transforming potential. Most people infected with these viruses will not develop cancer, viral growth-transforming activity being kept under control by the host's antigen-specific immune responses. Nonetheless, EBV and KSHV are associated with several malignancies in which various viral proteins, either predominantly or exclusively latency-associated, are expressed; at least some of these proteins also have immunomodulatory activities. Of these malignancies, some are the result of a disrupted virus/immune balance through genetic, infectious or iatrogenic immune suppression. Others develop in people that are not overtly immune suppressed and likely modulate the immunological response. This latter aspect of immune modulation by EBV and KSHV forms the basis of this review. PMID:21470769

  11. The UBAP1 Subunit of ESCRT-I Interacts with Ubiquitin via a SOUBA Domain

    PubMed Central

    Agromayor, Monica; Soler, Nicolas; Caballe, Anna; Kueck, Tonya; Freund, Stefan M.; Allen, Mark D.; Bycroft, Mark; Perisic, Olga; Ye, Yu; McDonald, Bethan; Scheel, Hartmut; Hofmann, Kay; Neil, Stuart J.D.; Martin-Serrano, Juan; Williams, Roger L.

    2012-01-01

    Summary The endosomal sorting complexes required for transport (ESCRTs) facilitate endosomal sorting of ubiquitinated cargo, MVB biogenesis, late stages of cytokinesis, and retroviral budding. Here we show that ubiquitin associated protein 1 (UBAP1), a subunit of human ESCRT-I, coassembles in a stable 1:1:1:1 complex with Vps23/TSG101, VPS28, and VPS37. The X-ray crystal structure of the C-terminal region of UBAP1 reveals a domain that we describe as a solenoid of overlapping UBAs (SOUBA). NMR analysis shows that each of the three rigidly arranged overlapping UBAs making up the SOUBA interact with ubiquitin. We demonstrate that UBAP1-containing ESCRT-I is essential for degradation of antiviral cell-surface proteins, such as tetherin (BST-2/CD317), by viral countermeasures, namely, the HIV-1 accessory protein Vpu and the Kaposi sarcoma-associated herpesvirus (KSHV) ubiquitin ligase K5. PMID:22405001

  12. Structured RNAs that evade or confound exonucleases: function follows form.

    PubMed

    Akiyama, Benjamin M; Eiler, Daniel; Kieft, Jeffrey S

    2016-02-01

    Cells contain powerful RNA decay machinery to eliminate unneeded RNA from the cell, and this process is an important and regulated part of controlling gene expression. However, certain structured RNAs have been found that can robustly resist degradation and extend the lifetime of an RNA. In this review, we present three RNA structures that use a specific three-dimensional fold to provide protection from RNA degradation, and discuss how the recently-solved structures of these RNAs explain their function. Specifically, we describe the Xrn1-resistant RNAs from arthropod-borne flaviviruses, exosome-resistant long non-coding RNAs associated with lung cancer metastasis and found in Kaposi's sarcoma-associated herpesvirus, and tRNA-like sequences occurring in certain plant viruses. These three structures reveal three different mechanisms to protect RNAs from decay and suggest RNA structure-based nuclease resistance may be a widespread mechanism of regulation. PMID:26797676

  13. (±)-Japonones A and B, two pairs of new enantiomers with anti-KSHV activities from Hypericum japonicum.

    PubMed

    Hu, Linzhen; Zhu, Hucheng; Li, Lei; Huang, Jinfeng; Sun, Weiguang; Liu, Junjun; Li, Hua; Luo, Zengwei; Wang, Jianping; Xue, Yongbo; Zhang, Yu; Zhang, Yonghui

    2016-01-01

    Two pairs of new enantiomers with unusual 5,5-spiroketal cores, termed (±)-japonones A and B [(±)-1 and (±)-2], were obtained from Hypericum japonicum Thunb. The absolute configurations of (±)-1 and (±)-2 were characterized by extensive analyses of spectroscopic data and calculated electronic circular dichroism (ECD) spectra, the application of modified Mosher's methods, and the assistance of quantum chemical predictions (QCP) of (13)C NMR chemical shifts. Among these metabolites, (+)-1 exhibited some inhibitory activity on Kaposi's sarcoma associated herpesvirus (KSHV). Virtual screening of (±)-1 and (±)-2 were conducted using the Surflex-Dock module in the Sybyl software, and (+)-1 exhibited ability to bind with ERK to form key interactions with residues Lys52, Pro56, Ile101, Asp165, Gly167 and Val99. PMID:27270221

  14. Chapter 15. Co-immunoprecipitation techniques for assessing RNA-protein interactions in vivo.

    PubMed

    Conrad, Nicholas K

    2008-01-01

    From the moment a nascent transcript emerges from an RNA polymerase until its ultimate destruction, an RNA is bound by proteins that govern its fate. Thus, in order to understand posttranscriptional regulation of gene expression, it is essential to ascertain which proteins bind a given RNA in vivo. This chapter describes three immunoprecipitation-based assays designed to query the in vivo makeup of RNA-protein complexes. Two of these, UV cross-linking and RNA immunoprecipitation (RIP), include cross-linking steps that trap complexes formed in vivo. A third, a cell mixing experiment, verifies that an interaction occurs in vivo by controlling for RNA-protein association subsequent to cell lysis. Using these protocols, this chapter presents evidence that the abundant nuclear RNA-binding protein hnRNP C interacts with the Kaposi's sarcoma-associated herpesvirus polyadenylated nuclear RNA in vivo. PMID:19215765

  15. Tousled-like kinases modulate reactivation of gammaherpesviruses from latency.

    PubMed

    Dillon, Patrick J; Gregory, Sean M; Tamburro, Kristen; Sanders, Marcia K; Johnson, Gary L; Raab-Traub, Nancy; Dittmer, Dirk P; Damania, Blossom

    2013-02-13

    Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to human malignancies. The majority of tumor cells harbor latent virus, and a small percentage undergo spontaneous lytic replication. Both latency and lytic replication are important for viral pathogenesis and spread, but the cellular players involved in the switch between the two viral life-cycle phases are not clearly understood. We conducted a small interfering RNA (siRNA) screen targeting the cellular kinome and identified Tousled-like kinases (TLKs) as cellular kinases that control KSHV reactivation from latency. Upon treatment of latent KSHV-infected cells with siRNAs targeting TLKs, we saw robust viral reactivation. Knockdown of TLKs in latent KSHV-infected cells induced expression of viral lytic proteins and production of infectious virus. TLKs were also found to play a role in regulating reactivation from latency of another related oncogenic gammaherpesvirus, Epstein-Barr virus. Our results establish the TLKs as cellular repressors of gammaherpesvirus reactivation. PMID:23414760

  16. At a crossroads: human DNA tumor viruses and the host DNA damage response.

    PubMed

    Nikitin, Pavel A; Luftig, Micah A

    2011-07-01

    Human DNA tumor viruses induce host cell proliferation in order to establish the necessary cellular milieu to replicate viral DNA. The consequence of such viral-programmed induction of proliferation coupled with the introduction of foreign replicating DNA structures makes these viruses particularly sensitive to the host DNA damage response machinery. In fact, sensors of DNA damage are often activated and modulated by DNA tumor viruses in both latent and lytic infection. This article focuses on the role of the DNA damage response during the life cycle of human DNA tumor viruses, with a particular emphasis on recent advances in our understanding of the role of the DNA damage response in EBV, Kaposi's sarcoma-associated herpesvirus and human papillomavirus infection. PMID:21927617

  17. Emmprin and KSHV: new partners in viral cancer pathogenesis

    PubMed Central

    Dai, Lu; Bai, Lihua; Lu, Ying; Xu, Zengguang; Reiss, Krys; Valle, Luis Del; Kaleeba, Johnan; Toole, Bryan P.; Parsons, Chris; Qin, Zhiqiang

    2013-01-01

    Emmprin (CD147; basigin) is a multifunctional glycoprotein expressed at higher levels by cancer cells and stromal cells in the tumor microenvironment. Through direct effects within tumor cells and promotion of tumor-stroma interactions, emmprin participates in induction of tumor cell invasiveness, angiogenesis, metastasis and chemoresistance. Although its contribution to cancer progression has been widely studied, the role of emmprin in viral oncogenesis still remains largely unclear, and only a small body of available literature implicates emmprin-associated mechanisms in viral pathogenesis and tumorigenesis. We summarize these data in this review, focusing on the role of emmprin in pathogenesis associated with the Kaposi sarcoma-associated herpesvirus (KSHV), a common etiology for cancers arising in the setting of immune suppression. We also discuss future directions for mechanistic studies exploring roles for emmprin in viral cancer pathogenesis. PMID:23743354

  18. Localization of latency-associated nuclear antigen (LANA) on mitotic chromosomes.

    PubMed

    Rahayu, Retno; Ohsaki, Eriko; Omori, Hiroko; Ueda, Keiji

    2016-09-01

    In latent infection of Kaposi's sarcoma-associated herpesvirus (KSHV), viral gene expression is extremely limited and copy numbers of viral genomes remain constant. Latency-associated nuclear antigen (LANA) is known to have a role in maintaining viral genome copy numbers in growing cells. Several studies have shown that LANA is localized in particular regions on mitotic chromosomes, such as centromeres/pericentromeres. We independently examined the distinct localization of LANA on mitotic chromosomes during mitosis, using super-resolution laser confocal microscopy and correlative fluorescence microscopy-electron microscopy (FM-EM) analyses. We found that the majority of LANA were not localized at particular regions such as telomeres/peritelomeres, centromeres/pericentromeres, and cohesion sites, but at the bodies of condensed chromosomes. Thus, LANA may undergo various interactions with the host factors on the condensed chromosomes in order to tether the viral genome to mitotic chromosomes and realize faithful viral genome segregation during cell division. PMID:27254595

  19. Laboratory and clinical aspects of human herpesvirus 6 infections.

    PubMed

    Agut, Henri; Bonnafous, Pascale; Gautheret-Dejean, Agnès

    2015-04-01

    Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of

  20. Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

    PubMed Central

    Bonnafous, Pascale; Gautheret-Dejean, Agnès

    2015-01-01

    SUMMARY Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and

  1. Lymphoid hyperplasia and lymphoma in KSHV K1 transgenic mice.

    PubMed

    Berkova, Zuzana; Wang, Shu; Sehgal, Lalit; Patel, Keyur Pravinchandra; Prakash, Om; Samaniego, Felipe

    2015-05-01

    Growing evidence supports the involvement of human herpervirus 8, Kaposi's sarcoma associated herpesvirus (KSHV), in the pathology of primary effusion lymphoma, multicentric Castleman's disease, and Kaposi's sarcoma, but the exact mechanism of KSHV contribution to the oncogenic process remains elusive. We studied transgenic mice expressing the ORF K1 of KSHV, whose position in the KSHV genome corresponds to known lymphoproliferative genes of other herpesviruses. K1 protein was previously shown to contain a constitutively active ITAM domain, involved in activation of Akt and pro-survival signaling, and to inhibit Fas-mediated apoptosis by interfering with binding of FasL. All this pointed to a possible role of K1 in the pathogenesis of KSHV-associated cancers. K1 transgenic mice (80-90%) developed lymphoid hyperplasia and splenomegaly at 8 and 10 months of age, 25% had confirmed diagnosis of lymphoma, and 50% developed abdominal and/or hepatic tumors by 18 months of age. Histological examination showed loss of splenic architecture and increased cellularity. Lymph nodes showed disrupted architecture with effaced follicles and other pathological changes, including signs of angiofollicular lymphoid hyperplasia. One of the livers showed signs of angiosarcoma. In summary, our histology results revealed pathological changes in K1 transgenic mice similar to lymphoma, Castleman's disease, and angiosarcoma, suggesting that K1 may contribute to the development of KSHV-associated cancers. PMID:25301266

  2. Primary effusion lymphoma presenting as a cutaneous intravascular lymphoma

    PubMed Central

    Crane, Genevieve M.; Xian, Rena R.; Burns, Kathleen H.; Borowitz, Michael J.; Duffield, Amy S.; Taube, Janis M.

    2015-01-01

    Primary effusion lymphoma (PEL) is a rare and aggressive lymphoma that arises in the context of immunosuppression and is characterized by co-infection with Epstein–Barr virus (EBV) and human herpesvirus-8/Kaposi sarcoma-associated herpesvirus (HHV-8/KSHV). It was originally described as arising in body cavity effusions, but presentation as a mass lesion (extracavitary PEL) is now recognized. Here, we describe a case of PEL with an initial presentation as an intravascular lymphoma with associated skin lesions. The patient was a 53-year-old man with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) who presented with fevers, weight loss and skin lesions concerning for Kaposi sarcoma (KS). A skin biopsy revealed no evidence of KS; however, dermal vessels contained large atypical cells that expressed CD31 and plasma cell markers but lacked most B- and T-cell antigens. The atypical cells expressed EBV and HHV-8. The patient subsequently developed a malignant pleural effusion containing the same neoplastic cell population. The findings in this case highlight the potential for unusual intravascular presentations of PEL in the skin as well as the importance of pursuing microscopic diagnosis of skin lesions in immunosuppressed patients. PMID:25355615

  3. Trends in Kaposi's Sarcoma in Miami Beach from 1987 to 2007

    PubMed Central

    Zeichner, Simon B.; Ruiz, Ana L.; Suciu, Gabriel P.; Zeichner, Rachel Lerner; Rodriguez, Estelamari

    2012-01-01

    Purpose. Kaposi's sarcoma (KS) is a rare low-grade vascular tumor associated with the human herpes virus 8. By analyzing the epidemiology, staging, and treatment of KS, we hoped to improve the quality of care at our institution. Methods. Review of the Mount Sinai Medical Center tumor registry database in Miami Beach, FL, USA, identified 143 cases of KS between January 1, 1987 and December 31, 2007. Results. The majority of patients were non-Hispanic whites, non smoking males diagnosed between 1987 and 1996. Most of the patients were HIV positive, with an equal percentage diagnosed with local or distant disease. Most patients received no chemotherapy or radiation. There were no significant differences in patient survival based on sex, HIV status, or radiation received. There was a trend toward improved survival among older patients who smoked, received no chemotherapy, and had localized stage at diagnosis. Multivariate analysis revealed that non-Hispanic whites had a significant worse survival than Hispanic whites (HR = 0.55, 95% CI (0.33, 0.90), P = 0.02). Patients diagnosed between 1987 and 1996 had a worse survival than those between 1997 and 2007 (HR = 0.33 (95% CI 0.19, 0.55), P < 0.0001). Conclusion. This large retrospective study provides further insight into KS. Ethnicity and date of diagnosis are important predictors of long-term survival. PMID:23320191

  4. Pharyngolaryngeal location of Kaposi's sarcoma with airway obstruction in an HIV-negative patient.

    PubMed

    Torretta, Sara; Gaffuri, Michele; Recalcati, Sebastiano; Marzano, Angelo Valerio; Cantarella, Giovanna; Iofrida, Elisabetta; Pignataro, Lorenzo

    2013-01-01

    Kaposi's sarcoma (KS) is a human herpes virus-8 (HHV-8)-associated angioproliferative disorder, and its occurrence may be favored by human immunodeficiency virus (HIV) infection and iatrogenic immunosuppression. It has also been postulated that a chronic inflammatory disease of the skin can pave the way to its development. KS generally involves mucosal and cutaneous sites, including the head and neck. An oropharyngeal location is quite common, but laryngeal involvement with possible upper airway obstruction and respiratory distress requiring tracheotomy is rare, and no hypopharyngeal locations have yet been reported. We describe the case of a 68-year-old male patient who developed KS after immunosuppressive treatment for pemphigus vulgaris, an autoimmune bullous disease presenting with blisters and erosions on the skin and the oral mucosa. KS was initially localized to the oral cavity and oropharynx, but subsequent involvement of the laryngeal and hypopharyngeal tract led to acute airway obstruction and the need for tracheotomy. This unique case of pharyngolaryngeal KS suggests that clinicians faced with purple nodular lesions should consider a differential diagnosis of KS in immunocompromised patients, even if they are HIV negative, and should carefully manage the patency of the upper airways. PMID:24362871

  5. Gastrointestinal Bleeding and Diffuse Skin Thickening as Kaposi Sarcoma Clinical Presentation

    PubMed Central

    Querido, Sara; Sousa, Henrique Silva; Pereira, Tiago Assis; Birne, Rita; Matias, Patrícia; Jorge, Cristina; Weigert, André; Adragão, Teresa; Bruges, Margarida; Machado, Domingos

    2015-01-01

    A 56-year-old African patient received a kidney from a deceased donor with 4 HLA mismatches in April 2013. He received immunosuppression with basiliximab, tacrolimus, mycophenolate mofetil, and prednisone. Immediate diuresis and a good allograft function were soon observed. Six months later, the serum creatinine level increased to 2.6 mg/dL. A renal allograft biopsy revealed interstitial fibrosis and tubular atrophy grade II. Toxicity of calcineurin inhibitor was assumed and, after a switch for everolimus, renal function improved. However, since March 2014, renal function progressively deteriorated. A second allograft biopsy showed no new lesions. Two months later, the patient was admitted due to anuria, haematochezia with anaemia, requiring 5 units of packed red blood cells, and diffuse skin thickening. Colonoscopy showed haemorrhagic patches in the colon and the rectum; histology diagnosis was Kaposi sarcoma (KS). A skin biopsy revealed cutaneous involvement of KS. Rapid clinical deterioration culminated in death in June 2014. This case is unusual as less than 20 cases of KS with gross gastrointestinal bleeding have been reported and only 6 cases had the referred bleeding originating in the lower gastrointestinal tract. So, KS should be considered in differential diagnosis of gastrointestinal bleeding in some kidney transplant patients. PMID:26783491

  6. Immunihistochemical detection of Bcl-2 in AIDS-associated and classical Kaposi's sarcoma.

    PubMed Central

    Morris, C. B.; Gendelman, R.; Marrogi, A. J.; Lu, M.; Lockyer, J. M.; Alperin-Lea, W.; Ensoli, B.

    1996-01-01

    Kaposi's Sarcoma (KS) is an angioproliferative disease that is characterized by proliferation of spindle-shaped cells predominantly of vascular endothelial cell origin, neoangiogenesis, inflammatory cell infiltration, and edema. Although the lesions of classical KS and AIDS-associated KS (AIDS-KS) share common histological features, AIDS-KS occurs at a markedly higher frequency with a more aggressive clinical course. Immunohistochemical analyses of 26 evolutionarily staged AIDS-KS lesions derived from HIV-infected patients demonstrate significant cytoplasmic levels of Bcl-2, a protooncogene known to prolong cellular viability and to antagonize apoptosis. Bcl-2 expression increases as the pathological stage of KS advances. Immunohistochemical analyses of classical KS lesions demonstrate prevalent expression of Bcl-2 as well, indicating that upregulation of Bcl-2 may be important in the pathogenesis of both classical and AIDS-associated KS. Coexpression of Bcl-2 and factor VIII-related antigen in spindle-shaped cells present within KS lesions suggests that Bcl-2 is upregulated within the vascular endothelial spindle-shaped cells of KS. The consequences of upregulated Bcl-2 expression within KS lesions may be prolonged spindle cell viability which, when coupled with dysregulated cellular proliferation due in part to synergistic activities of inflammatory and angiogenic cytokines and HIV-1 Tat protein, may result in the maintenance, growth, and progression of KS. Images Figure 1 Figure 2 Figure 3 PMID:8644847

  7. Maladie de kaposi classique avec atteinte surrénalienne: un nouveau cas

    PubMed Central

    Bouzidi, Hanae; Gallouj, Salim; Krich, Sanae; Mernissi, Fatima Zahra

    2014-01-01

    La maladie de kaposi est une pathologie connue généralement dans sa forme épidémique associée au sida ou celle endémique présente dans l'Afrique subsaharienne. La forme classique de cette maladie ou dite également méditerranéenne n'est pas bien connue étant assez rare. Elle touche les hommes âgés HIV séronégatifs originaires de l'Europe centrale, l'Europe de l'Est et les méditerranéens. Elle se manifeste essentiellement par une atteinte cutanée, éventuellement muqueuse mais l'atteinte viscérale reste moins fréquente, dominée par l'atteinte osseuse, pulmonaire et gastrique. La localisation surrénalienne est inhabituelle et très rare. Nous rapportons ce nouveau cas pour mettre le point sur cette pathologie rare et signaler cette localisation atypique. PMID:25170378

  8. Characteristics of HIV-1-associated Kaposi's sarcoma among women and men in South Africa.

    PubMed

    Mosam, A; Hurkchand, H P; Cassol, E; Page, T; Cassol, S; Bodasing, U; Aboobaker, J; Dawood, H; Friedland, G H; Coovadia, H M

    2008-06-01

    Despite the increase of HIV-1-associated Kaposi's sarcoma (KS), little is known about HIV-associated KS in the African setting, particularly among women. A descriptive study of the demographic, clinical, immunological and virological features of AIDS-associated KS from KwaZulu-Natal, South Africa was undertaken. Consecutively, recruited patients were clinically staged; CD4/CD8 cell counts, HIV-1 viral loads and clinical parameters were evaluated. Of the 152 patients (77 male and 75 female) 99% were black. Females were significantly younger (P = 0.02) and had poorer disease prognosis (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.4-5.4, P = 0.003) and were more likely to have extensive cutaneous KS when compared with males (OR = 3.1, 95% CI = 1.4-6.7, P = 0.003). One-third of patients had coexisting HIV-related disease, most commonly tuberculosis, and these were more frequent in females (56.7 vs. 43.3%). In conclusion, HIV-associated KS in South Africans has an equal female-to-male ratio. Females are younger and have more severe disease than males. PMID:18595878

  9. Gastrointestinal Bleeding and Diffuse Skin Thickening as Kaposi Sarcoma Clinical Presentation.

    PubMed

    Querido, Sara; Sousa, Henrique Silva; Pereira, Tiago Assis; Birne, Rita; Matias, Patrícia; Jorge, Cristina; Weigert, André; Adragão, Teresa; Bruges, Margarida; Machado, Domingos

    2015-01-01

    A 56-year-old African patient received a kidney from a deceased donor with 4 HLA mismatches in April 2013. He received immunosuppression with basiliximab, tacrolimus, mycophenolate mofetil, and prednisone. Immediate diuresis and a good allograft function were soon observed. Six months later, the serum creatinine level increased to 2.6 mg/dL. A renal allograft biopsy revealed interstitial fibrosis and tubular atrophy grade II. Toxicity of calcineurin inhibitor was assumed and, after a switch for everolimus, renal function improved. However, since March 2014, renal function progressively deteriorated. A second allograft biopsy showed no new lesions. Two months later, the patient was admitted due to anuria, haematochezia with anaemia, requiring 5 units of packed red blood cells, and diffuse skin thickening. Colonoscopy showed haemorrhagic patches in the colon and the rectum; histology diagnosis was Kaposi sarcoma (KS). A skin biopsy revealed cutaneous involvement of KS. Rapid clinical deterioration culminated in death in June 2014. This case is unusual as less than 20 cases of KS with gross gastrointestinal bleeding have been reported and only 6 cases had the referred bleeding originating in the lower gastrointestinal tract. So, KS should be considered in differential diagnosis of gastrointestinal bleeding in some kidney transplant patients. PMID:26783491

  10. Initial lesions of HIV-related Kaposi's sarcoma--a histological, immunohistochemical, and ultrastructural study.

    PubMed

    Schulze, H J; Rütten, A; Mahrle, G; Steigleder, G K

    1987-01-01

    Kaposi's sarcoma (KS) in human immunodeficiency virus infection (HIV) has become a rather frequent manifestation of the previously rare disease with fatal outcome. Initial lesions of KS were studied by means of histopathology, immunohistology, and electron microscopy in order to define the earliest alterations. The histopathological changes of initial lesions were distinct, consisting of (1) discrete proliferation of capillary vessels, (2) dissection of collagen by proliferating spindle cells which formed slits, (3) atypical spindle cells arranged in an Indian file pattern, and (4) the lack of any inflammatory cellular infiltrate. Double staining with antibodies against vimentin and immunohistochemical markers for endothelial cells revealed that slits forming vimentin-positive spindle cells displayed laminin, factor VIII, and PAL-E. Atypical vimentin-positive spindle cells arranged in an Indian file pattern inconsistently expressed laminin and factor VIII, but not PAL-E. KS cells rarely stained with the lectin UEA I, not even in case of less advanced dedifferentiation. Electron microscopy showed gradual transformation between spindle cells forming slits and those having lost the ability to form incomplete vessel walls. The present findings support the view that KS develops from the endothelial cells of the blood vessels. The proliferation of atypical endothelial cells as early as in initial lesions and the lack of inflammation favors the primary neoplastic genesis of KS. PMID:3324975

  11. Kaposi's sarcoma following allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia.

    PubMed

    de Medeiros, B C; Rezuke, W N; Ricci, A; Tsongalis, G; Shen, P U; Bona, R D; Feingold, J M; Edwards, R L; Tutschka, P J; Bilgrami, S

    2000-01-01

    Unlike solid organ transplantation, Kaposi's sarcoma (KS) occurs rarely following hematopoietic stem cell transplantation (HSCT). In fact, only 5 cases of KS have been reported after allogeneic or autologous HSCT. The usual treatment combines a substantial decrease in, or elimination of, immunosuppressive therapy along with local measures such as surgical excision, cryotherapy or radiation therapy. A 46-year-old woman with chronic myelogenous leukemia who had received an allogeneic HSCT previously from an HLA-identical sibling, presented on day +814 with human herpes virus-8-associated KS involving her left lower extremity. She had been on continuous immunosuppressive therapy since her transplant because of chronic graft-versus-host disease. The intensity of immunosuppressive therapy was decreased once a diagnosis of KS had been established. However, the nodular lesions continued to progress in size and number. Therefore, a course of irradiation was administered to sites of bulk disease on her legs. Furthermore, thalidomide was initiated along with a topical retinoid, alitretinoin 0.1% gel applied twice daily to the nonirradiated lesions. This approach yielded a partial response in both irradiated and nonirradiated lesions over the course of the following 7 months. Both thalidomide and alitretinoin 0.1% gel appear to be beneficial in HSCT-associated KS and exhibit tolerable side effects. PMID:11154986

  12. Suspected metastatic adrenocortical carcinoma revealing as pulmonary Kaposi sarcoma in adrenal Cushing’s syndrome

    PubMed Central

    2014-01-01

    Background Kaposi sarcoma (KS) is a malignant disease most commonly diagnosed in the setting of a human immunodeficiency virus (HIV) infection and in patients receiving immunosuppressive treatment. Pulmonary KS has never been reported in association with endogenous Cushing’s syndrome (CS). Case presentation A 60-year-old woman presented with symptoms and signs of CS. Adrenal CS was confirmed by standard biochemical evaluation. Imaging revealed a right adrenal lesion (diameter 3.5 cm) and multiple pulmonary nodules, suggesting a cortisol-secreting adrenal carcinoma with pulmonary metastases. The patient underwent right adrenalectomy with a pathohistological diagnosis of an adrenal adenoma. Subsequent thoracoscopic wedge resection of one lung lesion revealed pulmonary KS with positive immunostaining for human herpes virus 8 (HHV-8). HIV-serology was negative. Hydrocortisone replacement was initiated for secondary adrenal insufficiency after surgery. Post-operative follow up imaging showed complete remission of all KS-related pulmonary nodules solely after resolution of hypercortisolism. Conclusion KS may occur in the setting of endogenous CS and may go into remission after cure of hypercortisolism without further specific treatment. PMID:25077599

  13. African Kaposi's sarcoma in the light of global AIDS: antiblackness and viral visibility.

    PubMed

    Singh, Pawan; Cartwright, Lisa; Visperas, Cristina

    2014-12-01

    Drawing on the theoretical frameworks of antiblackness and intersectionality and the concept of viral visibility, this essay attends to the considerable archive of research about endemic Kaposi's sarcoma (KS) in sub-Saharan Africa accrued during the mid-20th century. This body of data was inexplicably overlooked in Western research into KS during the first decade of the AIDS epidemic, during which period European and Mediterranean KS cases were most often cited as precedents despite the volume of African data available. This paper returns to the research on KS conducted in Africa during the colonial and postcolonial period to consider visibility, racial erasure, and discourses of global epidemiology, suggesting that the dynamics of medical research on HIV/AIDS have proceeded according to a tacit paradigm of antiblackness manifest in multiple exclusions of Africa from global health agendas--most recently the exclusion of the region from antiretroviral (ARV) drug therapy during the first decades of the treatment's availability. During that decade KS all but disappeared among people with access to ARV therapy while KS became even more prevalent in sub-Saharan Africa, escalating along with HIV. PMID:25304011

  14. Kaposi's sarcoma with HHV8 infection and ANCA-associated vasculitis in a hemodialysis patient.

    PubMed

    Fatma, Lilia Ben; Rais, Lamia; Mebazza, Amel; Azzouz, Haifa; Beji, Somaya; Krid, Madiha; Smaoui, Wided; Maiz, Hedi Ben; Zouaghi, Karim; Zitouna, Moncef; Osmane, Amel Ben; Moussa, Fatma Ben

    2013-11-01

    The association between Kaposi's sarcoma (KS) and human herpes virus eight (HHV-8) infection is rarely reported in hemodialysis (HD) patients. We report here the rare association of KS, HHV-8 and hepatitis C virus (HCV) infection as well as syphilis in a HD patient. We report the case of a 72-year-old woman who presented with microscopic polyangiitis with alveolar hemorrhage and pauci-immune necrosing and crescentic glomerulonephritis as well as renal failure requiring HD. Biological tests showed positive HCV and syphilis tests. The patient was treated by HD and intravenous pulse, followed by oral corticosteroids and six cyclophosphamide monthly pulses with remission of the alveolar hemorrhage, but without renal functional recovery as the patient remained HD dependent. Five months after the first treatment administration, she developed extensive purpuric lesions on her lower limbs, abdomen face and neck. A skin biopsy showed KS. The HHV-8 test was positive, with positive polymerase chain reaction-HHV8 in the serum and skin. After immunosuppression withdrawal, the KS skin lesions regressed rapidly without relapse after 12 months of follow-up, but alveolar hemorrhage relapsed after 16 months of follow-up. Our case showed that the immunosuppressed state related to multiple factors such as aging, vasculitis, HHV-8, HCV, syphilis, immunosuppressive therapy and HD may all have contributed to the development of KS in our patient. PMID:24231484

  15. Coordinated and sequential transcription of the cyprinid herpesvirus-3 annotated genes.

    PubMed

    Ilouze, Maya; Dishon, Arnon; Kotler, Moshe

    2012-10-01

    Cyprinid herpesvirus-3 (CyHV-3) is the cause of a fatal disease in carp and koi fish. The disease is seasonal and appears when water temperatures range from 18 to 28°C. CyHV-3 is a member of the Alloherpesviridae, a family in the Herpesvirales order that encompasses mammalian, avian and reptilian viruses. CyHV-3 is a large double-stranded DNA (dsDNA) herpesvirus with a genome of approximately 295kbp, divergent from other mammalian, avian and reptilian herpesviruses, but bearing several genes similar to cyprinid herpesvirus-1 (CyHV-1), CyHV-2, anguillid herpesvirus-1 (AngHV-1), ictalurid herpesvirus-1 (IcHV-1) and ranid herpes virus-1 (RaHV-1). Here we show that viral DNA synthesis commences 4-8h post-infection (p.i.), and is completely inhibited by pre-treatment with cytosine β-d-arabinofuranoside (Ara-C). Transcription of CyHV-3 genes initiates after infection as early as 1-2h p.i., and precedes viral DNA synthesis. All 156 annotated open reading frames (ORFs) of the CyHV-3 genome are transcribed into RNAs, most of which can be classified into immediate early (IE or α), early (E or β) and late (L or γ) classes, similar to all other herpesviruses. Several ORFs belonging to these groups are clustered along the viral genome. PMID:22841491

  16. A novel herpesvirus associated with respiratory disease in Bourke's parrots (Neopsephotus bourkii).

    PubMed

    Shivaprasad, H L; Phalen, D N

    2012-12-01

    A novel herpesvirus infection in nine Bourke's parrots (Neopsephotus bourkii, formerly Neophema bourkii) housed in an outdoor aviary comprised of multiple species of birds was diagnosed based on histopathology, electron microscopy and polymerase chain reaction (PCR). Clinical signs in the parrots included anorexia, ruffled feathers, depression, loss of weight and respiratory distress. The most common gross lesions were moderately congested and oedematous lungs and a mild fibrinous exudate in the air sacs and lumen of the trachea. Histological examination revealed mild to severe bronchopneumonia and airsacculitis with syncytial cells containing eosinophilic intranuclear inclusion bodies in most birds. Other less frequent changes included tracheitis, syringitis, sinusitis, rhinitis, otitis media and conjunctivitis. Attempts to culture the virus in chicken embryos and chicken embryo liver cells were unsuccessful. Examination by transmission electron microscopy of syncytial cells from the lungs of two birds revealed intranuclear virus particles typical of the family Herpesviridae. DNA from a novel herpesvirus was amplified from lung tissue by PCR using degenerate primers derived from conserved avian herpesvirus sequences. The virus belongs in the genus Iltovirus of the Alphaherpesvirinae subfamily. It is not closely related to Psittacid herpesvirus 1 that causes Pacheco's disease but does group phylogenetically with a clade of herpesviruses that cause respiratory disease in a number of avian species. The proposed name for this herpesvirus is Psittacid herpesvirus 3. PMID:23237365

  17. Papiine herpesvirus 2 as a Predictive Model for Drug Sensitivity of Macacine herpesvirus 1 (Monkey B Virus)

    PubMed Central

    Brush, Lauren A; Black, Darla H; McCormack, Kimberly A; Maxwell, Lara K; Wright, George; Ritchey, Jerry W; Payton, Mark E; Eberle, Richard

    2014-01-01

    Monkey B virus (Macacine herpesvirus 1; BV) is endemic in macaques. BV (a BSL4 agent) is the primary zoonotic concern for persons working with macaques in research, and human BV infections frequently are fatal. We assessed the use of a BSL2 baboon herpesvirus (Papiine herpesvirus 1; HVP2) for predicting the drug sensitivity of BV by comparing the sensitivity of the 2 viruses to 12 antiherpetic drugs. Plaque reduction assays showed that 4 drugs (HBPG, BVdU, PFA, and BrdU) were ineffective against both viruses. Of the 8 effective drugs, both viruses were most sensitive to TFT, whereas sensitivity to the remaining 7 drugs varied between BV and HVP2 as well as between strains of HVP2. In addition, the efficacy of 5 drugs (ACV, PCV, GCV, CDV, and EDU) was tested by using a murine model. ACV and EDU were completely ineffective against both HVP2 and BV, and high doses of PCV only delayed death by a few days. GCV and CDV both protected mice against death, and CDV also prevented the development of neurologic symptoms. When the initiation of drug therapy was delayed until after virus gained access to the CNS, both GCV and CDV were ineffective. The similarity of the drug sensitivities of HVP2 and BV in both models validates the use of HVP2 as a BSL2 level model that can be used to predict drug sensitivity of BV. The greater efficacy of CDV relative to GCV suggests the potential for use of CDV in the treatment of zoonotic BV infections. PMID:25402179

  18. Prevention and control of herpesvirus diseases. Part 2. Epidemiology and immunology.

    PubMed

    1985-01-01

    This is the second of two articles summarizing the information currently available on herpes virus diseases. The first described the different members of the herpesvirus group, clinical expression of infection, laboratory diagnosis, and chemotherapy. This article dealing with the epidemiological and immunological aspects of herpesvirus infections also brings up the special problems caused by virus latency and risks associated with congenital infection and immunodeficiency or immunodepressive treatment. The prospects of preventing herpesvirus infections by vaccination and treatment with immune sera are also discussed. PMID:2994897

  19. Histone Deacetylases in Herpesvirus Replication and Virus-Stimulated Host Defense

    PubMed Central

    Guise, Amanda J.; Budayeva, Hanna G.; Diner, Benjamin A.; Cristea, Ileana M.

    2013-01-01

    Emerging evidence highlights a critical role for protein acetylation during herpesvirus infection. As prominent modulators of protein acetylation, histone deacetylases (HDACs) are essential transcriptional and epigenetic regulators. Not surprisingly, viruses have evolved a wide array of mechanisms to subvert HDAC functions. Here, we review the mechanisms underlying HDAC regulation during herpesvirus infection. We next discuss the roles of acetylation in host defense against herpesvirus infection. Finally, we provide a perspective on the contribution of current mass spectrometry-based “omic” technologies to infectious disease research, offering a systems biology view of infection. PMID:23807710

  20. Regulation of the retinoblastoma proteins by the human herpesviruses

    PubMed Central

    Hume, Adam J; Kalejta, Robert F

    2009-01-01

    Viruses are obligate intracellular parasites that alter the environment of infected cells in order to replicate more efficiently. One way viruses achieve this is by modulating cell cycle progression. The main regulators of progression out of G0, through G1, and into S phase are the members of the retinoblastoma (Rb) family of tumor suppressors. Rb proteins repress the transcription of genes controlled by the E2F transcription factors. Because the expression of E2F-responsive genes is required for cell cycle progression into the S phase, Rb arrests the cell cycle in G0/G1. A number of viral proteins directly target Rb family members for inactivation, presumably to create an environment more hospitable for viral replication. Such viral proteins include the extensively studied oncoproteins E7 (from human papillomavirus), E1A (from adenovirus), and the large T (tumor) antigen (from simian virus 40). Elucidating how these three viral proteins target and inactivate Rb has proven to be an invaluable approach to augment our understanding of both normal cell cycle progression and carcinogenesis. In addition to these proteins, a number of other virally-encoded inactivators of the Rb family have subsequently been identified including a surprising number encoded by human herpesviruses. Here we review how the human herpesviruses modulate Rb function during infection, introduce the individual viral proteins that directly or indirectly target Rb, and speculate about what roles Rb modulation by these proteins may play in viral replication, pathogenesis, and oncogenesis. PMID:19146698

  1. Clinical and laboratory features of human herpesvirus 6 chromosomal integration.

    PubMed

    Clark, D A

    2016-04-01

    Human herpesvirus 6 (HHV-6) comprises two separate viruses, HHV-6A and HHV-6B, although this distinction is not commonly made. HHV-6B is ubiquitous in the population with primary infection usually occurring in early childhood, and often resulting in febrile illness. HHV-6B is also recognized as a pathogen in the immunocompromised host, particularly in transplant recipients. HHV-6A is less well characterized and may have a more restricted prevalence. Both viruses are unique among the human herpesviruses in that the entire viral genome can be found integrated into the telomeric regions of host cell chromosomes. Approximately 1% of persons have inherited integrated viral sequences through the germline, and these individuals characteristically have very high viral loads in blood and other sample types. Emerging evidence suggests that HHV-6A and HHV-6B chromosomal integration may not just be an uncommon biological observation, but more likely a characteristic of the replication properties of these viruses. The integrated viral genome appears capable of excision from the chromosomal site and potentially allows viral replication. The clinical consequences of inherited chromosomally integrated HHV-6 have yet to be fully appreciated. PMID:26802216

  2. Pathogenesis of Herpesvirus sylvilagus infection in cottontail rabbits.

    PubMed

    Hesselton, R M; Yang, W C; Medveczky, P; Sullivan, J L

    1988-12-01

    Experimental infection with Herpesvirus sylvilagus produces clinical and histopathologic changes in its natural host, the cottontail rabbit (Sylvilagus floridanus), similar to those observed in humans acutely infected with Epstein-Barr virus (EBV). Twenty-seven seronegative cottontail rabbits were infected with Herpesvirus sylvilagus and all developed antibodies within 10 days. Neutralizing antibody was detected as early as 7 days after infection. Virus was isolated from blood mononuclear cells, spleen, bone marrow, thymus, lymph nodes, kidneys, lung, and liver as early as 3 days after infection. Infected animals showed leucocytosis, monocytosis, and lymphocytosis with the appearance of atypical lymphocytes. Peripheral blood abnormalities peaked at 10-14 days after infection, and returned to normal by 28 days after infection, with the exception of atypical lymphocytosis that persisted in some animals for more than 2 years after experimental infection. More severe histopathologic changes were seen in virus-infected juvenile rabbits than adult rabbits; these changes included viral myocarditis, interstitial pneumonia, and lymphocytic myositis. Reactive hyperplasia and subsequent lymphocytic depletion of spleen and lymph nodes were reminiscent of that seen in virus-associated hemophagocytosis syndrome. Prominent lymphoid hyperplasia of many nonlymphoid organs, most notably the kidney and lungs, was observed. The development of these lymphoproliferative lesions and other lymphoid changes during H. sylvilagus infection suggest that this system may be a model to study similar lesions induced by EBV infection in humans. PMID:2849303

  3. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection

    PubMed Central

    MacDuff, Donna A; Reese, Tiffany A; Kimmey, Jacqueline M; Weiss, Leslie A; Song, Christina; Zhang, Xin; Kambal, Amal; Duan, Erning; Carrero, Javier A; Boisson, Bertrand; Laplantine, Emmanuel; Israel, Alain; Picard, Capucine; Colonna, Marco; Edelson, Brian T; Sibley, L David; Stallings, Christina L; Casanova, Jean-Laurent; Iwai, Kazuhiro; Virgin, Herbert W

    2015-01-01

    Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies. DOI: http://dx.doi.org/10.7554/eLife.04494.001 PMID:25599590

  4. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection.

    PubMed

    MacDuff, Donna A; Reese, Tiffany A; Kimmey, Jacqueline M; Weiss, Leslie A; Song, Christina; Zhang, Xin; Kambal, Amal; Duan, Erning; Carrero, Javier A; Boisson, Bertrand; Laplantine, Emmanuel; Israel, Alain; Picard, Capucine; Colonna, Marco; Edelson, Brian T; Sibley, L David; Stallings, Christina L; Casanova, Jean-Laurent; Iwai, Kazuhiro; Virgin, Herbert W

    2015-01-01

    Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies. PMID:25599590

  5. Mutation hot spots in the canine herpesvirus thymidine kinase gene.

    PubMed

    Yamada, Shinya; Matsumoto, Yasunobu; Takashima, Yasuhiro; Otsuka, Haruki

    2005-08-01

    The guanine and cytosine content (GC-content) of alpha-herpesvirus genes are highly variable despite similar genome structures. It is known that drug resistant HSV, which has the genome with a high GC-content (approximately 70%), commonly includes frameshift mutations in homopolymer stretches of guanine (G) and cytosine (C) within the thymidine kinase (TK) gene. However, whether such mutation hotspots exist in the TK gene of canine herpesvirus (CHV) which has a low GC-content was unknown. In this study, we investigated mutations in the TK gene of CHV. CHV was passaged in the presence of iodo-deoxyuridine (IDU), and IDU-resistant clones were isolated. In all IDU-resistant virus clones, mutations in the TK gene were observed. The majority of these mutations were frameshift mutations of an adenine (A) insertion or deletion within either of 2 stretches of eight A's in the TK gene. It was demonstrated that CHV TK mutations frequently occur at a limited number of hot spots within long homopolymer nucleotide stretches. PMID:15965615

  6. Experimental Feline Herpesvirus Infection in the Pregnant Cat

    PubMed Central

    Hoover, Edward A.; Griesemer, Richard A.

    1971-01-01

    Intravenous inoculation of pregnant cats with feline herpesvirus produced minimal illness but resulted in abortion, intrauterine fetal death and congenital fetal infection. Placental lesions included multiple infarcts in the placental labyrinth, thrombosis of maternal vessels in the endometrium and placenta, and multifocal necrosis of the giant-cell trophoblast and endometrial epithelium in the junctional zone of the placenta associated with eosinophilic intranuclear inclusion bodies. The virus was isolated from all the placentas and uteri but from none of the fetuses aborted 6-9 days after maternal intravenous inoculation. Viral antigen was demonstrated in the uterine vessels and in the junctional zone of the placenta at this time. On postinoculation day 26, viral antigen was demonstrated in the chorioallantoic membrane on the fetal side of the placenta and in the liver of a congenitally infected fetus. Although all 4 pregnant cats inoculated intranasally with feline herpesvirus aborted, neither virus, viral antigen nor significant lesions were detected in the uteri, placentas or fetuses. Abortion after intranasal inoculation was interpreted as a nonspecific reaction secondary to the severe, debilitating upper respiratory disease that occurred. ImagesFig 1Fig 2Fig 7Fig 8Fig 9Fig 3Fig 4Fig 5Fig 6 PMID:4328861

  7. Isolated penile Kaposi's sarcoma in a HIV-positive patient stable on treatment for three years.

    PubMed

    Lebari, Dornubari; Gohil, Jesal; Patnaik, Lipsita; Wasef, Wafaa

    2014-07-01

    Kaposi's sarcoma (KS) is an AIDS-defining condition. Typically, KS affects the skin with or without visceral involvement. The extensive use of antiretroviral therapy (ART) has decreased the incidence of KS amongst the HIV-positive population. We report a case of a 40-year-old man with HIV-1 infection with CD4 count of 551 cells/mm(3)and an undetectable viral load who presented with two skin-coloured KS lesions on the prepuce of the penis. Diagnosis was confirmed by histopathology. He had been commenced on ART three years earlier with a nadir CD4 count of 255 cells/mm(3) He had achieved and maintained viral suppression since commencing ART. The patient was initially treated with cryotherapy and 5% imiquimod as the lesions were presumed to be warts. The lack of response to treatment prompted further investigation. We carried out a literature search of published cases of penile KS over the past 10 years. The majority of articles regarding penile KS were published in the pre-ART era and involved patients with AIDS. Over the past 10 years, published cases of penile KS have almost exclusively been in HIV-negative men. We found 10 published cases of penile KS in HIV-negative men and only one other published case of penile KS in a HIV-positive man, who had severe immune suppression with CD4 count below 200 cells/mm(3) This is the first case report to describe a HIV-positive patient stable on ART with a CD4 count above 200 cells/mm(3)and suppressed HIV-1 viral load, to develop two KS lesions on the penis. Clinicians have to remain suspicious of penile lesions and appreciate the crucial role a biopsy with histopathological analysis plays in confirming a diagnosis. In addition, this case illustrates that unusual presentations of KS can still occur in treated HIV-positive patients with sustained immune recovery. PMID:24492851

  8. Phase II Trial of Imatinib in AIDS-Associated Kaposi's Sarcoma: AIDS Malignancy Consortium Protocol 042

    PubMed Central

    Koon, Henry B.; Krown, Susan E.; Lee, Jeannette Y.; Honda, Kord; Rapisuwon, Suthee; Wang, Zhenghe; Aboulafia, David; Reid, Erin G.; Rudek, Michelle A.; Dezube, Bruce J.; Noy, Ariela

    2014-01-01

    Purpose Kaposi's sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection. In a pilot study, imatinib, a c-kit/PDGF-receptor inhibitor, induced partial regression of AIDS-associated KS (AIDS-KS) in five of 10 patients. Patients and Methods This multicenter phase II study was designed to estimate the response rate to imatinib in AIDS-KS. Secondary objectives included investigation of predictors of response and imatinib pharmacokinetics in patients on antiretrovirals. Patients received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at 3 months if their disease was stable. Results Thirty patients were treated at 12 AIDS Malignancy Consortium sites. Ten patients (33.3%) achieved partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression. Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks. Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism. Activating mutations in PDGF-R and c-kit were not found at baseline or at disease progression. We found no correlation with response with changes in any of the candidate cytokines. Conclusion Imatinib has activity in AIDS-KS. Pharmacokinetic interactions with antiretroviral drugs did not correlate with toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest imatinib is well tolerated and may be an alternative therapy for some patients with AIDS-KS. PMID:24378417

  9. Accuracy of Clinical Suspicion and Pathologic Diagnosis of Kaposi Sarcoma in East Africa

    PubMed Central

    Woodruff, Carina Martin; Forrestel, Amy; Wenger, Megan; McCalmont, Timothy; LeBoit, Philip; Maurer, Toby; Laker-Oketta, Miriam; Muyindike, Winnie; Bwana, Mwebesa; Buziba, Nathan; Busakhala, Naftali; Wools-Kaloustian, Kara; Martin, Jeffrey

    2016-01-01

    Background: HIV-associated Kaposi sarcoma (KS) is one of the most common malignancies in sub-Saharan Africa. The diagnosis is often based on clinical suspicion, without histopathologic confirmation. When biopsies are performed, the accuracy of interpretation by local pathologists is poorly understood. We assessed the accuracy of clinical suspicion and pathologic diagnosis of KS in 2 East African countries. Methods: At 2 large HIV care sites in Uganda and Kenya, we evaluated consecutive biopsies performed from October 2008 to January 2013 on HIV-infected adults with clinically suspected KS. Biopsies were interpreted by both local African pathologists and a group of US-based dermatopathologists from a high volume medical center. For the purpose of this analysis, the US-based dermatopathologist interpretation was used as the gold standard. Positive predictive value was used to characterize accuracy of local African clinical suspicion of KS, and concordance, sensitivity, and specificity were used to characterize accuracy of local pathologic diagnosis. Results: Among 1106 biopsies, the positive predictive value of clinical suspicion of KS was 77% (95% confidence interval: 74% to 79%). When KS was not histopathologically diagnosed, clinically banal conditions were found in 35%, medically significant disorders which required different therapy in 59% and life-threatening diseases in 6%. Concordance between African pathologists and US-based dermatopathologists was 69% (95% confidence interval: 66% to 72%). Sensitivity and specificity of African pathologic diagnoses were 68% and 89%, respectively. Conclusions: Among East African HIV-infected patients, we found suboptimal positive predictive value of clinical suspicion of KS and specific, but not sensitive, histopathologic interpretation. The findings call for abandonment of isolated clinical diagnosis of KS in the region and augmentation of local dermatopathologic services. PMID:26452066

  10. Mustelid herpesvirus-2, a novel herpes infection in northern sea otters (Enhydra lutris kenyoni).

    PubMed

    Tseng, Marion; Fleetwood, Michelle; Reed, Aimee; Gill, Verena A; Harris, R Keith; Moeller, Robert B; Lipscomb, Thomas P; Mazet, Jonna A K; Goldstein, Tracey

    2012-01-01

    Oral ulcerations and plaques with epithelial eosinophilic intranuclear inclusions were observed in northern sea otters (Enhydra lutris kenyoni) that died or were admitted for rehabilitation after the 1989 Exxon Valdez oil spill (EVOS) in Alaska, USA. Transmission electron microscopy demonstrated the presence of herpesviral virions. Additionally, a serologic study from 2004 to 2005 found a high prevalence of exposure to a herpesvirus in live-captured otters. Tissues from 29 otters after the EVOS and nasal swabs from 83 live-captured otters in the Kodiak Archipelago were tested for herpesviral DNA. Analysis identified a novel herpesvirus in the gamma subfamily, most closely related to Mustelid herpesvirus-1 from badgers. Results indicated that this herpesvirus is associated with ulcerative lesions but is also commonly found in secretions of healthy northern sea otters. PMID:22247388

  11. Human herpesvirus 7 is a constitutive inhabitant of adult human saliva.

    PubMed Central

    Wyatt, L S; Frenkel, N

    1992-01-01

    We report the frequent isolation of human herpesvirus 7 from the saliva of healthy adults. Virus isolates recovered from different individuals exhibited minimal restriction enzyme polymorphism, which was mostly confined to heterogeneous (het) sequences in the genome. DNAs of isolates recovered from the same individual over a period of several months showed the same characteristic het fragments, indicating the stability of the het sequences upon virus replication and shedding in vivo. In contrast to the results of previous reports, human herpesvirus 6, the causative agent of roseola infantum, could not be isolated from the saliva specimens, raising questions regarding oral transmission of human herpesvirus 6 and human herpesvirus 7 to young children. Images PMID:1348548

  12. In vitro inhibition of caprine herpesvirus 1 by acyclovir and mizoribine.

    PubMed

    Elia, G; Camero, M; Decaro, N; Lovero, A; Martella, V; Tempesta, M; Buonavoglia, C; Crescenzo, G

    2015-04-01

    Caprine herpesvirus 1 (CpHV-1) infection in goats induces genital vesicular-ulcerative lesions that strictly resemble the lesions induced by herpesvirus 2 in the human host. The immunosuppressive drug Mizoribine (MIZ) was found to increase the antiviral activity of Acyclovir (ACV) against herpesvirus infections, raising interesting perspectives on new combined therapeutic strategies. In this study the anti-CpHV-1 activity in vitro of ACV alone or in combination with MIZ was characterized. When applied alone at non-toxic concentrations, ACV had a slight effect on CpHV-1 replication while in combination with MIZ a dose-dependent inhibition of the virus yield was observed with an IC50 of ACV of 28.5 µM. These findings suggest that combined therapy of ACV and MIZ is potentially exploitable in the treatment of genital infection by herpesviruses. PMID:25660402

  13. The Equine Herpesvirus 2 E1 Open Reading Frame Encodes a Functional Chemokine Receptor

    PubMed Central

    Camarda, Grazia; Spinetti, Gaia; Bernardini, Giovanni; Mair, Catherine; Davis-Poynter, Nick; Capogrossi, Maurizio C.; Napolitano, Monica

    1999-01-01

    Several herpesviruses contain open reading frames (ORFs) that encode potential homologs of eucaryotic genes. Equine herpesvirus 2 (EHV-2) is a gammaherpesvirus related to other lymphotropic herpesviruses such as herpesvirus saimiri and Epstein-Barr virus. The E1 ORF of EHV-2, a G protein-coupled receptor homolog, shows 31 to 47% amino acid identity with known CC chemokine receptors. To investigate whether E1 may encode a functional receptor, we cloned the E1 ORF and expressed it in stably transfected cell lines. We report here the identification of the CC chemokine eotaxin as a functional ligand for the EHV-2 E1 receptor. Chemokines are likely to play a role in the regulation of immune functions in equine hosts during EHV-2 infection and, via interaction with E1, may affect viral replication and/or escape from immune responses. PMID:10559296

  14. Complete Genome Sequence of Reticuloendotheliosis Virus Strain MD-2, Isolated from a Contaminated Turkey Herpesvirus Vaccine

    PubMed Central

    Li, Junping; Yang, Chenghuai; Li, Qihong; Li, Huijiao; Xia, Yecai; Liu, Dan

    2013-01-01

    Here, we present the complete genomic sequence of a reticuloendotheliosis virus (REV) isolated from a contaminated turkey herpesvirus (HVT) vaccine. This report will be helpful for epidemiological studies on REV infection in avian flocks. PMID:24092783

  15. Survival of a cat with pneumonia due to cowpox virus and feline herpesvirus infection.

    PubMed

    Johnson, M S; Martin, M; Stone, B; Hetzel, U; Kipar, A

    2009-09-01

    Cowpox virus infection in cats is rare and usually leads to cutaneous lesions alone. Pulmonary infection and pneumonia have been documented occasionally but all such cases described to date have been fatal. Although usually affecting the upper respiratory tract, feline herpesvirus can also induce pneumonia. The present report describes the case of a cat that recovered from a pneumonia in which both poxvirus and feline herpesvirus were demonstrated. PMID:19769672

  16. Immunofluorescent Detection of Herpesvirus Antigens in Exfoliated Cells from Human Cervical Carcinoma

    PubMed Central

    Royston, Ivor; Aurelian, Laure

    1970-01-01

    Exfoliated cells from patients with squamous carcinoma of the cervix contain antigens related to herpesvirus subtype 2, as revealed by direct or indirect immunofluorescent techniques. Normal squamous cells from the same subjects and from controls without the disease, and cells from a small number of tumors at sites other than the cervix, did not react with anti-herpesvirus subtype 2 serum. Antisera to adenovirus 18 or mycoplasma orale did not react with the exfoliated cells. Images PMID:4318779

  17. A Gateway recombination herpesvirus cloning system with negative selection that produces vectorless progeny.

    PubMed

    Kunec, Dusan; van Haren, Sandra; Burgess, Shane C; Hanson, Larry A

    2009-01-01

    Crossover recombination based on the lambda phage integration/excision functions enables insertion of a gene of interest into a specific locus by a simple one-step in vitro recombination reaction. Recently, a highly efficient recombination system for targeted mutagenesis, which utilizes lambda phage crossover recombination cloning, has been described for a human herpesvirus 2 bacterial artificial chromosome (BAC). The disadvantages of the system are that it allows only neutral selection (loss of green fluorescent protein) of desired recombinants and that it regenerates herpesvirus progeny containing the BAC sequence inserted in the herpesvirus genome. In this study, the existing channel catfish herpesvirus (CCV) infectious clone (in the form of overlapping fragments) was modified to allow introduction of foreign genes by modified lambda phage crossover recombination cloning. This novel system enables negative and neutral selection and regenerates vectorless herpesvirus progeny. Construction of two CCV mutants expressing lacZ, one from the native CCV ORF5 promoter and the other from the immediate-early cytomegalovirus promoter, demonstrated the efficiency and reliability of this system. This novel cloning system enables rapid incorporation, direct delivery and high-level expression of foreign genes by a herpesvirus. This system has broad utility and could be used to facilitate development of recombinant viruses, viral vectors and better vaccines. PMID:18948138

  18. Isolation of a new herpesvirus from human CD4+ T cells.

    PubMed Central

    Frenkel, N; Schirmer, E C; Wyatt, L S; Katsafanas, G; Roffman, E; Danovich, R M; June, C H

    1990-01-01

    A new human herpesvirus has been isolated from CD4+ T cells purified from peripheral blood mononuclear cells of a healthy individual (RK), following incubation of the cells under conditions promoting T-cell activation. The virus could not be recovered from nonactivated cells. Cultures of lymphocytes infected with the RK virus exhibited a cytopathic effect, and electron microscopic analyses revealed a characteristic herpesvirus structure. RK virus DNA did not hybridize with large probes derived from herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, and human cytomegalovirus. The genetic relatedness of the RK virus to the recently identified T-lymphotropic human herpesvirus 6 (HHV-6) was investigated by restriction enzyme analyses using 21 different enzymes and by blot hybridization analyses using 11 probes derived from two strains of HHV-6 (Z29 and U1102). Whereas the two HHV-6 strains exhibited only limited restriction enzyme polymorphism, cleavage of the RK virus DNA yielded distinct patterns. Of the 11 HHV-6 DNA probes tested, only 6 cross-hybridized with DNA fragments derived from the RK virus. Taken together, the maximal homology amounted to 31 kilobases of the 75 kilobases tested. We conclude that the RK virus is distinct from previously characterized human herpesviruses. We propose to designate it as the prototype of a new herpesvirus, the seventh human herpesvirus identified to date. Images PMID:2153965

  19. Human herpesviruses respiratory infections in patients with acute respiratory distress (ARDS).

    PubMed

    Bonizzoli, Manuela; Arvia, Rosaria; di Valvasone, Simona; Liotta, Francesco; Zakrzewska, Krystyna; Azzi, Alberta; Peris, Adriano

    2016-08-01

    Acute respiratory distress syndrome (ARDS) is today a leading cause of hospitalization in intensive care unit (ICU). ARDS and pneumonia are closely related to critically ill patients; however, the etiologic agent is not always identified. The presence of human herpes simplex virus 1, human cytomegalovirus and Epstein-Barr virus in respiratory samples of critically ill patients is increasingly reported even without canonical immunosuppression. The main aim of this study was to better understand the significance of herpesviruses finding in lower respiratory tract of ARDS patients hospitalized in ICU. The presence of this group of herpesviruses, in addition to the research of influenza viruses and other common respiratory viruses, was investigated in respiratory samples from 54 patients hospitalized in ICU, without a known microbiological causative agent. Moreover, the immunophenotype of each patient was analyzed. Herpesviruses DNA presence in the lower respiratory tract seemed not attributable to an impaired immunophenotype, whereas a significant correlation was observed between herpesviruses positivity and influenza virus infection. A higher ICU mortality was significantly related to the presence of herpesvirus infection in the lower respiratory tract as well as to impaired immunophenotype, as patients with poor outcome showed severe lymphopenia, affecting in particular T (CD3+) cells, since the first days of ICU hospitalization. In conclusion, these results indicate that herpesviruses lower respiratory tract infection, which occurs more frequently following influenza virus infection, can be a negative prognostic marker. An independent risk factor for ICU patients with ARDS is an impaired immunophenotype. PMID:27138606

  20. Increasing incidence of Kaposi's sarcoma in black South Africans in KwaZulu-Natal, South Africa (1983-2006).

    PubMed

    Mosam, A; Carrara, H; Shaik, F; Uldrick, T; Berkman, A; Aboobaker, J; Coovadia, H M

    2009-08-01

    The aim of the study was to describe the temporal trends in the incidence of Kaposi's sarcoma (KS) in black South Africans in KwaZulu-Natal (KZN). The study was designed as a retrospective record review. The incidence of Kaposi's sarcoma was estimated using administrative records for patients receiving care for KS through public sector oncology clinics in KZN, 1983-2006. Annual age-standardized incidence rates were calculated using provincial census data for the denominator. Age-specific rates were calculated for the pre-AIDS (1983-1989) and for the generalized AIDS epidemic eras (2006). Age-standardized incidence of KS increased in KZN from <1:100,000 in 1990 to at least 15:100,000 in 2006; this increase was observed in both men and women. There was a shift in the peak age-specific incidence rates from the sixth decade of life in the pre-AIDS era to the fourth and fifth decades in the AIDS era. In conclusion, KS is a growing public health problem in KZN, South Africa. These data reinforce the need for comprehensive national access to and roll-out of antiretroviral drugs, given their success in prevention and treatment of KS in first-world settings. PMID:19625587

  1. Central nervous system disease and genital disease in harbor porpoises (Phocoena phocoena) are associated with different herpesviruses.

    PubMed

    van Elk, Cornelis; van de Bildt, Marco; van Run, Peter; de Jong, Anton; Getu, Sarah; Verjans, Georges; Osterhaus, Albert; Kuiken, Thijs

    2016-01-01

    Herpesvirus infection causes disease of variable severity in many species, including cetaceans. However, little is known about herpesvirus infection in harbor porpoises (Phocoena phocoena), despite being widespread in temperate coastal waters of the Northern Hemisphere. Therefore, we examined harbor porpoises that stranded alive in the Netherlands, Belgium, and Germany between 2000 and 2014 for herpesvirus infection and associated disease. Porpoises that died or had to be euthanized were autopsied, and samples were collected for virological and pathological analyses. We found one known herpesvirus (Phocoena phocoena herpesvirus type 1, PPHV-1)--a gammaherpesvirus--and two novel herpesviruses (PPHV-2 and PPHV-3)--both alphaherpesviruses--in these porpoises. A genital plaque, in which PPHV-1 was detected, occurred in 1% (1/117) of porpoises. The plaque was characterized by epithelial hyperplasia and intranuclear inclusion bodies that contained herpesvirus-like particles, and that stained positive by a PPHV-1-specific in situ hybridization test. PPHV-2 occurred in the brain of 2% (1/74) of porpoises. This infection was associated with lymphocytic encephalitis, characterized by neuronal necrosis and intranuclear inclusion bodies containing herpesvirus-like particles. PPHV-3 had a prevalence of 5% (4/74) in brain tissue, 5% (2/43) in blowhole swabs, and 2% (1/43) in genital swabs, but was not associated with disease. Phylogenetically, PPHV-1 was identical to a previously reported herpesvirus from a harbor porpoise, PPHV-2 showed closest identity with two herpesviruses from dolphins, and PPHV-3 showed closest identity with a cervid herpesvirus. In conclusion, harbor porpoises may be infected with at least three different herpesviruses, one of which can cause clinically severe neurological disease. PMID:26861818

  2. Coexistence of intestinal Kaposi sarcoma and plasmablastic lymphoma in an HIV/AIDS patient: case report and review of the literature

    PubMed Central

    Wang, Bing; Song, Bingbing; Oster, Cyrus; Cao, Jeffery; Raza, Anwar

    2016-01-01

    Human immunodeficiency virus (HIV) infection or acquired immunodeficiency disease (AIDS) is associated with increased risk for various malignancies including Kaposi sarcoma (KS) and lymphoma. We report a rare case of coexistence of KS and plasmablastic lymphoma (PBL) in the gastrointestinal (GI) tract in a HIV/AIDS patient. A brief review of literature is also presented. PMID:27034819

  3. Kaposi's sarcoma of the hand mimicking squamous cell carcinoma in a woman with no evidence of HIV infection: a case report

    PubMed Central

    Kosmidis, Christophoros; Efthimiadis, Christopher; Anthimidis, Georgios; karayannopoulou, Georgia; Grigoriou, Marios; Vassiliadou, Kalliopi; Berovali, Eleni; Fachantidis, Panagiotis; Fahantidis, Epaminondas

    2008-01-01

    Introduction Kaposi's sarcoma is a vascular neoplasm mainly affecting the skin of the lower extremities. Although it is the most common neoplasm affecting patients with AIDS, sporadic cases in HIV-negative people have been reported. It is a lesion mainly affecting men and its clinical presentation presents a challenge, as it can resemble other benign or malignant skin lesions. Case presentation We report a rare case of Kaposi's sarcoma presenting in a 68-year-old Mediterranean woman with no evidence of HIV infection. The patient had a 6-month history of a slowly progressing pigmented lesion on the dorsum of her left hand. The lesion clinically resembled a squamous cell carcinoma. The patient was treated with a wide excision of the lesion and primary reconstruction with a full thickness skin graft. Histopathological and immunohistochemical analysis of the excised lesion revealed the presence of Kaposi's sarcoma. Serologic investigation for HIV was negative but polymerase chain reaction for human herpes virus type 8 infection was positive. Thorough clinical and imaging investigation of the abdomen and chest were both negative for loci of disease. Conclusion Kaposi's sarcoma, although rare in its sporadic form, should be considered in the differential diagnosis of indeterminate skin lesions, especially those affecting the extremities. PMID:18565232

  4. A novel herpesvirus in 3 species of pheasants: mountain peacock pheasant (Polyplectron inopinatum), Malayan peacock pheasant (Polyplectron malacense), and Congo peafowl (Afropavo congensis).

    PubMed

    Seimon, T A; McAloose, D; Raphael, B; Honkavuori, K S; Chang, T; Hirschberg, D L; Lipkin, W I

    2012-05-01

    The mountain peacock pheasant (Polyplectron inopinatum), the Malayan peacock pheasant (Polyplectron malacense), and the Congo peafowl (Afropavo congensis) are all listed as vulnerable to extinction under the International Union for Conservation of Nature Red List of Threatened Species. Here the authors report fatal infection with a novel herpesvirus in all 3 species of birds. DNA was extracted from the livers of birds with hepatocellular necrosis and intranuclear eosinophilic inclusions consistent with herpesvirus infection. Based on degenerate herpesvirus primers and polymerase chain reaction, 220- and 519-base pair products of the herpes DNA polymerase and DNA terminase genes, respectively, were amplified. Sequence analysis revealed that all birds were likely infected with the same virus. At the nucleotide level, the pheasant herpesvirus had 92% identity with gallid herpesvirus 3 and 77.7% identity with gallid herpesvirus 2. At the amino acid level, the herpes virus had 93.8% identity with gallid herpesvirus 3 and 89.4% identity with gallid herpesvirus 2. These findings indicate that the closest relative to this novel herpesvirus is gallid herpesvirus 3, a nonpathogenic virus used widely in a vaccine against Marek's disease. In situ hybridization using probes specific to the peacock pheasant herpesvirus DNA polymerase revealed strong intranuclear staining in the necrotic liver lesions of an infected Malayan peacock pheasant but no staining in normal liver from an uninfected bird. The phasianid herpesvirus reported here is a novel member of the genus Mardivirus of the subfamily Alphaherpesvirinae and is distinct from other galliform herpesviruses. PMID:22075776

  5. Modulation of the Translational Landscape During Herpesvirus Infection

    PubMed Central

    Glaunsinger, Britt A.

    2016-01-01

    Herpesviral mRNAs are produced and translated by cellular machinery, rendering them susceptible to the network of regulatory events that impact translation. In response, these viruses have evolved to infiltrate and hijack translational control pathways as well as to integrate specialized host translation strategies into their own repertoire. They are robust systems to dissect mechanisms of mammalian translational regulation and continue to offer insight into cis-acting mRNA features that impact assembly and activity of the translation apparatus. Here, I discuss recent advances revealing the extent to which the three herpesvirus subfamilies regulate both host and viral translation, thereby dramatically impacting the landscape of protein synthesis in infected cells. PMID:26958918

  6. Epidemiology and control of bovine herpesvirus 1 infection in Europe.

    PubMed

    Raaperi, Kerli; Orro, Toomas; Viltrop, Arvo

    2014-09-01

    Bovine herpesvirus 1 (BHV-1) causes infectious bovine rhinotracheitis (IBR), infectious pustular vulvovaginitis, abortion and balanoposthitis, as well as neurological and systemic disease in cattle. The virus is endemic in cattle populations worldwide although in Europe six countries and several regions in other countries have achieved 'IBR-free' status by implementing control measures. According to European Union (EU) directives, all member states must comply with specific requirements related to BHV-1 infection status in semen and embryos. The requirement that 'IBR-free' states restrict the importation of cattle from endemically infected regions has motivated several European countries to instigate disease eradication programmes. Despite such control measures within the EU, outbreaks of IBR persist in 'IBR-free' states contiguous with infected countries. This review presents a summary of recent research on the epidemiology of BHV-1, highlights the control measures and surveillance systems in place, and discusses the challenges facing eradication schemes. PMID:24954868

  7. Structural basis of the herpesvirus M3-chemokine interaction.

    PubMed

    Alcami, Antonio

    2003-05-01

    Viruses have been fighting the immune systems of their hosts for millions of years and have evolved evasion strategies to ensure their survival. Viruses can teach us efficient mechanisms to control the immune system, and this information can be used to design new strategies of immune modulation that we might apply to diminish immunopathological responses that cause human diseases. Large DNA viruses, such as poxviruses and herpesviruses, encode proteins that are secreted from infected cells, bind cytokines and neutralize their activity. A subgroup of these viral proteins binds chemokines, a complex family of cytokines that control the recruitment of cells to sites of infection and inflammation. One of the major unresolved questions in the field was to understand how these viral secreted proteins bind chemokines with high affinity, despite having no amino acid sequence similarity to the host chemokine receptors, which are seven-transmembrane-domain proteins that cannot be engineered as soluble proteins. PMID:12781515

  8. Herpesviruses and Intermediate Filaments: Close Encounters with the Third Type

    PubMed Central

    Hertel, Laura

    2011-01-01

    Intermediate filaments (IF) are essential to maintain cellular and nuclear integrity and shape, to manage organelle distribution and motility, to control the trafficking and pH of intracellular vesicles, to prevent stress-induced cell death, and to support the correct distribution of specific proteins. Because of this, IF are likely to be targeted by a variety of pathogens, and may act in favor or against infection progress. As many IF functions remain to be identified, however, little is currently known about these interactions. Herpesviruses can infect a wide variety of cell types, and are thus bound to encounter the different types of IF expressed in each tissue. The analysis of these interrelationships can yield precious insights into how IF proteins work, and into how viruses have evolved to exploit these functions. These interactions, either known or potential, will be the focus of this review. PMID:21994768

  9. Tales from the crypt and coral reef: the successes and challenges of identifying new herpesviruses using metagenomics

    PubMed Central

    Houldcroft, Charlotte J.; Breuer, Judith

    2015-01-01

    Herpesviruses are ubiquitous double-stranded DNA viruses infecting many animals, with the capacity to cause disease in both immunocompetent and immunocompromised hosts. Different herpesviruses have different cell tropisms, and have been detected in a diverse range of tissues and sample types. Metagenomics—encompassing viromics—analyses the nucleic acid of a tissue or other sample in an unbiased manner, making few or no prior assumptions about which viruses may be present in a sample. This approach has successfully discovered a number of novel herpesviruses. Furthermore, metagenomic analysis can identify herpesviruses with high degrees of sequence divergence from known herpesviruses and does not rely upon culturing large quantities of viral material. Metagenomics has had success in two areas of herpesvirus sequencing: firstly, the discovery of novel exogenous and endogenous herpesviruses in primates, bats and cnidarians; and secondly, in characterizing large areas of the genomes of herpesviruses previously only known from small fragments, revealing unexpected diversity. This review will discuss the successes and challenges of using metagenomics to identify novel herpesviruses, and future directions within the field. PMID:25821447

  10. Melissa officinalis oil affects infectivity of enveloped herpesviruses.

    PubMed

    Schnitzler, P; Schuhmacher, A; Astani, A; Reichling, Jürgen

    2008-09-01

    Extracts and essential oils of medicinal plants are increasingly of interest as novel drugs of antimicrobial and antiviral agents, since herpes simplex virus (HSV) might develop resistance to commonly used antiviral agents. Melissa officinalis essential oil was phytochemically examined by GC-MS analysis, its main constituents were identified as monoterpenaldehydes citral a, citral b and citronellal. The antiviral effect of lemon balm oil, the essential oil of Melissa officinalis, on herpes simplex virus was examined. The inhibitory activity against herpes simplex virus type 1 (HSV-1)and herpes simplex virus type 2 (HSV-2) was tested in vitro on monkey kidney cells using a plaque reduction assay. The 50% inhibitory concentration (IC50) of balm oil for herpes simplex virus plaque formation was determined at high dilutions of 0.0004% and 0.00008% for HSV-1 and HSV-2, respectively. At noncytotoxic concentrations of the oil,plaque formation was significantly reduced by 98.8% for HSV-1 and 97.2% for HSV-2, higher concentrations of lemon balm oil abolished viral infectivity nearly completely. In order to determine the mode of antiviral action of this essential oil, time-on-addition assays were performed. Both herpesviruses were significantly inhibited by pretreatment with balm oil prior to infection of cells. These results indicate that Melissa oil affected the virus before adsorption, but not after penetration into the host cell, thus lemon balm oil is capable of exerting a direct antiviral effect on herpesviruses. Considering the lipophilic nature of lemon balm essential oil, which enables it to penetrate the skin, and a high selectivity index, Melissa officinalis oil might be suitable for topical treatment of herpetic infections. PMID:18693101

  11. Human Herpesviruses 6A, 6B, and 7.

    PubMed

    Agut, Henri; Bonnafous, Pascale; Gautheret-Dejean, Agnès

    2016-06-01

    Human roseoloviruses include three different species, human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, HHV-7), genetically related to human cytomegalovirus. They exhibit a wide cell tropism in vivo and, like other herpesviruses, induce a lifelong latent infection in humans. In about 1% of the general population, HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6). Many active infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. They also may cause serious diseases, particularly in immunocompromised individuals, including hematopoietic stem-cell transplant (HSCT) and solid-organ transplant recipients, and acquired immunodeficiency syndrome (AIDS) patients. This opportunistic pathogenic role is formally established for HHV-6 infection and less clear for HHV-7. It mainly concerns the central-nervous system, bone marrow, lungs, gastrointestinal tract, skin, and liver. As the best example, HHV-6 causes both exanthema subitum, a benign disease associated with primary infection, and severe encephalitis associated with virus reactivations in HSCT recipients. Diagnosis using serologic and direct antigen-detection methods currently exhibits limitations. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time polymerase-chain reaction (PCR). The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active infections, but there is currently no consensus regarding the indications of treatment or specifics of drug administration. Numerous questions about HHV-6A, HHV-6B, HHV-7 are still pending, concerning in particular clinical impact and therapeutic options in immunocompromised patients. PMID:27337451

  12. Review of Elephant Endotheliotropic Herpesviruses and Acute Hemorrhagic Disease.

    PubMed

    Long, Simon Y; Latimer, Erin M; Hayward, Gary S

    2016-01-01

    More than 100 young captive and wild Asian elephants are known to have died from a rapid-onset, acute hemorrhagic disease caused primarily by multiple distinct strains of two closely related chimeric variants of a novel herpesvirus species designated elephant endotheliotropic herpesvirus (EEHV1A and EEHV1B). These and two other species of Probosciviruses (EEHV4 and EEHV5) are evidently ancient and likely nearly ubiquitous asymptomatic infections of adult Asian elephants worldwide that are occasionally shed in trunk wash secretions. Although only a handful of similar cases have been observed in African elephants, they also have proved to harbor their own multiple and distinct species of Probosciviruses-EEHV2, EEHV3, EEHV6, and EEHV7-found in lung and skin nodules or saliva. For reasons that are not yet understood, approximately 20% of Asian elephant calves appear to be susceptible to the disease when primary infections are not controlled by normal innate cellular and humoral immune responses. Sensitive specific polymerase chain reaction (PCR) DNA blood tests have been developed, routine monitoring has been established, the complete large DNA genomes of each of the four Asian EEHV species have now been sequenced, and PCR gene subtyping has provided unambiguous evidence that this is a sporadic rather than epidemic disease that it is not being spread among zoos or other elephant housing facilities. Nevertheless, researchers have not yet been able to propagate EEHV in cell culture, determine whether or not human antiherpesvirus drugs are effective inhibitors, or develop serology assays that can distinguish between antibodies against the multiple different EEHV species. PMID:26912715

  13. Risk of Kaposi sarcoma during the first months on combination antiretroviral therapy

    PubMed Central

    Lacombe, Jean-Marc; Boue, François; Grabar, Sophie; Viget, Nathalie; Gazaignes, Sandrine; Lascaux-Cametz, Anne-Sophie; Pacanowski, Jérome; Partisani, Marialuisa; Launay, Odile; Matheron, Sophie; Rosenthal, Eric; Rouveix, Elisabeth; Tattevin, Pierre; de Truchis, Pierre; Costagliola, Dominique; Goedert, James J

    2013-01-01

    Objective Determine if incident AIDS-defining Kaposi sarcoma (KS) or Pneumocystis jiroveci pneumonia (PJP) is associated with combination antiretroviral therapy (cART) initiation. Design Compare risk for KS and PJP by time on cART and CD4 reconstitution. Methods In the FHDH-ANRS CO4 cohort (N=66,369), KS (N=1811) and PJP (N=1718) incidence rates were computed by demographic and HIV strata. Crude and adjusted relative risk (RR) with 95% confidence intervals (CI) following cART initiation were calculated by Poisson regression with untreated patients during 1996–2009 as reference. CD4 counts were compared by Wilcoxon rank sum tests. Results KS risk was very high during months 1–3 on cART (N=160, RRCrude 3.94, CI 3.26–4.76), which was incompletely attenuated by adjustment for demographics and contemporaneous CD4 count (RRAdj 1.25, CI 1.02–1.53). Corresponding PJP risk was minimally elevated (N=84, RRCrude 1.80, CI 1.42–2.30) and markedly reduced with adjustment on the same variables and PJP prophylaxis (RRAdj 0.52, CI 0.41–0.67). HIV load had no added effect. Median CD4 cell count at cART initiation was much lower in patients with incident KS (82/mm3) or PJP (61/mm3) within 3 months compared with those without (>250/mm3). Notably, median CD4 change was +44 cells/month with incident KS within 3 months of cART initiation versus 0 cells/month with incident PJP (P=0.0003). Conclusions Failure of CD4 reconstitution during months 1–3 on cART fully accounted for incident PJP. In contrast, there were 1.6 additional KS cases per 1000 person-years during months 1–3 on cART, suggesting that immune reconstitution may contribute to the risk for AIDS-defining KS. PMID:23196937

  14. Lipoxins exert antiangiogenic and anti-inflammatory effects on Kaposi's sarcoma cells.

    PubMed

    Marginean, Alexandru; Sharma-Walia, Neelam

    2015-08-01

    Lipoxin A4 (LXA4) is an endogenously produced host molecule with anti-inflammatory resolution effects. Previous studies demonstrated it to be involved in anti-vascular endothelial growth factor (VEGF)-mediated angiogenesis and in a possible anticancer role via interaction with its receptor, lipoxin A 4 receptor (ALXR). Here, we examined the effects of LXA4 and its epimer 15-epi-LXA4 in inhibiting proinflammatory and angiogenic functions in a human Kaposi's sarcoma tumor-derived cell line (KS-IMM). KS-IMM cells expressed increased levels of inflammatory cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LO) pathway enzymes when compared with human microvascular dermal endothelial cells (HMVEC-d). KS-IMM cells secreted high levels of prostaglandin E2 (PGE2) and chemotactic leukotriene B4 (LTB4). Treatment with LXA4 or 15-epi-LXA4 effectively reduced the levels of COX-2, 5-LO proteins, and secretion of PGE2 and LTB4 in KS-IMM cells. LXA4 or 15-epi-LXA4 treatment also decreased secretion of proinflammatory interleukin 6 (IL-6) and IL-8 cytokines but induced the secretion of anti-inflammatory IL-10. LXA4 treatment reduced the phosphorylation of VEGF receptor (VEGFR) and ephrin family receptor tyrosine kinases. LXA4 treatment effectively induced dephosphorylation of multiple cellular kinases such as Focal Adhesion Kinase, Protein kinase B, nuclear factor kappa-light-chain-enhancer of activated B cells, and Extracellular signal-regulated kinases (ERK)1/2, and reduced angiogenic factor VEGF-C secretion in KS cells. LX treatment drastically induced the Src-homology 2 domain-containing phosphatase tyrosine (Y542) phosphatase and reduced VEGFR-2 phosphorylation at sites Y1059, Y1175, and Y1212. Treatment of KS-IMM cells with LXA4 resulted in selective localization of VEGFR-2 in nonlipid raft (non-LR) and ALXR to LR fractions. These results demonstrated that LXA4 or 15-epi-LXA4 induce anti-inflammatory and antiangiogenic effects in KS cells and suggest that treatment with LXs is

  15. Neck Kaposiform haemangioendothelioma in a Fischer's lovebird (Agapornis fischeri).

    PubMed

    Rossi, Giacomo; Galosi, Livio; Berardi, Sara; Piano, Maria Assunta; Robino, Patrizia; Rose, Timothy; Calabrò, Maria Luisa

    2016-06-01

    A six-year-old female Fischer's lovebird (Agapornis fischeri) presented at necropsy with a cutaneous mass on the neck, 3.5cm in diameter, yielding and with blood content. Histopathological findings showed a neoplasm characterized by proliferation of vascular endothelial cells. The histology of the mass revealed a multinodular, focally infiltrating tumor. Deeper dermal nodules were made of spindle cells forming vascular slits reminiscent of the histology seen in Kaposi's sarcoma (KS). More superficially located dermal nodules consisted of small blood vessels, with histology resembling capillary hemangioma. The spindle cells and capillaries were strongly positive for Vimentin, endothelial cell marker CD31, and negative for sarcomeric α-smooth muscle actin (α-SMA). Intravascular platelet trapping and Periodic acid-Schiff (PAS)-positive hyaline globules were also observed. Differential diagnosis included Kaposi's sarcoma, capillary haemangioma, spindle cell haemangioendothelioma, and epithelioid haemangioendothelioma. Based on morphological and immunohistochemical findings, the tumor was diagnosed as a cutaneous Kaposiform haemangioendothelioma (KHE), a rare, low-grade malignant vascular neoplasm. Other organs showed no abnormalities. PCR amplifications, conducted using Kaposi's sarcoma-associated herpesvirus (KSHV)-specific primers and degenerate sets of primers designed to detect and characterize members of the Herpesviridae, on DNA extracted from tumor tissue and from whole blood failed to amplify any KSHV-related sequence. Moreover, no specific signal was obtained using primers for detection of psittacine herpesvirus, known to be linked to Pacheco's disease in parrots. To the best of our knowledge, this unusual case is the third report of KHE in a non-human animal species, the first described in a bird. PMID:27234547

  16. Replacement of glycoprotein B in alcelaphine herpesvirus 1 by its ovine herpesvirus 2 homolog: implications in vaccine development for sheep associated-malignant catarrhal fever

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Vaccine development is a top priority in malignant catarrhal fever (MCF) research. In the case of sheep-associated MCF (SA-MCF), caused by ovine herpesvirus 2 (OvHV-2), progress towards this objective has been hindered by the absence of methods to attenuate or modify the virus, since it cannot be pr...

  17. Severe human herpesvirus 6-associated encephalopathy in three children: analysis of cytokine profiles and the carnitine palmitoyltransferase 2 gene.

    PubMed

    Matsumoto, Hiroshi; Hatanaka, Daisuke; Ogura, Yumi; Chida, Ayako; Nakamura, Yasuko; Nonoyama, Shigeaki

    2011-11-01

    Three children developed severe encephalopathy associated with human herpesvirus 6 infection. Magnetic resonance imaging of the brain showed either basal ganglia involvement or diffusion abnormalities in the cerebral white matter. Coagulopathy with hypercytokinemia was observed in 2 patients. One demonstrated thermolabile variation in carnitine palmitoyltransferase 2. These results suggest a heterogeneous pathogenic mechanism in encephalopathy associated with human herpesvirus 6 infection. PMID:21654547

  18. Isolation and molecular characterization of herpesvirus from cultured European eels Anguilla anguilla in Taiwan.

    PubMed

    Chang, Pen Heng; Pan, Yie Hour; Wu, Chein Ming; Kuo, Shu Ting; Chung, Huu Yun

    2002-07-01

    A herpesvirus has been isolated for the first time from a population of European eels Anguilla anguilla cultured in a recirculated system in Taiwan. Syncytia formation was detected in EP-1 (eel epidermis) cell cultures inoculated with cell-free homogenates prepared from both integument and visceral organs of moribund fish. Inoculation of homogenates onto EK (eel kidney) cell cultures induced giant cell formation. Subsequent passages produced a consistent and progressive cytopathic effect (CPE) in cell cultures. In this study, EP-1 cell cultures infected with EEHV (European eel herpesvirus) were examined using an electron microscope. Numerous nucleocapsids of about 100 nm in diameter were found within the nucleus of infected cells, whereas enveloped particles were observed within the cytoplasm. The mature viral particle, about 235 nm in diameter, had an electron-dense core with a hexagonal nucleocapsid surrounded by a coarse capsule. Histopathological examination of moribund fish showed epithelial hyperplasia with intracytoplasmic metabolic inclusions in the skin. Macrophage aggregates were found in liver, spleen, and kidney. A pair of primers designed from channel catfish virus and salmonid herpesvirus 1 was used in a polymerase chain reaction. A 402 bp fragment was amplified and cloned from genomic DNA of EEHV. The nucleotide homology was 99% (298 of 300) with DNA polymerase of eel herpesvirus (anguillid herpesvirus). EEHV nucleic acids were detected within melanomacrophages in the skin, liver, spleen and kidney by in situ hybridization (ISH). PMID:12180701

  19. In vitro immortalization of marmoset cells with three subgroups of herpesvirus saimiri.

    PubMed Central

    Szomolanyi, E; Medveczky, P; Mulder, C

    1987-01-01

    Sequences within the rightmost 7 kilobases of the unique L DNA of herpesvirus saimiri are required for oncogenicity of the virus. The same DNA region has been found to be highly variable among different strains of herpesvirus saimiri. On the basis of this variability, herpesvirus saimiri strains were classified into groups A, B, and non-A, non-B. Herpesvirus saimiri strains representing the three groups were used successfully for in vitro immortalization of phytohemagglutinin-activated, interleukin 2 (IL-2)-expanded peripheral blood lymphocytes of common marmosets (Callithrix jacchus). Peripheral blood leukocytes could be immortalized from only a subset of common marmosets (5 of 13). All of the immortalized cell lines contained covalently closed circular viral DNA molecules and initially showed a low level of virus production. Cells immortalized by group A and group non-A, non-B strains did not require IL-2 in the medium. However, the only group B immortalized cell line, 473-SMHI, did not grow well in the absence of IL-2. The different characteristics of cell lines immortalized by herpesvirus saimiri strains belonging to different groups may help to elucidate some functions coded by the highly variable DNA region which is involved in the oncogenic process. Images PMID:2822956

  20. Divergent Evolution of Nuclear Localization Signal Sequences in Herpesvirus Terminase Subunits.

    PubMed

    Sankhala, Rajeshwer S; Lokareddy, Ravi K; Cingolani, Gino

    2016-05-20

    The tripartite terminase complex of herpesviruses assembles in the cytoplasm of infected cells and exploits the host nuclear import machinery to gain access to the nucleus, where capsid assembly and genome-packaging occur. Here we analyzed the structure and conservation of nuclear localization signal (NLS) sequences previously identified in herpes simplex virus 1 (HSV-1) large terminase and human cytomegalovirus (HCMV) small terminase. We found a monopartite NLS at the N terminus of large terminase, flanking the ATPase domain, that is conserved only in α-herpesviruses. In contrast, small terminase exposes a classical NLS at the far C terminus of its helical structure that is conserved only in two genera of the β-subfamily and absent in α- and γ-herpesviruses. In addition, we predicted a classical NLS in the third terminase subunit that is partially conserved among herpesviruses. Bioinformatic analysis revealed that both location and potency of NLSs in terminase subunits evolved more rapidly than the rest of the amino acid sequence despite the selective pressure to keep terminase gene products active and localized in the nucleus. We propose that swapping NLSs among terminase subunits is a regulatory mechanism that allows different herpesviruses to regulate the kinetics of terminase nuclear import, reflecting a mechanism of virus:host adaptation. PMID:27033706

  1. Human herpesvirus 6-related fulminant myocarditis and hepatitis in an immunocompetent adult with fatal outcome.

    PubMed

    Chang, Yilan L; Parker, Mark E; Nuovo, Gerard; Miller, Joel B

    2009-05-01

    A 59-year-old previously healthy man had flulike symptoms of fever and diarrhea for a week, which worsened despite treatment with antibiotics. After admission, his medical condition rapidly deteriorated with renal failure, heart failure, and a marked increase of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase. The patient died of a cardiac arrhythmia 3 days after the admission. The autopsy showed diffuse myocarditis with a granulocytic and monocytic infiltrate, necrotizing arteritis of the coronary arteries, and fulminant hepatitis, with microvesicular steatosis and necrosis. Cell-free serum showed high copies of human herpesvirus 6 B variant DNA by polymerase chain reaction. Human herpesvirus 6 B was identified in the heart, liver, lung, and spleen by immunohistochemistry. No parvovirus B19 was evident in the heart by immunohistochemistry. Human herpesvirus 6 is increasingly found in association with myocarditis in immunocompromised patients; however, histopathologic features and the clinical severity of this disease have not yet been clearly defined. Only 4 to 5 cases of human herpesvirus 6 fulminant myocarditis have been reported, all in young children or immunosuppressed patients. To the best of our knowledge, this is the first case in the English literature of human herpesvirus 6 fulminant myocarditis and hepatitis in an immunocompetent adult with a fatal outcome. In addition, several pathologic features of our case have not been previously reported. PMID:19144379

  2. Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review.

    PubMed

    Rees, Chris A; Keating, Elizabeth M; Lukolyo, Heather; Danysh, Heather E; Scheurer, Michael E; Mehta, Parth S; Lubega, Joseph; Slone, Jeremy S

    2016-08-01

    Children with human immunodeficiency virus (HIV) have an increased risk of developing Kaposi Sarcoma (KS) and non-Hodgkin lymphoma (NHL) compared to HIV-negative children. We compiled currently published epidemiologic data on KS and NHL among children in sub-Saharan Africa (SSA). Among countries with available data, the median incidence of KS was 2.05/100,000 in the general pediatric population and 67.35/100,000 among HIV-infected children. The median incidence of NHL was 1.98/100,000 among the general pediatric population, while data on NHL incidence among HIV-infected children were lacking. Larger regional studies are needed to better address the dearth of epidemiologic information on pediatric KS and NHL in SSA. PMID:27082516

  3. Angiomatous reaction Kaposi-sarcoma-like as a side effect of topical corticosteroid therapy in lichen sclerosus of the penis.

    PubMed

    Catricalà, Caterina; Marenda, Samantha; Muscardin, Luca Maria; Donati, Pietro; Lepri, Andrea; Eibenschutz, Laura

    2009-01-01

    Lichen sclerosus (LS) is a chronic inflammatory skin condition usually located in the anogenital area. Topical corticosteroid therapy is the first choice treatment which may arrest or delay the progression of the disorder. We report the case of a 74-year-old man presented with a 6-month history of nodular lesions localized on penis. The man had a previous history of genital lesions that had been diagnosed as LS and treated with long-term topical corticosteroid therapy. After 3 months of corticosteroid therapy, the patient observed the appearance of several nodular erythematous lesions on the penis with progressive disappearance of the clinical symptoms of LS. These purple to red asymptomatic angiomatoid nodules resembled the clinical features of Kaposi sarcoma. PMID:19580581

  4. The Role of PI3K/Akt in Human Herpesvirus Infection: from the Bench to the Bedside

    PubMed Central

    Liu, XueQiao; Cohen, Jeffrey I.

    2015-01-01

    The phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway regulates several key cellular functions including protein synthesis, cell growth, glucose metabolism, and inflammation. Many viruses have evolved mechanisms to manipulate this signaling pathway to ensure successful virus replication. The human herpesviruses undergo both latent and lytic infection, but differ in cell tropism, growth kinetics, and disease manifestations. Herpesviruses express multiple proteins that target the PI3K/Akt cell signaling pathway during the course of their life cycle to facilitate viral infection, replication, latency, and reactivation. Rare human genetic disorders with mutations in either the catalytic or regulatory subunit of PI3K that result in constitutive activation of the protein predispose to severe herpesvirus infections as well as to virus-associated malignancies. Inhibiting the PI3K/Akt pathway or its downstream proteins using drugs already approved for other diseases can block herpesvirus lytic infection and may reduce malignancies associated with latent herpesvirus infections. PMID:25798530

  5. The role of PI3K/Akt in human herpesvirus infection: From the bench to the bedside.

    PubMed

    Liu, XueQiao; Cohen, Jeffrey I

    2015-05-01

    The phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway regulates several key cellular functions including protein synthesis, cell growth, glucose metabolism, and inflammation. Many viruses have evolved mechanisms to manipulate this signaling pathway to ensure successful virus replication. The human herpesviruses undergo both latent and lytic infection, but differ in cell tropism, growth kinetics, and disease manifestations. Herpesviruses express multiple proteins that target the PI3K/Akt cell signaling pathway during the course of their life cycle to facilitate viral infection, replication, latency, and reactivation. Rare human genetic disorders with mutations in either the catalytic or regulatory subunit of PI3K that result in constitutive activation of the protein predispose to severe herpesvirus infections as well as to virus-associated malignancies. Inhibiting the PI3K/Akt pathway or its downstream proteins using drugs already approved for other diseases can block herpesvirus lytic infection and may reduce malignancies associated with latent herpesvirus infections. PMID:25798530

  6. Broad-spectrum non-nucleoside inhibitors of human herpesviruses

    PubMed Central

    McClain, Lora; Zhi, Yun; Cheng, Hoyee; Ghosh, Ayantika; Piazza, Paolo; Yee, Michael B.; Kumar, Santosh; Milosevic, Jadranka; Bloom, David C.; Arav-Boger, Ravit; Kinchington, Paul R.; Yolken, Robert; Nimgaonkar, Vishwajit; D’Aiuto, Leonardo

    2015-01-01

    Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of ‘quiescent’ HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo. PMID:26079681

  7. Herpesvirus infection in stranded Pacific harbor seals of coastal California.

    PubMed

    Gulland, F M; Lowenstine, L J; Lapointe, J M; Spraker, T; King, D P

    1997-07-01

    Histopathological examination revealed multifocal acute to chronic adrenal necrosis in 74 of 162 (45%) Pacific harbor seal pups (Phoca vitulina richardsi) dying during rehabilitation following live stranding along the coast of central and northern California (USA). Necrotic adrenal cells contained amphophilic, smudgy intranuclear inclusion bodies that were stained positive for DNA. Fifty of these seals also had lesions typical of sepsis, bacterial omphalophlebitis, pneumonia or gastroenteritis. Twenty four seals had no lesions other than thymic atrophy and occasional multifocal hepatic necrosis. Prior to death, affected seals had a marked lymphopenia. Electron microscopy revealed unenveloped intranuclear hexagonal to round viral particles approximately 100 nm in diameter, and cytoplasmic enveloped virions approximately 160 nm in diameter. These were morphologically consistent with herpesvirus. Inoculation of phocine adrenal and kidney cell lines with an adrenal tissue homogenate from affected animals produced a cytopathic effect in 5 days. Electron microscopy of cell cultures showing this cytopathic effect revealed similar viral particles to those observed in affected adrenal glands. Cases with characteristic inclusion bodies were observed in 42 of 95 (44%) male and 32 of 67 (47%) female seals. Affected animals had been in rehabilitation 0 to 63 days and were below average birth weight for this species. PMID:9249689

  8. [Human Herpesvirus-6 Encephalitis in Allogeneic Hematopoietic Stem Cell Transplantation].

    PubMed

    Ogata, Masao

    2015-07-01

    The reactivation of human herpesvirus-6B (HHV-6B) is common after allogeneic hematopoietic cell transplantation (allo-HCT), and it is sporadically associated with the development of HHV-6 encephalitis. HHV-6 encephalitis typically develops around 2-6 weeks after allo-HCT, and it is characterized by short-term memory loss. Magnetic resonance imaging typically shows bilateral signal abnormalities in the limbic system. The incidence of HHV-6 encephalitis is reportedly 0-11.6% after bone marrow or peripheral blood stem cell transplantation and 4.9-21.4% after cord blood transplantation. The mortality of HHV-6 encephalitis is high, and survivors are often left with serious sequelae. Antiviral therapy using foscarnet or ganciclovir is recommended for the treatment of HHV-6 encephalitis, but the efficacy of the currently available treatment is insufficient once HHV-6 encephalitis has developed. The elucidation of the pathogenesis of HHV-6 encephalitis and the establishment of preventative therapy are needed to overcome this disease. PMID:26160819

  9. Characterization of pseudorabies virus glycoprotein B expressed by canine herpesvirus.

    PubMed

    Nishikawa, Y; Xuan, X; Kimura, M; Otsuka, H

    1999-10-01

    A recombinant canine herpesvirus (CHV) which expressed glycoprotein B (gB) of pseudorabies virus (PrV) was constructed. The antigenicity of the PrV gB expressed by the recombinant CHV is similar to that of the native PrV. The expressed PrV gB was shown to be transported to the surface of infected cells as judged by an indirected immunofluorescence test. Antibodies raised in mice immunized with the recombinant CHV neutralized the infectivity of PrV in vitro. It is known that the authentic PrV gB exists as a glycoprotein complex, which consists of gBa, gBb and gBc. In MDCK cells, PrV gB expressed by the recombinant CHV was processed like authentic PrV gB, suggesting that the cleavage mechanism of PrV gB depends on a functional cleavage domain from PrV gB gene and protease from infected cells. PMID:10563288

  10. Genotypic characterization of psittacid herpesvirus isolates from Brazil

    PubMed Central

    Luppi, Marcela Miranda; Luiz, Ana Paula Moreira Franco; Coelho, Fabiana Magalhães; Ecco, Roselene; da Fonseca, Flávio Guimarães; Resende, Mauricio

    2016-01-01

    Thirty-six isolates of psittacid herpesvirus (PsHV), obtained from 12 different species of psittacids in Brazil, were genotypically characterized by restriction fragment length polymorphism (RFLP) analysis and PCR amplification. RFLP analysis with the PstI enzyme revealed four distinct restriction patterns (A1, X, W and Y), of which only A1 (corresponding to PsHV-1) had previously been described. To study PCR amplification patterns, six pairs of primers were used. Using this method, six variants were identified, of which, variants 10, 8, and 9 (in this order) were most prevalent, followed by variants 1, 4, and 5. It was not possible to correlate the PCR and RFLP patterns. Twenty-nine of the 36 isolates were shown to contain a 419 bp fragment of the UL16 gene, displaying high similarity to the PsHV-1 sequences available in GenBank. Comparison of the results with the literature data suggests that the 36 Brazilian isolates from this study belong to genotype 1 and serotype 1. PMID:26887248

  11. Broad-spectrum non-nucleoside inhibitors of human herpesviruses.

    PubMed

    McClain, Lora; Zhi, Yun; Cheng, Hoyee; Ghosh, Ayantika; Piazza, Paolo; Yee, Michael B; Kumar, Santosh; Milosevic, Jadranka; Bloom, David C; Arav-Boger, Ravit; Kinchington, Paul R; Yolken, Robert; Nimgaonkar, Vishwajit; D'Aiuto, Leonardo

    2015-09-01

    Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of 'quiescent' HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo. PMID:26079681

  12. Evidence for two koi herpesvirus (KHV) genotypes in South Korea.

    PubMed

    Kim, Hyoung Jun; Kwon, Se Ryun

    2013-06-13

    The geographic distribution of koi herpesvirus (KHV) has recently been analyzed by polymerase chain reaction (PCR, based on the alleles of 3 domains) and sequence analysis using 3 regions of KHV genomic DNA (SphI-5, 9/5, and the thymidine kinase gene). In this study, samples from 6 carp showing symptoms of KHV infection in 2008 were examined for the presence of KHV by using PCR and cell culture isolation methods. KHV was detected in 2 (Pyeongtaek and Buan) of the samples. Sequence analysis revealed that the genotype of the KHV PT-08 isolate was Asia genotype variant 1 (A1), and the genotype of the KHV BA-08 isolate was European genotype variant 4 (E4). In addition, PCR patterns and sequence analysis based on the alleles of 3 domains of an alternate KHV classification system confirmed that the genotype of the KHV PT-08 isolate was CyHV3-J, and the genotype of the KHV BA-08 isolate was CyHV3-third genotype. To our knowledge, this is the first study to demonstrate the presence of 2 genotypes of KHV (genotype A1/CyHV3-J; genotype E4/CyHV3-third genotype) in South Korea. PMID:23759557

  13. Novel Heparan Sulfate-Binding Peptides for Blocking Herpesvirus Entry

    PubMed Central

    Dogra, Pranay; Martin, Emily B.; Williams, Angela; Richardson, Raphael L.; Foster, James S.; Hackenback, Nicole; Kennel, Stephen J.; Sparer, Tim E.; Wall, Jonathan S.

    2015-01-01

    Human cytomegalovirus (HCMV) infection can lead to congenital hearing loss and mental retardation. Upon immune suppression, reactivation of latent HCMV or primary infection increases morbidity in cancer, transplantation, and late stage AIDS patients. Current treatments include nucleoside analogues, which have significant toxicities limiting their usefulness. In this study we screened a panel of synthetic heparin-binding peptides for their ability to prevent CMV infection in vitro. A peptide designated, p5+14 exhibited ~ 90% reduction in murine CMV (MCMV) infection. Because negatively charged, cell-surface heparan sulfate proteoglycans (HSPGs), serve as the attachment receptor during the adsorption phase of the CMV infection cycle, we hypothesized that p5+14 effectively competes for CMV adsorption to the cell surface resulting in the reduction in infection. Positively charged Lys residues were required for peptide binding to cell-surface HSPGs and reducing viral infection. We show that this inhibition was not due to a direct neutralizing effect on the virus itself and that the peptide blocked adsorption of the virus. The peptide also inhibited infection of other herpesviruses: HCMV and herpes simplex virus 1 and 2 in vitro, demonstrating it has broad-spectrum antiviral activity. Therefore, this peptide may offer an adjunct therapy for the treatment of herpes viral infections and other viruses that use HSPGs for entry. PMID:25992785

  14. Short communication: Pasteurization of milk abolishes bovine herpesvirus 4 infectivity.

    PubMed

    Bona, C; Dewals, B; Wiggers, L; Coudijzer, K; Vanderplasschen, A; Gillet, L

    2005-09-01

    Bovine herpesvirus 4 (BoHV-4) is a gammaherpesvirus highly prevalent in the cattle population that has been isolated from the milk and the serum of healthy infected cows. Several studies reported the sensitivity and the permissiveness of some human cells to BoHV-4 infection. Moreover, our recent study demonstrated that some human cells sensitive but not permissive to BoHV-4 support a persistent infection protecting them from tumor necrosis factor-alpha-induced apoptosis. Together, these observations suggested that BoHV-4 could represent a danger for public health. To evaluate the risk of human infection by BoHV-4 through milk or serum derivatives, we investigated the resistance of BoHV-4 to the mildest thermal treatments usually applied to these products. The results demonstrated that milk pasteurization and thermal decomplementation of serum abolish BoHV-4 infectivity by inactivation of its property to enter permissive cells. Consequently, our results demonstrate that these treatments drastically reduce the risk of human infection by BoHV-4 through treated milk or serum derivatives. PMID:16107396

  15. Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors

    PubMed Central

    de Munnik, Sabrina M.; Smit, Martine J.; Leurs, Rob; Vischer, Henry F.

    2015-01-01

    Human herpesviruses (HHVs) are widespread infectious pathogens that have been associated with proliferative and inflammatory diseases. During viral evolution, HHVs have pirated genes encoding viral G protein-coupled receptors (vGPCRs), which are expressed on infected host cells. These vGPCRs show highest homology to human chemokine receptors, which play a key role in the immune system. Importantly, vGPCRs have acquired unique properties such as constitutive activity and the ability to bind a broad range of human chemokines. This allows vGPCRs to hijack human proteins and modulate cellular signaling for the benefit of the virus, ultimately resulting in immune evasion and viral dissemination to establish a widespread and lifelong infection. Knowledge on the mechanisms by which herpesviruses reprogram cellular signaling might provide insight in the contribution of vGPCRs to viral survival and herpesvirus-associated pathologies. PMID:25805993

  16. Prolonged persistence of bovine herpesvirus in small cattle herds: a model-based analysis.

    PubMed

    Mollema, L; de Jong, M C M; van Boven, M

    2005-02-01

    Herpesviruses can remain dormant in once-infected hosts and, upon reactivation, cause such hosts to become infectious. This phenomenon of latency and reactivation may enable herpesviruses to persist for a long time in small host populations. To quantify the effect of reactivation on persistence, the time to extinction of bovine herpesvirus type 1 (BHV-1) in small cattle populations was calculated. For realistic parameter values the mean time to extinction is already more than 100 years in a population of 10 animals. In a population of 20 animals the time to extinction is approximately 2000 years. The effects of vaccination on persistence were also studied, revealing that continued vaccination of the whole population could result in much faster eradication. For instance, in an isolated herd of 20 animals BHV-1 could be eradicated in 44 years. PMID:15724721

  17. Remodeling nuclear architecture allows efficient transport of herpesvirus capsids by diffusion.

    PubMed

    Bosse, Jens B; Hogue, Ian B; Feric, Marina; Thiberge, Stephan Y; Sodeik, Beate; Brangwynne, Clifford P; Enquist, Lynn W

    2015-10-20

    The nuclear chromatin structure confines the movement of large macromolecular complexes to interchromatin corrals. Herpesvirus capsids of approximately 125 nm assemble in the nucleoplasm and must reach the nuclear membranes for egress. Previous studies concluded that nuclear herpesvirus capsid motility is active, directed, and based on nuclear filamentous actin, suggesting that large nuclear complexes need metabolic energy to escape nuclear entrapment. However, this hypothesis has recently been challenged. Commonly used microscopy techniques do not allow the imaging of rapid nuclear particle motility with sufficient spatiotemporal resolution. Here, we use a rotating, oblique light sheet, which we dubbed a ring-sheet, to image and track viral capsids with high temporal and spatial resolution. We do not find any evidence for directed transport. Instead, infection with different herpesviruses induced an enlargement of interchromatin domains and allowed particles to diffuse unrestricted over longer distances, thereby facilitating nuclear egress for a larger fraction of capsids. PMID:26438852

  18. Remodeling nuclear architecture allows efficient transport of herpesvirus capsids by diffusion

    PubMed Central

    Bosse, Jens B.; Hogue, Ian B.; Feric, Marina; Thiberge, Stephan Y.; Sodeik, Beate; Brangwynne, Clifford P.; Enquist, Lynn W.

    2015-01-01

    The nuclear chromatin structure confines the movement of large macromolecular complexes to interchromatin corrals. Herpesvirus capsids of approximately 125 nm assemble in the nucleoplasm and must reach the nuclear membranes for egress. Previous studies concluded that nuclear herpesvirus capsid motility is active, directed, and based on nuclear filamentous actin, suggesting that large nuclear complexes need metabolic energy to escape nuclear entrapment. However, this hypothesis has recently been challenged. Commonly used microscopy techniques do not allow the imaging of rapid nuclear particle motility with sufficient spatiotemporal resolution. Here, we use a rotating, oblique light sheet, which we dubbed a ring-sheet, to image and track viral capsids with high temporal and spatial resolution. We do not find any evidence for directed transport. Instead, infection with different herpesviruses induced an enlargement of interchromatin domains and allowed particles to diffuse unrestricted over longer distances, thereby facilitating nuclear egress for a larger fraction of capsids. PMID:26438852

  19. Herpesvirus Entry into Host Cells Mediated by Endosomal Low pH.

    PubMed

    Nicola, Anthony V

    2016-09-01

    Herpesviral pathogenesis stems from infection of multiple cell types including the site of latency and cells that support lytic replication. Herpesviruses utilize distinct cellular pathways, including low pH endocytic pathways, to enter different pathophysiologically relevant target cells. This review details the impact of the mildly acidic milieu of endosomes on the entry of herpesviruses, with particular emphasis on herpes simplex virus 1 (HSV-1). Epithelial cells, the portal of primary HSV-1 infection, support entry via low pH endocytosis mechanisms. Mildly acidic pH triggers reversible conformational changes in the HSV-1 class III fusion protein glycoprotein B (gB). In vitro treatment of herpes simplex virions with a similar pH range inactivates infectivity, likely by prematurely activating the viral entry machinery in the absence of a target membrane. How a given herpesvirus mediates both low pH and pH-independent entry events is a key unresolved question. PMID:27126894

  20. [Progress on the Function of Herpesvirus-encoded MicroRNAs].

    PubMed

    Cai, Zhenzhen; Jia, Renyong

    2015-11-01

    Since Epstein Barr virus was shown to encode microRNAs(miRNAs) in 2004, more than 470 miRNAs have been discovered in α-, β-, and γ-herpesviruses. MiRNAs are small non-coding RNA molecules and generally only have 18-25 nucleotides in length, which can regulate the expression of target genes by targeting its transcripts. Herpesvirus-encoded miRNAs not only target the key genes from latency to lytic replication, but also regulate various host cellular genes. Current data manifest that herpesvirus-encoded miRNAs can regulate viral latent infection and lytic replication, immune recognition, apoptosis, and tumorigenesis. The purpose of this paper is to summarize the targets and their fuction of hepesvirus-encoded miRNAs, in order to provide theoretical support for further analysis herpesviral pathogenesis. PMID:26951018

  1. Herpesvirus Late Gene Expression: A Viral-Specific Pre-initiation Complex Is Key

    PubMed Central

    Gruffat, Henri; Marchione, Roberta; Manet, Evelyne

    2016-01-01

    During their productive cycle, herpesviruses exhibit a strictly regulated temporal cascade of gene expression that can be divided into three general stages: immediate-early (IE), early (E), and late (L). This expression program is the result of a complex interplay between viral and cellular factors at both the transcriptional and post-transcriptional levels, as well as structural differences within the promoter architecture for each of the three gene classes. Since the cellular enzyme RNA polymerase II (RNAP-II) is responsible for the transcription of herpesvirus genes, most viral promoters contain DNA motifs that are common with those of cellular genes, although promoter complexity decreases from immediate-early to late genes. Immediate-early and early promoters contain numerous cellular and viral cis-regulating sequences upstream of a TATA box, whereas late promoters differ significantly in that they lack cis-acting sequences upstream of the transcription start site (TSS). Moreover, in the case of the β- and γ-herpesviruses, a TATT box motif is frequently found in the position where the consensus TATA box of eukaryotic promoters usually localizes. The mechanisms of transcriptional regulation of the late viral gene promoters appear to be different between α-herpesviruses and the two other herpesvirus subfamilies (β and γ). In this review, we will compare the mechanisms of late gene transcriptional regulation between HSV-1, for which the viral IE transcription factors – especially ICP4 – play an essential role, and the two other subfamilies of herpesviruses, with a particular emphasis on EBV, which has recently been found to code for its own specific TATT-binding protein. PMID:27375590

  2. Circular Herpesvirus sylvilagus DNA in spleen cells of experimentally infected cottontail rabbits.

    PubMed

    Medveczky, P; Kramp, W J; Sullivan, J L

    1984-11-01

    Cottontail rabbits (Sylvilagus floridanus) were infected with Herpesvirus sylvilagus, and spleen cells were analyzed for the presence of virus-specific, covalently closed circular, and linear DNA molecules by a simple electrophoretic technique, followed by transfer to nitrocellulose filters and hybridization with cloned viral DNA (Gardella et al., J. Virol. 50:248-254, 1984). Approximately 0.2 copies per cell of circular DNA and 0.2 copies per cell of linear DNA were detected by hybridization with a cloned viral DNA fragment. The size of the viral DNA was estimated at ca. 158 kilobase pairs. Restriction endonuclease patterns suggested structural similarities to cottontail herpesvirus DNA. PMID:6092696

  3. Induction of hyaluronan production by oncogenic KSHV and the contribution to viral pathogenesis in AIDS patients.

    PubMed

    Dai, Lu; Chen, Yihan; Bonstaff, Karlie; Doyle, Lisa; Toole, Bryan; Parsons, Chris; Qin, Zhiqiang

    2015-07-01

    Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), malignancies arising primarily in immunocompromised patients particularly AIDS-patients, which still lack effective therapy. Hyaluronan (HA) is a large glucuronic acid and has been found closely related to multiple functions in cancer cells, although its role in viral oncogenesis remains largely unknown. Here we provide first evidence that KSHV de novo infection induces HA production from primary endothelial cells through upregulation of HA synthase gene 1 (Has1) and a multifunctional glycoprotein, CD147. Further data demonstrate that KSHV-induced HA production requires viral latent protein, LANA (in particular functional domain A) and MAPK/ERK signaling activities. In functions, HA production is necessary for KSHV/LANA-induced primary endothelial cell invasion, a hallmark feature for KS development. For clinical relevance, our data indicate that the KSHV+ group has higher levels of HA and Has1 activities in its plasma than the KSHV- group of cohort HIV-infected patients. Together, our findings provide innovative insights into the mechanisms of oncogenic virus activation of HA production and its role in virus-associated malignancy pathogenesis, which may help to develop novel therapeutic strategies by targeting HA and related signaling. PMID:25837851

  4. MicroRNA-34a promotes genomic instability by a broad suppression of genome maintenance mechanisms downstream of the oncogene KSHV-vGPCR.

    PubMed

    Krause, Claudia J; Popp, Oliver; Thirunarayanan, Nanthakumar; Dittmar, Gunnar; Lipp, Martin; Müller, Gerd

    2016-03-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded chemokine receptor vGPCR acts as an oncogene in Kaposi's sarcomagenesis. Until now, the molecular mechanisms by which the vGPCR contributes to tumor development remain incompletely understood. Here, we show that the KSHV-vGPCR contributes to tumor progression through microRNA (miR)-34a-mediated induction of genomic instability. Large-scale analyses on the DNA, gene and protein level of cell lines derived from a mouse model of vGPCR-driven tumorigenesis revealed that a vGPCR-induced upregulation of miR-34a resulted in a broad suppression of genome maintenance genes. A knockdown of either the vGPCR or miR-34a largely restored the expression of these genes and confirmed miR-34a as a downstream effector of the KSHV-vGPCR that compromises genome maintenance mechanisms. This novel, protumorigenic role of miR-34a questions the use of miR-34a mimetics in cancer therapy as they could impair genome stability. PMID:26871287

  5. Suppression of KSHV-induced angiopoietin-2 inhibits angiogenesis, infiltration of inflammatory cells, and tumor growth.

    PubMed

    Yu, Xiaolan; Sha, Jingfeng; Xiang, Shao; Qin, Sanhai; Conrad, Patricia; Ghosh, Santosh K; Weinberg, Aaron; Ye, Fengchun

    2016-08-01

    Kaposi's sarcoma (KS) is a highly angiogenic and inflammatory neoplasia. The angiogenic and inflammatory cytokine angiopoietin-2 (Ang-2) is strongly expressed in KS due to Kaposi's sarcoma-associated herpesvirus (KSHV) infection. In the present study, we determined how Ang-2 contributes to development of KS by using telomerase-immortalized human umbilical vein endothelial cells (TIVE) as a model, which become malignantly transformed and express increased levels of Ang-2 following KSHV infection. Ang-2 released from TIVE-KSHV cells induces tyrosine phosphorylation of Tie-2 receptor from both human and mouse endothelial cells and promotes angiogenesis in nude mice. Functional inhibition or expressional "knock-down" of Ang-2 in these cells blocks angiogenesis and inhibits tumor growth. Ang-2 suppression also reduces the numbers of infiltrating monocytes/macrophages in tumors. In transwell-based cell migration assays, Ang-2 indeed enhances migration of human monocytes in a dose-dependent manner. These results underscore a pivotal role of KSHV-induced Ang-2 in KS tumor development by promoting both angiogenesis and inflammation. Our data also suggest that selective drug targeting of Ang-2 may be used for treatment of KS. PMID:27294705

  6. Extracellular Hsp90 serves as a co-factor for MAPK activation and latent viral gene expression during de novo infection by KSHV

    SciTech Connect

    Qin Zhiqiang; DeFee, Michael; Isaacs, Jennifer S.; Parsons, Chris

    2010-07-20

    The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an important cause of morbidity and mortality in immunocompromised patients. KSHV interaction with the cell membrane triggers activation of specific intracellular signal transduction pathways to facilitate virus entry, nuclear trafficking, and ultimately viral oncogene expression. Extracellular heat shock protein 90 localizes to the cell surface (csHsp90) and facilitates signal transduction in cancer cell lines, but whether csHsp90 assists in the coordination of KSHV gene expression through these or other mechanisms is unknown. Using a recently characterized non-permeable inhibitor specifically targeting csHsp90 and Hsp90-specific antibodies, we show that csHsp90 inhibition suppresses KSHV gene expression during de novo infection, and that this effect is mediated largely through the inhibition of mitogen-activated protein kinase (MAPK) activation by KSHV. Moreover, we show that targeting csHsp90 reduces constitutive MAPK expression and the release of infectious viral particles by patient-derived, KSHV-infected primary effusion lymphoma cells. These data suggest that csHsp90 serves as an important co-factor for KSHV-initiated MAPK activation and provide proof-of-concept for the potential benefit of targeting csHsp90 for the treatment or prevention of KSHV-associated illnesses.

  7. MicroRNA-34a promotes genomic instability by a broad suppression of genome maintenance mechanisms downstream of the oncogene KSHV-vGPCR

    PubMed Central

    Krause, Claudia J.; Popp, Oliver; Thirunarayanan, Nanthakumar; Dittmar, Gunnar; Lipp, Martin; Müller, Gerd

    2016-01-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded chemokine receptor vGPCR acts as an oncogene in Kaposi's sarcomagenesis. Until now, the molecular mechanisms by which the vGPCR contributes to tumor development remain incompletely understood. Here, we show that the KSHV-vGPCR contributes to tumor progression through microRNA (miR)-34a-mediated induction of genomic instability. Large-scale analyses on the DNA, gene and protein level of cell lines derived from a mouse model of vGPCR-driven tumorigenesis revealed that a vGPCR–induced upregulation of miR-34a resulted in a broad suppression of genome maintenance genes. A knockdown of either the vGPCR or miR-34a largely restored the expression of these genes and confirmed miR-34a as a downstream effector of the KSHV-vGPCR that compromises genome maintenance mechanisms. This novel, protumorigenic role of miR-34a questions the use of miR-34a mimetics in cancer therapy as they could impair genome stability. PMID:26871287

  8. KSHV Latency Locus Cooperates with Myc to Drive Lymphoma in Mice

    PubMed Central

    Sin, Sang-Hoon; Kim, Yongbaek; Eason, Anthony; Dittmer, Dirk P.

    2015-01-01

    Kaposi sarcoma-associated herpesvirus (KSHV) has been linked to Kaposi sarcoma and B-cell malignancies. Mechanisms of KSHV-induced oncogenesis remain elusive, however, in part due to lack of reliable in vivo models. Recently, we showed that transgenic mice expressing the KSHV latent genes, including all viral microRNAs, developed splenic B cell hyperplasia with 100% penetrance, but only a fraction converted to B cell lymphomas, suggesting that cooperative oncogenic events were missing. Myc was chosen as a possible candidate, because Myc is deregulated in many B cell lymphomas. We crossed KSHV latency locus transgenic (latency) mice to Cα Myc transgenic (Myc) mice. By itself these Myc transgenic mice develop lymphomas only rarely. In the double transgenic mice (Myc/latency) we observed plasmacytosis, severe extramedullary hematopoiesis in spleen and liver, and increased proliferation of splenocytes. Myc/latency mice developed frank lymphoma at a higher rate than single transgenic latency or Myc mice. These data indicate that the KSHV latency locus cooperates with the deregulated Myc pathways to further lymphoma progression. PMID:26327622

  9. Herpesvirus ateles and herpesvirus saimiri transform marmoset T cells into continuously proliferating cell lines that can mediate natural killer cell-like cytotoxicity.

    PubMed Central

    Johnson, D R; Jondal, M

    1981-01-01

    Herpesvirus ateles (HVA) and herpesvirus saimiri (HVS) have the capacity to transform cotton-topped marmoset T lymphocytes into continuously proliferating cell lines that retain some functions associated with cell-mediated immunity. In the present paper, we demonstrate that HVA/HVS-transformed T cell lines are cytotoxic in a short-term 51Cr release assay and that this killing resembles killing by marmoset natural killer (NK) cells. The relationship between NK cells and HVA/HVS-transformed killer cell lines is discussed in view of present knowledge of the origin and function of the NK system. It is suggested that the described cytotoxic cell lines may be useful for further defining cellular cytotoxicity with regard to cell surface recognition, regulatory events, and lytic mechanisms. PMID:6273869

  10. Human Herpesvirus Type 8-positive Multicentric Castleman Disease.

    PubMed

    Melikyan, Anait L; Egorova, Elena K; Julhakyan, Hunan L; Kovrigina, Alla L; Savchenko, Valeriy G

    2016-08-01

    Castleman disease (CD) is rare lymphoproliferative disorder with local lesionsor with multiple lessions (multicentric CD [MCD]-usually with plasma cell or mix cell morphology). Patients with human herpesvirus (HHV) type 8-positive MCD were included in a separate group owing to its extremely aggressive course and the high risk of transformation into HHV8(+) plasmablastic lymphoma. At our hematologic center, from 1996 to the present, the clinical and morphologic features of 87 patients with CD were analyzed. Immunohistochemical examination revealed DNA HHV8(+) lymph node tissue in patients with plasma cell and mixed cell morphology. In 45 patients, plasma cell or mixed cell variant CD was diagnosed. In 21 patients (8%), the manifestation of CD was local and in 29 (9%), it was multicentric. HHV8 was identified in only 6 cases (23.1%) of MCD (5 men and 1 woman, with a median age of 48.2 years; range, 36-77 years). The median follow-up point was 39.2 months. In 4 patients, the mixed cell variant was diagnosed and in 2, the plasma cell variant was diagnosed. In all the patients, constitutional symptoms, generalized lymphadenopathy, and hepatosplenomegaly were detected. Various laboratory changes were observed, but the most significant were anemia, thrombocytopenia, hypergammaglobulinemia, M-component, increased erythrocyte sedimentation rate, and circulating immune complexes. In 2 cases of HHV8(+) CD, MCD was combined with autoimmune hemolytic anemia and in 2 cases with non-Hodgkin lymphoma. At the last follow-up point, 2 patients were still alive after CHOP (cyclophosphamide, prednisone, Adriamycin, vincristine) and R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate [Oncovin], prednisone) therapy with rituximab maintenance. HHV8(+) MCD results in aggressive multiorgan lesions and pronounced changes in laboratory test results. It is characterized by an unfavorable prognosis with a high risk of transformation to plasmablastic lymphoma and

  11. Experimental Infection of Reindeer with Cervid Herpesvirus 2▿

    PubMed Central

    das Neves, Carlos G.; Mørk, Torill; Godfroid, Jacques; Sørensen, Karen K.; Breines, Eva; Hareide, Ellinor; Thiry, Julien; Rimstad, Espen; Thiry, Etienne; Tryland, Morten

    2009-01-01

    Cervid herpesvirus 2 (CvHV2) has been isolated from reindeer (Rangifer tarandus tarandus), and serological data indicate that in reindeer this virus is endemic in Fennoscandia, Alaska, Canada, and Greenland. CvHV2 has been described as a cause of subclinical genital infections in reindeer, but little information on primary infections exists. In this study, six seronegative and presumably pregnant reindeer were allocated to one of two groups. Two animals were inoculated with CvHV2 intratracheally, and two animals intravaginally, with one control animal in each group receiving sterile water. Mild hyperthermia and serous discharges from the vagina and nose were observed. No abortions were recorded, but one calf died shortly after birth. Inoculated animals seroconverted and had neutralizing antibodies after days 7 to 10 postinfection. CvHV2 was detected by PCR in nasal and vaginal swabs from animals in both groups but could be isolated only from nasal swabs in the respiratory group and from vaginal swabs in the genital group. CvHV2 was detected by PCR in various organs and tissues postmortem. In control animals, the virus could not be isolated in spite of PCR-positive nasal and vaginal swab samples and some degree of positive immunostaining. One of the animals that were inoculated intratracheally developed a hemorrhagic, necrotizing bronchopneumonia, which was CvHV2 positive by PCR and immunohistochemistry. We conclude that CvHV2 can cause systemic infection, that both genital and respiratory inoculations can lead to virus shedding, and that the virus can infect the fetus in utero. PMID:19846680

  12. Immunological correlates of vaccination and infection for equine herpesvirus 1.

    PubMed

    Goodman, Laura B; Wimer, Christine; Dubovi, Edward J; Gold, Carvel; Wagner, Bettina

    2012-02-01

    Equine herpesvirus 1 (EHV-1) induces a variety of disease manifestations, including respiratory disease, abortions, and myeloencephalopathy. Several vaccines are commercially available but could not previously be distinguished by serologic testing from infection with EHV-1 (or the closely related EHV-4). Currently available vaccines are not reliably protective against the severe manifestations of the disease, including fatal myeloencephalopathy. We determined immunological parameters that can differentiate vaccinated from previously infected animals by comparing humoral and cellular EHV-1-specific responses in clinically healthy horses 10 months after vaccination. Forty-seven horses with known histories of vaccination and infection were studied, including a group of horses that survived a severe neurological outbreak 5 years prior to vaccination. Results of serum virus neutralization (SN), serum IgG isotyping, and cytokine profiling of lymphocyte subsets were compared. IgG4/7 levels strongly correlated with virus neutralization (P < 0.0001). IgG1/3 and SN values distinguished vaccinated/outbreak-exposed (vacc/outbreak) horses from vaccinated horses (P < 0.05). EHV-1-specific gamma interferon (IFN-γ)-producing CD4(+) (but not CD8(+)) T-cell numbers were also increased in vacc/outbreak horses, which distinguished them from vaccinated horses (P < 0.01). IFN-α secretion was similar between all groups and independent of previous exposure or vaccination. Our data suggest that IgG isotype responses to EHV-1 are more diverse under field conditions than is revealed by experimental studies and that the current modified-live virus (MLV) vaccine induces a more restricted IgG isotype response than does natural exposure to EHV-1. Since these parameters can be assessed in a high-throughput manner, they may prove useful in screening future vaccine candidates and assessing levels of protection. PMID:22205656

  13. Alcelaphine herpesvirus 1 glycoprotein B: recombinant expression and antibody recognition.

    PubMed

    Dry, Inga; Todd, Helen; Deane, David; Percival, Ann; Mclean, Kevin; Inglis, Neil F; Manson, Erin D T; Haig, David M; Nayuni, Shilpa; Hutt-Fletcher, Lindsey M; Grant, Dawn M; Bartley, Kathryn; Stewart, James P; Russell, George C

    2016-03-01

    The gammaherpesvirus alcelaphine herpesvirus 1 (AlHV-1) causes fatal malignant catarrhal fever (MCF) in susceptible species including cattle, but infects its reservoir host, wildebeest, without causing disease. Pathology in cattle may be influenced by virus-host cell interactions mediated by the virus glycoproteins. Cloning and expression of a haemagglutinin-tagged version of the AlHV-1 glycoprotein B (gB) was used to demonstrate that the AlHV-1-specific monoclonal antibody 12B5 recognised gB and that gB was the main component of the gp115 complex of AlHV-1, a glycoprotein complex of five components identified on the surface of AlHV-1 by immunoprecipitation and radiolabelling. Analysis of AlHV-1 virus particles showed that the native form of gB was detected by mAb 12B5 as a band of about 70 kDa, whilst recombinant gB expressed by transfected HEK293T cells appeared to be subject to additional cleavage and incomplete post-translational processing. Antibody 12B5 recognised an epitope on the N-terminal furin-cleaved fragment of gB on AlHV-1 virus particles. It could be used to detect recombinant and virus-expressed gB on western blots and on the surface of infected cells by flow cytometry, whilst recombinant gB was detected on the surface of transfected cells by immunofluorescence. Recombinant gB has potential as an antigen for ELISA detection of MCF virus infection and as a candidate vaccine antigen. PMID:26650040

  14. Potential of bovine herpesvirus 4 as a gene delivery vector.

    PubMed

    Donofrio, Gaetano; Cavirani, Sandro; Simone, Taddei; van Santen, Vicky L

    2002-03-01

    A cloning system was developed for construction of BHV-4 recombinants and recombinant virus BHV-4EGFPDeltaTK containing an enhanced green fluorescent protein (EGFP) gene was constructed. The host range of BHV-4EGFPDeltaTK was characterized in vitro. When cell lines from various species and tissues were infected, most of the non-bovine cell lines exhibited neither cytopathic effect (CPE) nor supported viral replication, but EGFP expression was clearly observed. Next, embryonic stem cells were infected and induced to either non-specific or neural differentiation to determine whether they could survive and differentiate after BHV-4EGFPDeltaTK infection. Embryonic stem cells were infected successfully, as indicated by EGFP expression prior to differentiation, and EGFP expression could be detected in many differentiated cells. No CPE was noted. Therefore, BHV-4EGFPDeltaTK infection caused neither cell death nor interfered with non-specific or neural differentiation of embryonic stem cells. Finally, to assess the capability of BHV-4EGFPDeltaTK to infect post-mitotic neurons, cultures from brains of 2-weeks old mice were infected. No death of neuronal cells due to infection was observed and EGFP expression persisted for at least 15 days. Several biological characteristics of BHV-4 demonstrated previously make it a good candidate for a gene delivery vector. These include: little or no pathogenicity, unlikely oncogenicity, ability to establish persistent infection, and capability of herpesviruses to accommodate large amounts of foreign genetic material. These findings add the ability to infect several cell types coming from different animal species, usually without CPE, lack of interference with differentiation, and ability to maintain transgene expression in both undifferentiated and differentiated cells. PMID:11849683

  15. Immunological Correlates of Vaccination and Infection for Equine Herpesvirus 1

    PubMed Central

    Goodman, Laura B.; Wimer, Christine; Dubovi, Edward J.; Gold, Carvel

    2012-01-01

    Equine herpesvirus 1 (EHV-1) induces a variety of disease manifestations, including respiratory disease, abortions, and myeloencephalopathy. Several vaccines are commercially available but could not previously be distinguished by serologic testing from infection with EHV-1 (or the closely related EHV-4). Currently available vaccines are not reliably protective against the severe manifestations of the disease, including fatal myeloencephalopathy. We determined immunological parameters that can differentiate vaccinated from previously infected animals by comparing humoral and cellular EHV-1-specific responses in clinically healthy horses 10 months after vaccination. Forty-seven horses with known histories of vaccination and infection were studied, including a group of horses that survived a severe neurological outbreak 5 years prior to vaccination. Results of serum virus neutralization (SN), serum IgG isotyping, and cytokine profiling of lymphocyte subsets were compared. IgG4/7 levels strongly correlated with virus neutralization (P < 0.0001). IgG1/3 and SN values distinguished vaccinated/outbreak-exposed (vacc/outbreak) horses from vaccinated horses (P < 0.05). EHV-1-specific gamma interferon (IFN-γ)-producing CD4+ (but not CD8+) T-cell numbers were also increased in vacc/outbreak horses, which distinguished them from vaccinated horses (P < 0.01). IFN-α secretion was similar between all groups and independent of previous exposure or vaccination. Our data suggest that IgG isotype responses to EHV-1 are more diverse under field conditions than is revealed by experimental studies and that the current modified-live virus (MLV) vaccine induces a more restricted IgG isotype response than does natural exposure to EHV-1. Since these parameters can be assessed in a high-throughput manner, they may prove useful in screening future vaccine candidates and assessing levels of protection. PMID:22205656

  16. Induction of T-cell apoptosis by human herpesvirus 6.

    PubMed Central

    Inoue, Y; Yasukawa, M; Fujita, S

    1997-01-01

    The mechanisms of cell death in CD4+ T cells mediated by human herpesvirus 6 (HHV-6) were investigated. The frequency of cell death in the human CD4+ T-cell line JJHAN, which had been inoculated with HHV-6 variant A or B, appeared to be augmented by tumor necrosis factor alpha (TNF-alpha). Agarose gel electrophoresis of DNA from HHV-6-inoculated cells showed DNA fragmentation in multiples of the oligonucleosome length unit. The degree of DNA fragmentation increased when HHV-6-inoculated cells were cultured in the presence of TNF-alpha. Flow cytometry and Scatchard analysis of TNF receptors revealed an increase in the number of the p55 form of TNF receptors on JJHAN cells after HHV-6 inoculation. It also appeared that treatment with anti-Fas monoclonal antibody (MAb) induced marked apoptosis in HHV-6-inoculated cells. Transmission electron microscopy showed characteristics of apoptosis, such as chromatin condensation and fragmentation of nuclei, but virus particles were hardly detected in apoptotic cells. Two-color flow cytometric analysis using anti-HHV-6 MAb and propidium iodide revealed that DNA fragmentation was present predominantly in uninfected cells but not in productively HHV-6-infected cells. In addition, JJHAN cells incubated with UV light-irradiated and ultracentrifuged culture supernatant of HHV-6-infected cells appeared to undergo apoptosis. The present study demonstrated that both HHV-6 variants A and B induce apoptosis in CD4+ T cells by indirect mechanisms, as reported recently in human immunodeficiency virus type 1 infection. PMID:9094650

  17. Evidence of widespread natural recombination among field isolates of equine herpesvirus 4 but not among field isolates of equine herpesvirus 1.

    PubMed

    Vaz, P K; Horsington, J; Hartley, C A; Browning, G F; Ficorilli, N P; Studdert, M J; Gilkerson, J R; Devlin, J M

    2016-03-01

    Recombination in alphaherpesviruses allows evolution to occur in viruses that have an otherwise stable DNA genome with a low rate of nucleotide substitution. High-throughput sequencing of complete viral genomes has recently allowed natural (field) recombination to be studied in a number of different alphaherpesviruses, however, such studies have not been applied to equine herpesvirus 1 (EHV-1) or equine herpesvirus 4 (EHV-4). These two equine alphaherpesviruses are genetically similar, but differ in their pathogenesis and epidemiology. Both cause economically significant disease in horse populations worldwide. This study used high-throughput sequencing to determine the full genome sequences of EHV-1 and EHV-4 isolates (11 and 14 isolates, respectively) from Australian or New Zealand horses. These sequences were then analysed and examined for evidence of recombination. Evidence of widespread recombination was detected in the genomes of the EHV-4 isolates. Only one potential recombination event was detected in the genomes of the EHV-1 isolates, even when the genomes from an additional 11 international EHV-1 isolates were analysed. The results from this study reveal another fundamental difference between the biology of EHV-1 and EHV-4. The results may also be used to help inform the future safe use of attenuated equine herpesvirus vaccines. PMID:26691326

  18. Phylogenetic characterization of a novel herpesvirus found in the liver and lungs of a Chilean flamingo (Phoenicopterus chilensis).

    PubMed

    Coverdill, Christopher C; Barnes, Julie A; Garner, Michael M; Hinton, Kevin L; Childress, April L; Wellehan, James F X

    2016-05-01

    A novel herpesvirus was detected in a 17-day-old Chilean flamingo (Phoenicopterus chilensis) with pneumonia, hepatopathy, and severe anemia that was housed in California. Postmortem examination identified a pale, enlarged liver, mildly increased fluid in the lungs, and red foci in the spleen. Histologic examination revealed marked hepatic necrosis with syncytia, splenic necrosis, and interstitial pneumonia with eosinophilic intranuclear inclusions within hepatocytes and in unidentified cells of the lung. Transmission electron microscopy identified virions consistent with a herpesvirus in the nucleus and cytoplasm of degenerative hepatocytes. Nested consensus PCR, sequencing, and phylogenetic analysis identified a novel herpesvirus within the genus Iltovirus in the subfamily Alphaherpesvirinae. PMID:27026105

  19. Experimental induction of malignant catarrhal fever in pigs with ovine herpesvirus 2 by intranasal nebulization

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Malignant catarrhal fever (MCF), a frequently fatal herpesviral disease, has been sporadically reported in pigs. All cases of naturally-occurring porcine MCF reported to date have been linked to ovine herpesvirus 2 (OvHV-2), a gammaherpesvirus in the genus Macavirus carried by sheep. Experimental in...

  20. Malignant catarrhal fever in American bison (Bison bison) experimentally infected with alcelaphine herpesvirus 2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Malignant catarrhal fever (MCF) due to ovine herpesvirus-2 (OvHV-2) causes appreciable death loss in ranched bison (Bison bison) throughout North America. No vaccine exists to protect animals from disease. Since OvHV-2 has not been propagated in vitro, one strategy to develop a modified live vaccine...