Quantitative analysis of Epstein-Barr virus (EBV)-related gene expression in patients with chronic active EBV infection.

PubMed

Iwata, Seiko; Wada, Kaoru; Tobita, Satomi; Gotoh, Kensei; Ito, Yoshinori; Demachi-Okamura, Ayako; Shimizu, Norio; Nishiyama, Yukihiro; Kimura, Hiroshi

2010-01-01

Chronic active Epstein-Barr virus (CAEBV) infection is a systemic Epstein-Barr virus (EBV)-positive lymphoproliferative disorder characterized by persistent or recurrent infectious mononucleosis-like symptoms in patients with no known immunodeficiency. The detailed pathogenesis of the disease is unknown and no standard treatment regimen has been developed. EBV gene expression was analysed in peripheral blood samples collected from 24 patients with CAEBV infection. The expression levels of six latent and two lytic EBV genes were quantified by real-time RT-PCR. EBV-encoded small RNA 1 and BamHI-A rightward transcripts were abundantly detected in all patients, and latent membrane protein (LMP) 2 was observed in most patients. EBV nuclear antigen (EBNA) 1 and LMP1 were detected less frequently and were expressed at lower levels. EBNA2 and the two lytic genes were not detected in any of the patients. The pattern of latent gene expression was determined to be latency type II. EBNA1 was detected more frequently and at higher levels in the clinically active patients. Quantifying EBV gene expression is useful in clarifying the pathogenesis of CAEBV infection and may provide information regarding a patient's disease prognosis, as well as possible therapeutic interventions.

Systemic lupus erythematosus associated with acute Epstein-Barr virus infection.

PubMed

Dror, Y; Blachar, Y; Cohen, P; Livni, N; Rosenmann, E; Ashkenazi, A

1998-11-01

Systemic lupus erythematosus (SLE) is a multisystem disease of unknown origin, characterized by a variety of autoimmune phenomena. Viruses have long been postulated to play a role in its pathogenesis. Several observations suggested a link between Epstein-Barr virus (EBV) and SLE. We describe a 14-year-old girl who presented with acute onset of SLE concurrently with clinical and laboratory findings consistent with EBV-induced infectious mononucleosis (IM). Evidence for acute EBV infection was confirmed by serological studies and detection of specific EBV antigens on kidney biopsy. This close association between EBV and SLE suggests a possible role of the virus in the pathogenesis of SLE in this patient.

The Definition of Epstein Barr Virus (EBV)’s Role in HTLV-III Infected USAF Personnel as Related to Disease Progression

DTIC Science & Technology

1988-12-27

were considerably greater than those noted in patients with acute EBV induced infectious mononucleosis (IM), while the antibody levels to early... infectious (WR 1 - 6) (WR 1 only) (WR 1) Controls mononucleosis Oropharyngeat EBV 14/20 (70 ) 6/10 (60 ) 19/30 (63 ) 5/23 (21.7) 17/19 (89.5) Spontaneous... EBV infection in patients with ARC and AIDS. B cell lymphomas containing EBV - DNA are being reported in increased frequency in homosexuals and AIDS

Characterization of Epstein-Barr virus (EBV) BZLF1 gene promoter variants and comparison of cellular gene expression profiles in Japanese patients with infectious mononucleosis, chronic active EBV infection, and EBV-associated hemophagocytic lymphohistiocytosis.

PubMed

Imajoh, Masayuki; Hashida, Yumiko; Murakami, Masanao; Maeda, Akihiko; Sato, Tetsuya; Fujieda, Mikiya; Wakiguchi, Hiroshi; Daibata, Masanori

2012-06-01

Epstein-Barr virus (EBV) genotypes can be distinguished based on gene sequence differences in EBV nuclear antigens 2, 3A, 3B, and 3C, and the BZLF1 promoter zone (Zp). EBV subtypes and BZLF1 Zp variants were examined in Japanese patients with infectious mononucleosis, chronic active EBV infection, and EBV-associated hemophagocytic lymphohistiocytosis. The results of EBV typing showed that samples of infectious mononucleosis, chronic active EBV infection, and EBV-associated hemophagocytic lymphohistiocytosis all belonged to EBV type 1. However, sequencing analysis of BZLF1 Zp found three polymorphic Zp variants in the same samples. The Zp-P prototype and the Zp-V3 variant were both detected in infectious mononucleosis and chronic active EBV infection. Furthermore, a novel variant previously identified in Chinese children with infectious mononucleosis, Zp-V1, was also found in 3 of 18 samples of infectious mononucleosis, where it coexisted with the Zp-P prototype. This is the first evidence that the EBV variant distribution in Japanese patients resembles that found in other Asian patients. The expression levels of 29 chronic active EBV infection-associated cellular genes were also compared in the three EBV-related disorders, using quantitative real-time reverse transcription polymerase chain reaction analysis. Two upregulated genes, RIPK2 and CDH9, were identified as common specific markers for chronic active EBV infection in both in vitro and in vivo studies. RIPK2 activates apoptosis and autophagy, and could be responsible for the pathogenesis of chronic active EBV infection. Copyright © 2012 Wiley Periodicals, Inc.

Infectious mononucleosis accompanied by clonal proliferation of EBV-infected cells and infection of CD8-positive cells.

PubMed

Arai, Ayako; Yamaguchi, Takeshi; Komatsu, Honami; Imadome, Ken-Ichi; Kurata, Morito; Nagata, Kaoru; Miura, Osamu

2014-01-01

A 22-year-old male was admitted for a sustained fever of 2 months, lymphadenopathy, and liver dysfunction. Anti-VCA-IgM antibody was positive, with elevated Epstein-Barr virus (EBV)-DNA load in the peripheral blood. Liver biopsy revealed infiltration of CD8-positive and EBV-positive cells. Most peripheral blood mononuclear cells (PBMCs) were also positive for CD8, and showed detectable levels of EBV-DNA. Monoclonal proliferation of EBV-infected cells was detected in the PBMCs by Southern blotting for EBV-terminal repeat (EBV-TR). Although EBV-positive T-cell lymphoproliferative disease (EBV-T-LPD) was suspected, the symptoms spontaneously resolved within 12 months. Anti-VCA-IgM antibody and the clonal band of EBV-TR were negative 1 year after the onset, while anti-EBNA antibody was positive. The final diagnosis was thus confirmed as infectious mononucleosis (IM). Our results indicate that EBV-infected CD8-positive cells and clonal proliferation of EBV-infected cells may be temporally detected in IM. EBV-T-LPDs should be carefully excluded in such cases.

Efficient Immortalization of Primary Nasopharyngeal Epithelial Cells for EBV Infection Study

PubMed Central

Yip, Yim Ling; Pang, Pei Shin; Deng, Wen; Tsang, Chi Man; Zeng, Musheng; Hau, Pok Man; Man, Cornelia; Jin, Yuesheng; Yuen, Anthony Po Wing; Tsao, Sai Wah

2013-01-01

Nasopharyngeal carcinoma (NPC) is common among southern Chinese including the ethnic Cantonese population living in Hong Kong. Epstein-Barr virus (EBV) infection is detected in all undifferentiated type of NPC in this endemic region. Establishment of stable and latent EBV infection in premalignant nasopharyngeal epithelial cells is an early event in NPC development and may contribute to its pathogenesis. Immortalized primary nasopharyngeal epithelial cells represent an important tool for investigation of EBV infection and its tumorigenic potential in this special type of epithelial cells. However, the limited availability and small sizes of nasopharyngeal biopsies have seriously restricted the establishment of primary nasopharyngeal epithelial cells for immortalization. A reliable and effective method to immortalize primary nasopharyngeal epithelial cells will provide unrestricted materials for EBV infection studies. An earlier study has reported that Bmi-1 expression could immortalize primary nasopharyngeal epithelial cells. However, its efficiency and actions in immortalization have not been fully characterized. Our studies showed that Bmi-1 expression alone has limited ability to immortalize primary nasopharyngeal epithelial cells and additional events are often required for its immortalization action. We have identified some of the key events associated with the immortalization of primary nasopharyngeal epithelial cells. Efficient immortalization of nasopharyngeal epithelial cells could be reproducibly and efficiently achieved by the combined actions of Bmi-1 expression, activation of telomerase and silencing of p16 gene. Activation of MAPK signaling and gene expression downstream of Bmi-1 were detected in the immortalized nasopharyngeal epithelial cells and may play a role in immortalization. Furthermore, these newly immortalized nasopharyngeal epithelial cells are susceptible to EBV infection and supported a type II latent EBV infection program characteristic

Ganetespib, an HSP90 inhibitor, kills Epstein-Barr virus (EBV)-infected B and T cells and reduces the percentage of EBV-infected cells in the blood.

PubMed

Shatzer, Amber; Ali, Mir A; Chavez, Mayra; Dowdell, Kennichi; Lee, Min-Jung; Tomita, Yusuke; El-Hariry, Iman; Trepel, Jane B; Proia, David A; Cohen, Jeffrey I

2017-04-01

HSP90 inhibitors have been shown to kill Epstein-Barr virus (EBV)-infected cells by reducing the level of EBV EBNA-1 and/or LMP1. We treated virus-infected cells with ganetespib, an HSP90 inhibitor currently being evaluated in multiple clinical trials for cancer and found that the drug killed EBV-positive B and T cells and reduced the level of both EBV EBNA-1 and LMP1. Treatment of cells with ganetespib also reduced the level of pAkt. Ganetespib delayed the onset of EBV-positive lymphomas and prolonged survival in SCID mice inoculated with one EBV-transformed B-cell line, but not another B-cell line. The former cell line showed lower levels of EBNA-1 after treatment with ganetespib in vitro. Treatment of a patient with T-cell chronic active EBV with ganetespib reduced the percentage of EBV-positive cells in the peripheral blood. These data indicate that HSP90 inhibitors may have a role in the therapy of certain EBV-associated diseases.

Detailed kinetics of EBV-specific CD4+ and CD8+ T cells during primary EBV infection in a kidney transplant patient.

PubMed

Piriou, Erwan R W A N; van Dort, Karel; Weel, Jan F L; Bemelman, Frederike J; Gamadia, Laila E; van Oers, Marinus H J; van Baarle, Debbie

2006-04-01

The etiology of infectious mononucleosis is poorly understood and usually detected many weeks after infection. Here, we present a unique case of primary symptomatic EBV infection after kidney transplantation, in whom we analyzed both EBV-specific CD4+ and CD8+ T cells in detail from the moment of infection up to latency. We show that EBV-specific T-cell responses in peripheral blood during primary EBV infection after kidney transplantation peaked early after the appearance of viral load, but well before onset of IM symptoms, suggesting that IM in this case is not caused by high numbers of CD8+ T cells per se but may be caused by lack of homing to lymph nodes or tonsils.

EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood

PubMed Central

Hong, Mineui; Yoo, Keon Hee; Koo, Hong Hoe; Kim, Seok Jin; Kim, Won Seog

2013-01-01

Background Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality. Methods Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed. Results STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis. Conclusions EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment. PMID:23667373

EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood.

PubMed

Hong, Mineui; Ko, Young Hyeh; Yoo, Keon Hee; Koo, Hong Hoe; Kim, Seok Jin; Kim, Won Seog; Park, Heejung

2013-04-01

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality. Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed. STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis. EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment.

Primary EBV infection of human umbilical cord lymphocytes and EBV genome-negative lymphoblastoid cell lines (BJAB and Ramos).

PubMed

Takimoto, T; Sato, H; Ogura, H

1986-01-01

The appearance of Epstein-Barr virus (EBV)-associated nuclear antigen (EBNA) and induction of EBV-induced early antigen (EA) in human umbilical cord blood lymphocytes (HUCLs) and two EBV genome-negative Burkitt's lymphoma (BL) lines (BJAB and Ramos) were studied by infection with EBVs prepared from three different cell lines: marmoset cell line (B95-8) derived from infections mononucleosis, BL-derived cell line (P3HR-1) and human epithelial hybrid cell line (NPC-KT) derived from nasopharyngeal carcinoma. B95-8 virus can transform HUCLs but cannot superinfect Raji cells. P3HR-1 virus can transform HUCLs cells but cannot transform HUCLs. NPC-KT virus can transform HUCLs and can superinfect Raji cells. We have examined the time sequence of EBNA appearance and EA induction in HUCLs, BJAB cells and Ramos cells, in order to determine if three different strains of EBV differ in their abilities to infect their cells. We found that all three strains of EBV can induce EBNA in HUCLs, BJAB cells and Ramos cells. On the other hand, we found that P3HR-1 virus and NPC-KT virus can induce EA in BJAB cells and Ramos cells, but B95-8 virus cannot induce EA in their cells.

CD95 (Fas) ligand expression of Epstein-Barr virus (EBV)-infected lymphocytes: a possible mechanism of immune evasion in chronic active EBV infection.

PubMed

Ohshima, K; Suzumiya, J; Sugihara, M; Nagafuchi, S; Ohga, S; Kikuchi, M

1999-01-01

The Epstein-Barr virus (EBV) induces infectious mononucleosis (IM) and can be associated with chronic active EBV infection (CAEBV). Cytotoxic T lymphocytes (CTL) play an important role in excluding EBV-infected cells. Two cytotoxic mechanisms of CTL have been demonstrated: one perforin/granzyme-based and the other Fas (CD95)/Fas ligand (FasL)-based. To clarify these two pathways in CAEBV, we analyzed six patients with CAEBV and four patients with IM using immunohistochemical staining of the lymph nodes. In both CAEBV and IM, CD8+ T-cells increased in number, but CD56+ natural killer cells were rare. In four of six cases with CAEBV, approximately half the lymphocytes were positive for T cell-restricted intracellular antigens (TIA-1), which were recognized by the cytolytic granules of CTL. In IM, the number of TIA-1 positive cells was smaller than that in CAEBV. Fas-positive lymphocytes were frequently encountered in both CAEBV and IM. However, FasL-positive lymphocytes increased in three of six patients with CAEBV, but not in patients with IM. Except for one case with CAEBV, the number of perforin- and/or granzyme-positive cells was small in number in both CAEBV and IM cases. In double-staining FasL and EBV in situ hybridization, FasL-positive EBV-infected lymphocytes were detected in CAEBV but not in IM. In CAEBV, the Fas/FasL pathway and not perforin pathways appears to play an important role in the pathogenesis. The data suggest that EBV-infected lymphocytes may evade immune attack through the expression of FasL.

Epstein-Barr virus (EBV)–encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3

PubMed Central

Iwakiri, Dai; Zhou, Li; Samanta, Mrinal; Matsumoto, Misako; Ebihara, Takashi; Seya, Tsukasa; Imai, Shosuke; Fujieda, Mikiya; Kawa, Keisei

2009-01-01

Epstein-Barr virus–encoded small RNA (EBER) is nonpolyadenylated, noncoding RNA that forms stem-loop structure by intermolecular base-pairing, giving rise to double-stranded RNA (dsRNA)–like molecules, and exists abundantly in EBV-infected cells. Here, we report that EBER induces signaling from the Toll-like receptor 3 (TLR3), which is a sensor of viral double-stranded RNA (dsRNA) and induces type I IFN and proinflammatory cytokines. A substantial amount of EBER, which was sufficient to induce signaling from TLR3, was released from EBV-infected cells, and the majority of the released EBER existed as a complex with a cellular EBER-binding protein La, suggesting that EBER was released from the cells by active secretion of La. Sera from patients with infectious mononucleosis (IM), chronic active EBV infection (CAEBV), and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), whose general symptoms are caused by proinflammatory cytokines contained EBER, and addition of RNA purified from the sera into culture medium induced signaling from TLR3 in EBV-transformed lymphocytes and peripheral mononuclear cells. Furthermore, DCs treated with EBER showed mature phenotype and antigen presentation capacity. These findings suggest that EBER, which is released from EBV-infected cells, is responsible for immune activation by EBV, inducing type I IFN and proinflammatory cytokines. EBER-induced activation of innate immunity would account for immunopathologic diseases caused by active EBV infection. PMID:19720839

Identical IgM antibodies recognizing a glycine-alanine epitope are induced during acute infection with Epstein-Barr virus and cytomegalovirus.

PubMed

Rhodes, G; Smith, R S; Rubin, R E; Vaughan, J; Horwitz, C A

1990-01-01

We studied antibody production in serial serum samples from patients with acute Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. Sera were analyzed both by enzyme-linked immunosorbent assay (ELISA) using a synthetic peptide (P62) derived from the glycine-alanine repeating region of the Epstein-Barr nuclear antigen (EBNA-1) and by immunoblotting. In prior studies, we have shown that patients with acute EBV infection make IgM antibodies that react with this peptide, that recognize a viral-specific protein (EBNA-1), and that bind with a number of proteins present in uninfected cells; however, antibody binding to these autoantigens was inhibited by the peptide. IgG antibodies reactive with the peptide did not appear until months after the disease and were specific for the EBNA-1 protein. We now find that patients with acute CMV infection but not those with acute infections from a variety of other nonherpes organisms also produce IgM antibodies that recognize the EBV-derived peptide P62. These antibodies also appear to recognize the same cellular proteins as the EBV-induced IgM antibodies. The IgM antibodies appeared in all acutely infected CMV patients studied and occurred both in patients with previous EBV infections and in one patient studied who had not previously been exposed to EBV. It appears that infection with EBV or CMV can induce the synthesis of a very similar or identical set of IgM antibodies.

Acute or chronic life-threatening diseases associated with Epstein-Barr virus infection.

PubMed

Okano, Motohiko; Gross, Thomas G

2012-06-01

Infectious mononucleosis (IM) is one of the representative, usually benign, acute diseases associated with primary Epstein-Barr virus (EBV) infection. IM is generally self-limiting and is characterized mostly by transient fever, lymphadenopathy and hepatosplenomegaly. However, very rarely primary EBV infection results in severe or fatal conditions such as hemophagocytic lymphohistiocytosis together with fulminant hepatitis designated as severe or fatal IM or EBV-associated hemophagocytic lymphohistiocytosis alone. In addition, chronic EBV-associated diseases include Burkitt's lymphoma, undifferentiated nasopharyngeal carcinoma, Hodgkin lymphoma, T-cell lymphoproliferative disorder (LPD)/lymphoma, natural killer-cell LPD including leukemia or lymphoma, gastric carcinoma, pyothorax-associated lymphoma and senile B-cell LPD as well as chronic active EBV infection and LPD/lymphoma in patients with immunodeficiency. The number of chronic life-threatening diseases linked to the EBV infection is increasingly reported and many of these diseases have a poor prognosis. This review will focus on the historical, pathogenetic, diagnostic, therapeutic and prophylactic issues of EBV-associated life-threatening diseases.

Heterogeneous, restricted patterns of Epstein-Barr virus (EBV) latent gene expression in patients with chronic active EBV infection.

PubMed

Yoshioka, M; Ishiguro, N; Ishiko, H; Ma, X; Kikuta, H; Kobayashi, K

2001-10-01

Epstein-Barr virus (EBV) has been shown to infect T lymphocytes and to be associated with a chronic active infection (CAEBV), which has been recognized as a mainly non-neoplastic T-cell lymphoproliferative disorder (T-cell LPD). The systemic distribution of EBV genomes was studied, by real-time PCR, in multiple tissues from six patients with CAEBV, including three patients with T-cell LPD, one patient with B-cell LPD and two patients with undetermined cell-type LPD. There were extremely high loads of EBV genomes in all tissues from the patients. This reflects an abundance of circulating and infiltrating EBV-infected cells and a wide variety of clinical symptoms in the affected tissues. We chose one sample from each patient that was shown by real-time PCR to contain a high load of EBV genomes and examined the expression of EBV latent genes by RT-PCR. EBER1 and EBNA1 transcripts were detected in all samples. Only one sample also expressed EBNA2, LMP1 and LMP2A transcripts in addition to EBER1 and EBNA1 transcripts. Two of the remaining five samples expressed LMP1 and LMP2A transcripts. One sample expressed LMP2A but not LMP1 and EBNA2 transcripts. Another sample expressed EBNA2 but not LMP1 and LMP2A transcripts. The other sample did not express transcripts of any of the other EBNAs or LMPs. None of the samples expressed the viral immediate-early gene BZLF1. These results showed that EBV latent gene expression in CAEBV is heterogeneous and that restricted forms of EBV latency might play a pathogenic role in the development of CAEBV.

Acute Infection with Epstein-Barr Virus Targets and Overwhelms the Peripheral Memory B-Cell Compartment with Resting, Latently Infected Cells

PubMed Central

Hochberg, Donna; Souza, Tatyana; Catalina, Michelle; Sullivan, John L.; Luzuriaga, Katherine; Thorley-Lawson, David A.

2004-01-01

In this paper we demonstrate that during acute infection with Epstein-Barr virus (EBV), the peripheral blood fills up with latently infected, resting memory B cells to the point where up to 50% of all the memory cells may carry EBV. Despite this massive invasion of the memory compartment, the virus remains tightly restricted to memory cells, such that, in one donor, fewer than 1 in 104 infected cells were found in the naive compartment. We conclude that, even during acute infection, EBV persistence is tightly regulated. This result confirms the prediction that during the early phase of infection, before cellular immunity is effective, there is nothing to prevent amplification of the viral cycle of infection, differentiation, and reactivation, causing the peripheral memory compartment to fill up with latently infected cells. Subsequently, there is a rapid decline in infected cells for the first few weeks that approximates the decay in the cytotoxic-T-cell responses to viral replicative antigens. This phase is followed by a slower decline that, even by 1 year, had not reached a steady state. Therefore, EBV may approach but never reach a stable equilibrium. PMID:15113901

Quercetin-induced apoptosis prevents EBV infection

PubMed Central

Lee, Minjung; Son, Myoungki; Ryu, Eunhyun; Shin, Yu Su; Kim, Jong Gwang; Kang, Byung Woog; Sung, Gi-Ho; Cho, Hyosun; Kang, Hyojeung

2015-01-01

Epstein-Barr virus (EBV) is a human gamma-1 herpesvirus that establishes a lifelong latency in over 90% of the world's population. During latency, virus exists predominantly as a chromatin-associated, multicopy episome in the nuclei of a variety of tumor cells derived from B cells, T cells, natural killer (NK) cells, and epithelial cells. Licorice is the root of Glycyrrhiza uralensis or G. glabra that has traditionally cultivated in eastern part of Asia. Licorice was reported to have anti-viral, anti-inflammatory, anti-atopic, hepatoprotective, anti-neurodegenerative, anti-tumor, anti-diabetic effects and so forth. Quercetin and isoliquiritigenin are produced from licorice and highly similar in molecular structure. They have diverse bioactive effects such as antiviral activity, anti-asthmatic activity, anti-cancer activity, anti-inflammation activity, monoamine-oxidase inhibitor, and etc. To determine anti-EBV and anti-EBVaGC (Epstein-Barr virus associated gastric carcinoma) effects of licorice, we investigated antitumor and antiviral effects of quercetin and isoliquiritigenin against EBVaGC. Although both quercetin and isoliquiritigenin are cytotoxic to SNU719 cells, quercetin induced more apoptosis in SNU719 cells than isoliquiritigenin, more completely eliminated DNMT1 and DNMT3A expressions than isoliquiritigenin, and more strongly affects the cell cycle progression of SNU719 than isoliquiritigenin. Both quercetin and isoliquiritigenin induce signal transductions to stimulate apoptosis, and induce EBV gene transcription. Quercetin enhances frequency of F promoter use, whereas isoliquiritigenin enhances frequency of Q promoter use. Quercetin reduces EBV latency, whereas isoliquiritigenin increases the latency. Quercetin increases more the EBV progeny production, and inhibits more EBV infection than isoliquiritigenin. These results indicate that quercetin could be a promising candidate for antiviral and antitumor agents against EBV and human gastric carcinoma

Unique Epstein-Barr virus (EBV) latent gene expression, EBNA promoter usage and EBNA promoter methylation status in chronic active EBV infection.

PubMed

Yoshioka, Mikio; Kikuta, Hideaki; Ishiguro, Nobuhisa; Ma, Xiaoming; Kobayashi, Kunihiko

2003-05-01

Chronic active Epstein-Barr virus infection (CAEBV) has been considered to be a non-neoplastic T-cell lymphoproliferative disease associated with Epstein-Barr virus (EBV) infection. In EBV-associated diseases, the cell phenotype-dependent differences in EBV latent gene expression may reflect the strategy of the virus in relation to latent infection. We previously reported that EBV latent gene expression was restricted; EBV nuclear antigen 1 (EBNA1) transcripts were consistently detected in all spleen samples from five CAEBV patients, but EBNA2 transcripts were detected in only one sample. EBV latent gene expression is controlled by distinct usage of three EBNA promoters (Cp, Wp and Qp). In this study, we examined the EBNA promoter usage by RT-PCR and the methylation status in the Cp and Wp regions using bisulfite PCR analysis in spleen samples from CAEBV patients. EBNA1 transcripts were unexpectedly initiated not from Qp but from Cp in all samples in spite of the restricted form of latency. Furthermore, while Cp was active, Cp was heavily methylated, indicating that CAEBV has unique EBV latent gene expression, EBNA promoter usage and EBNA promoter methylation status, in part due to unique splicing of Cp-initiated transcripts and an activation mechanism in hypermethylated Cp.

Profiling of EBV-Encoded microRNAs in EBV-Associated Hemophagocytic Lymphohistiocytosis.

PubMed

Zhou, Chen; Xie, Zhengde; Gao, Liwei; Liu, Chunyan; Ai, Junhong; Zhang, Li; Shen, Kunling

2015-10-01

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening complication of EBV infection. MicroRNAs (miRNAs) were small non-coding RNA, and EBV could encode miRNAs that are involved in the progression of infection. However, the profiles of EBV-miRNAs in EBV-HLH were unknown. Here, we aimed to profile the expression of EBV-miRNAs in children with EBV-HLH by analyzing 44 known EBV-miRNAs, encoded within the BamHI fragment H rightward open reading frame 1 (BHRF1) and the BamHI-A region rightward transcript (BART), in plasma and cellular targets by real-time quantitative PCR. The study included 15 children with EBV-HLH, 15 children with infectious mononucleosis (IM), and 15 healthy controls. CD8(+) T cells were found to be the cellular target of EBV infection in EBV-HLH, while CD19(+) B cells were infected with EBV in IM. We also found the greater levels of several miRNAs encoded by BART in EBV-HLH, compared to those in IM and healthy controls, whereas the levels of BHRF1 miRNAs were lower than those in IM. The profile and pattern of EBV-miRNAs in EBV-HLH indicated that EBV could display type II latency in EBV-HLH. Importantly, the level of plasma miR-BART16-1 continued decreasing during the whole chemotherapy, suggesting that plasma miR-BART16-1 could be a potential biomarker for monitoring EBV-HLH progression. The pathogenesis of EBV-HLH might be attributed to the abundance of EBV-miRNAs in EBV-HLH. These findings help elucidate the roles of EBV miRNAs in EBV-HLH, enabling the understanding of the basis of this disease and providing clues for its treatment.

Mouse model for acute Epstein-Barr virus infection.

PubMed

Wirtz, Tristan; Weber, Timm; Kracker, Sven; Sommermann, Thomas; Rajewsky, Klaus; Yasuda, Tomoharu

2016-11-29

Epstein-Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBV-infected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas. We have modeled acute EBV infection of naive and GC B cells in mice through timed expression of LMP1 and LMP2A. Although lethal when induced in all B cells, induction of LMP1 and LMP2A in just a small fraction of naive B cells initiated a phase of rapid B-cell expansion followed by a proliferative T-cell response, clearing the LMP-expressing B cells. Interfering with T-cell activity prevented clearance of LMP-expressing B cells. This was also true for perforin deficiency, which in the human causes a life-threatening EBV-related immunoproliferative syndrome. LMP expression in GC B cells impeded the GC reaction but, upon loss of T-cell surveillance, led to fatal B-cell expansion. Thus, timed expression of LMP1 together with LMP2A in subsets of mouse B cells allows one to study major clinically relevant features of human EBV infection in vivo, opening the way to new therapeutic approaches.

Transcriptional profiling of Epstein–Barr virus (EBV) genes and host cellular genes in nasal NK/T-cell lymphoma and chronic active EBV infection

PubMed Central

Zhang, Y; Ohyashiki, J H; Takaku, T; Shimizu, N; Ohyashiki, K

2006-01-01

Nasal NK/T-cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma (NHL) that is closely associated with Epstein–Barr virus (EBV). The clonal expansion of EBV-infected NK or T cells is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might share a partially similar mechanism by which EBV affects host cellular gene expression. To understand the pathogenesis of EBV-associated NK/T-cell lymphoproliferative disorders (LPD) and design new therapies, we employed a novel EBV DNA microarray to compare patterns of EBV expression in six cell lines established from EBV-associated NK/T-cell LPD. We found that expression of BZLF1, which encodes the immediate-early gene product Zta, was expressed in SNK/T cells and the expression levels were preferentially high in cell lines from CAEBV infection. We also analyzsd the gene expression patterns of host cellular genes using a human oligonucleotide DNA microarray. We identified a subset of pathogenically and clinically relevant host cellular genes, including TNFRSF10D, CDK2, HSPCA, IL12A as a common molecular biological properties of EBV-associated NK/T-cell LPD and a subset of genes, such as PDCD4 as a putative contributor for disease progression. This study describes a novel approach from the aspects of viral and host gene expression, which could identify novel therapeutic targets in EBV-associated NK/T-cell LPD. PMID:16449999

Persistently high Epstein-Barr virus (EBV) loads in peripheral blood lymphocytes from patients with chronic active EBV infection.

PubMed

Maeda, A; Wakiguchi, H; Yokoyama, W; Hisakawa, H; Tomoda, T; Kurashige, T

1999-04-01

Chronic active Epstein-Barr virus infection (CAEBV) is a severe illness with unusual EBV activation that persists for years, and its pathogenesis is largely unknown. After the creation of an accurate and reproducible polymerase chain reaction system to quantify EBV DNA, virus loads in peripheral blood lymphocytes (PBL) were determined in 54 children: 15 with CAEBV, 16 with infectious mononucleosis (IM), and 23 healthy children. Children with CAEBV and those with IM had high virus loads. Lower loads were detected in 47% of seropositive healthy donors. There were two distinct differences between children with CAEBV and those with IM: The former had greater viral replication (10(3)-10(7) copies/2.5x10(5) PBL) than those with IM, and viral replication declined in children with IM whereas active replication persisted for years in subjects with CAEBV. Persisting high virus loads are a possible diagnostic criterion for CAEBV. EBV loads may enable classification and prognosis of EBV infections.

NKG2ChiCD57+ Natural Killer cells respond specifically to acute infection with cytomegalovirus and not Epstein-Barr virus

PubMed Central

Hendricks, Deborah W.; Balfour, Henry H.; Dunmire, Samantha K.; Schmeling, David O.; Hogquist, Kristin A.; Lanier, Lewis L.

2014-01-01

Cytomegalovirus (CMV) induces the expansion of a unique subset of human NK cells expressing high levels of the activating CD94-NKG2C receptor that persist after control of the infection. We investigated whether this subset is indeed CMV-specific or is also responsive to acute infection with Epstein-Barr virus (EBV). Here we describe a longitudinal study of CMV-seronegative and -seropositive students who were acutely infected with EBV. The NKG2Chi NK subset was not expanded by EBV infection. However, EBV infection caused a decrease in the absolute number of immature CD56brightCD16− NK cells in the blood, and in CMV-seropositive individuals, induced an increased frequency of mature CD56dimNKG2A+CD57+ NK cells in the blood that persisted into latency. These results provide further evidence that NKG2C+ NK cells are CMV-specific, and suggest that EBV infection alters the repertoire of NK cells in the blood. PMID:24740502

Anti-MOG antibody-positive ADEM following infectious mononucleosis due to a primary EBV infection: a case report.

PubMed

Nakamura, Yoshitsugu; Nakajima, Hideto; Tani, Hiroki; Hosokawa, Takafumi; Ishida, Shimon; Kimura, Fumiharu; Kaneko, Kimihiko; Takahashi, Toshiyuki; Nakashima, Ichiro

2017-04-19

Anti-Myelin oligodendrocyte glycoprotein (MOG) antibodies are detected in various demyelinating diseases, such as pediatric acute disseminated encephalomyelitis (ADEM), recurrent optic neuritis, and aquaporin-4 antibody-seronegative neuromyelitis optica spectrum disorder. We present a patient who developed anti-MOG antibody-positive ADEM following infectious mononucleosis (IM) due to Epstein-Barr virus (EBV) infection. A 36-year-old healthy man developed paresthesia of bilateral lower extremities and urinary retention 8 days after the onset of IM due to primary EBV infection. The MRI revealed the lesions in the cervical spinal cord, the conus medullaris, and the internal capsule. An examination of the cerebrospinal fluid revealed pleocytosis. Cell-based immunoassays revealed positivity for anti-MOG antibody with a titer of 1:1024 and negativity for anti-aquaporin-4 antibody. His symptoms quickly improved after steroid pulse therapy followed by oral betamethasone. Anti-MOG antibody titer at the 6-month follow-up was negative. This case suggests that primary EBV infection would trigger anti-MOG antibody-positive ADEM. Adult ADEM patients can be positive for anti-MOG antibody, the titers of which correlate well with the neurological symptoms.

Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases.

PubMed

Pender, Michael P

2003-11-01

I hypothesize that human chronic autoimmune diseases are based on infection of autoreactive B lymphocytes by Epstein-Barr virus (EBV), in the following proposed scenario. During primary infection, autoreactive B cells are infected by EBV, proliferate and become latently infected memory B cells, which are resistant to the apoptosis that occurs during normal B-cell homeostasis because they express virus-encoded anti-apoptotic molecules. Genetic susceptibility to the effects of B-cell infection by EBV leads to an increased number of latently infected autoreactive memory B cells, which lodge in organs where their target antigen is expressed, and act there as antigen-presenting cells. When CD4(+) T cells that recognize antigens within the target organ are activated in lymphoid organs by cross-reactivity with infectious agents, they migrate to the target organ but fail to undergo activation-induced apoptosis because they receive a co-stimulatory survival signal from the infected B cells. The autoreactive T cells proliferate and produce cytokines, which recruit other inflammatory cells, with resultant target organ damage and chronic autoimmune disease.

Differential kinetics and specificity of EBV-specific CD4+ and CD8+ T cells during primary infection.

PubMed

Precopio, Melissa L; Sullivan, John L; Willard, Courtney; Somasundaran, Mohan; Luzuriaga, Katherine

2003-03-01

The generation and maintenance of virus-specific CD4(+) T cells in humans are not well understood. We used short in vitro stimulation assays followed by intracellular cytokine staining to characterize the timing, magnitude, and Ag specificity of CD4(+) T cells over the course of primary EBV infection. Lytic and latent protein-specific CD4(+) T cells were readily detected at presentation with acute infectious mononucleosis and declined rapidly thereafter. Responses to BZLF-1, BMLF-1, and Epstein-Barr nuclear Ag-3A were more commonly detected than responses to Epstein-Barr nuclear Ag-1. Concurrent analyses of BZLF-1-specific CD4(+) and CD8(+) T cells revealed differences in the expansion, specificity, and stability of CD4(+) and CD8(+) T cell-mediated responses over time. Peripheral blood EBV load directly correlated with the frequency of EBV-specific CD4(+) T cell responses at presentation and over time, suggesting that EBV-specific CD4(+) T cell responses are Ag-driven.

Clonal expansion of Epstein-Barr virus (EBV)-infected γδ T cells in patients with chronic active EBV disease and hydroa vacciniforme-like eruptions.

PubMed

Wada, Taizo; Toga, Akiko; Sakakibara, Yasuhisa; Toma, Tomoko; Hasegawa, Minoru; Takehara, Kazuhiko; Shigemura, Tomonari; Agematsu, Kazunaga; Yachie, Akihiro

2012-10-01

Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is a systemic EBV-positive lymphoproliferative disorder characterized by fever, lymphadenopathy, and splenomegaly. Patients with CAEBV may present with cutaneous symptoms, including hypersensitivity to mosquito bites and hydroa vacciniforme (HV)-like eruptions. HV is a rare photodermatosis characterized by vesicles and crust formation after exposure to sunlight, with onset in childhood, and is associated with latent EBV infection. While γδ T cells have recently been demonstrated to be the major EBV-infected cell population in HV, the immunophenotypic features of EBV-infected γδ T cells in CAEBV with HV-like eruptions or HV remain largely undetermined. We describe three patients with CAEBV whose γδ T cells were found to be the major cellular target of EBV. HV-like eruptions were observed in two of these patients. A clonally expanded subpopulation of γδ T cells that were highly activated and T cell receptor Vγ9- and Vδ2-positive cells was demonstrated in all patients. We also show that the clonally expanded γδ T cells infiltrated into the HV-like eruptions in one patient from whom skin biopsy specimens were available. These results suggest the pathogenic roles of clonally expanded γδ T cells infected by EBV in patients with CAEBV and HV-like eruptions.

[Systemic EBV+ T-cell lymphoproliferative disease of childhood].

PubMed

Lemaire, Anne-Sophie; Daussay, Dorothée; Bouchindhomme, Brigitte; Grardel, Nathalie; Botte, Astrid; Copin, Marie-Christine

2014-08-01

Systemic EBV+ T-cell lymphoproliferative disease of childhood is a recent entity described in the 2008 World Health Organisation tumours of haematopoietic system and lymphoid tissues as a clonal T-cell EBV+ systemic proliferation. It occurs after acute or chronic active EBV infection. We report the case of a caucasian, immunocompetent 12-year-old girl, with no particular history, who presented with hemophagocytic lymphohistiocytosis in the aftermath of an infectious mononucleosis. Main symptoms were multiple organ failure, hepatosplenomegaly and pancytopenia. Histopathology of peripheral lymph node and bone marrow revealed a T-cell, CD8+, EBV+ lymphoproliferation. An elevated viral load was detected in blood by PCR. The patient died within 3 weeks. Since most of the cases have been reported in Asia and South America, few cases still have been described in Europe. Unlike B-cell lymphoproliferation in immunocompromised individuals, T-cell EBV+ lymphoproliferation occurs in immunocompetent patients and seems to be the consequence of a proliferative disorder of EBV-infected T-cells, attributed to a cytotoxic T-cell response deficiency. These T-cell proliferations are more frequently immunoreactive for CD8 than CD4. A key feature of the diagnosis might be EBV viral load. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Cutting edge: NKG2C(hi)CD57+ NK cells respond specifically to acute infection with cytomegalovirus and not Epstein-Barr virus.

PubMed

Hendricks, Deborah W; Balfour, Henry H; Dunmire, Samantha K; Schmeling, David O; Hogquist, Kristin A; Lanier, Lewis L

2014-05-15

CMV induces the expansion of a unique subset of human NK cells expressing high levels of the activating CD94-NKG2C receptor that persist after control of the infection. We investigated whether this subset is CMV specific or is also responsive to acute infection with EBV. We describe a longitudinal study of CMV(-) and CMV(+) students who were acutely infected with EBV. The NKG2C(hi) NK subset was not expanded by EBV infection. However, EBV infection caused a decrease in the absolute number of immature CD56(bright)CD16(-) NK cells in the blood and, in CMV(+) individuals, induced an increased frequency of mature CD56(dim)NKG2A(+)CD57(+) NK cells in the blood that persisted into latency. These results provide further evidence that NKG2C(+) NK cells are CMV specific and suggest that EBV infection alters the repertoire of NK cells in the blood.

The Definition of Epstein Barr Virus (EBV)’s Role in HTLV-III Infected USAF Personnel as Related to Disease Progression.

DTIC Science & Technology

1987-10-27

individuals and patients with acute EBV infectious mononucleosis . Of 124 mouthwash specimens from III patients, 33% were positive for EBV DNA with...controls and persons with acute EBV infectious mononucleosis , including those with oropharyngeal ERV detected by the bioassay. By the quantitative...oropharyngeal secretions compared to patients with acute infectious " mononucleosis (Table 5). EBV genotyping findings. Southern analysis using the Epstein-Barr

EBV and Autoimmunity.

PubMed

Ascherio, Alberto; Munger, Kassandra L

2015-01-01

Although a role of EBV in autoimmunity is biologically plausible and evidence of altered immune responses to EBV is abundant in several autoimmune diseases, inference on causality requires the determination that disease risk is higher in individuals infected with EBV than in those uninfected and that in the latter it increases following EBV infection. This determination has so far been possible only for multiple sclerosis (MS) and, to some extent, for systemic lupus erythematosus (SLE), whereas evidence is either lacking or not supportive for other autoimmune conditions. In this chapter, we present the main epidemiological findings that justify the conclusion that EBV is a component cause of MS and SLE and possible mechanisms underlying these effects.

Epstein-Barr-Virus-Positive B-Cell Lymphoma of Recipient Origin Despite of the Elimination of Clonally EBV-Infected T Cells by Allogeneic Stem Cell Transplantation in a Patient with Chronic Active EBV Infection

PubMed Central

Nagasawa, Masayuki

2012-01-01

A 20-year-old patient with chronic active EBV infection (CAEBV) received peripheral blood stem cell transplantation (PBSCT) from HLA-one-locus-mismatched mother. Although EB-virus-infected T cells were eliminated after PBSCT, she developed EB-virus-positive B-cell lymphoma of recipient origin in the brain. By reducing the immunosuppressive therapy, the initial lesion disappeared. However, another lesion in the opposite lateral brain appeared later and was resistant to further reduction of immunosuppressive therapy. EBV-DNA was persistently negative after PBSCT in the peripheral blood. This case is suggestive in management of EBV reactivation after SCT and understanding alloimmune response to EBV. PMID:23213608

Successful Immunosuppressive Therapy for Severe Infectious Mononucleosis in a Patient with Clonal Proliferation of EBV-infected CD8-positive Cells.

PubMed

Hosoi, Hiroki; Sonoki, Takashi; Murata, Shogo; Mushino, Toshiki; Kuriyama, Kodai; Nishikawa, Akinori; Hanaoka, Nobuyoshi; Ohshima, Koichi; Imadome, Ken-Ichi; Nakakuma, Hideki

2015-01-01

A 30-year-old woman was diagnosed with severe infectious mononucleosis (IM). The Epstein-Barr virus (EBV) had infected both CD19- and CD8-positive cells, and clonal proliferation of EBV-infected cells and T-cells was detected. Although we suspected malignant lymphoma, her condition improved following immunosuppressive therapy. A similar case was recently reported; therefore, this case is the second case of IM with EBV-infected CD8-positive cells and clonal proliferation of EBV-infected cells. Our results demonstrate that the clonal proliferation of EBV-infected cells is not always an indication for chemotherapy in the primary infection phase and that monitoring the EBV viral load is useful for therapeutic decision-making.

Proposed categorization of pathological states of EBV-associated T/natural killer-cell lymphoproliferative disorder (LPD) in children and young adults: overlap with chronic active EBV infection and infantile fulminant EBV T-LPD.

PubMed

Ohshima, Koichi; Kimura, Hiroshi; Yoshino, Tadashi; Kim, Chul Woo; Ko, Young H; Lee, Seung-Suk; Peh, Suat-Cheng; Chan, John K C

2008-04-01

EBV-associated T/natural killer (NK)-cell lymphoproliferative disorder (EBV-T/NK LPD) of children and young adults is generally referred to with the blanket nosological term of severe chronic active EBV infection (CAEBV). This disease is rare, associated with high morbidity and mortality, and appears to be more prevalent in East Asian countries. But because there is no grading or categorization system for CAEBV, pathologists and clinicians often disagree regarding diagnosis and therapy. EBV-T/NK LPD includes polyclonal, oligoclonal, and monoclonal proliferation of cytotoxic T and/or NK cells. Moreover, a unique disease previously described as infantile fulminant EBV-associated T-LPD has been identified and overlaps with EBV-T/NK LPD. In the present review a clinicopathological categorization of EBV-T/NK LPD is proposed, based on pathological evaluation and molecular data, as follows: (i) category A1, polymorphic LPD without clonal proliferation of EBV-infected cells; (ii) category A2, polymorphic LPD with clonality; (iii) category A3, monomorphic LPD (T-cell or NK cell lymphoma/leukemia) with clonality; and (iv) category B, monomorphic LPD (T-cell lymphoma) with clonality and fulminant course. Categories A1, A2, and A3 possibly constitute a continuous spectrum and together are equivalent to CAEBV. Category B is the exact equivalent of infantile fulminant EBV-associated T-LPD. It is expected that this categorization system will provide a guide for the better understanding of this disorder. This proposal was approved at the third meeting of the Asian Hematopathology Association (Nagoya, 2006).

A Rare Case of Chronic Active Epstein-Barr Virus (EBV) Infection Accompanied by the Infiltration of EBV-infected CD8+ T Cells into the Muscle.

PubMed

Kobayashi, Nobuhiko; Mitsui, Takeki; Ogawa, Yoshiyuki; Iriuchishima, Hirono; Takizawa, Makiko; Yokohama, Akihiko; Saitoh, Takayuki; Koiso, Hiromi; Tsukamoto, Norifumi; Murakami, Hirokazu; Nojima, Yoshihisa; Handa, Hiroshi

2018-04-01

We describe a rare case of chronic active Epstein-Barr virus (CAEBV) infection, with infiltration of the skeletal muscle. A 19-year-old woman with swollen cervical lymph nodes and a fever was referred to our hospital. Swelling of the trapezium muscle and elevation of creatinine kinase level were observed. Biopsy results of the brachialis muscle revealed infiltration of Epstein-Barr virus (EBV)-encoded RNA-positive CD8 T lymphocytes. The EBV virus load in the peripheral blood was high, and EBV monoclonality was determined by Southern blot analysis. Owing to the rarity of CAEBV with skeletal muscle infiltration, this case alerts physicians to the potential diagnostic pitfalls of CAEBV.

Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus.

PubMed

Vernon, Suzanne D; Whistler, Toni; Cameron, Barbara; Hickie, Ian B; Reeves, William C; Lloyd, Andrew

2006-01-31

Acute infectious diseases are typically accompanied by non-specific symptoms including fever, malaise, irritability and somnolence that usually resolve on recovery. However, in some individuals these symptoms persist in what is commonly termed post-infective fatigue. The objective of this pilot study was to determine the gene expression correlates of post-infective fatigue following acute Epstein Barr virus (EBV) infection. We followed 5 people with acute mononucleosis who developed post-infective fatigue of more than 6 months duration and 5 HLA-matched control subjects who recovered within 3 months. Subjects had peripheral blood mononuclear cell (PBMC) samples collected at varying time points including at diagnosis, then every 2 weeks for 3 months, then every 3 months for a year. Total RNA was extracted from the PBMC samples and hybridized to microarrays spotted with 3,800 oligonucleotides. Those who developed post-infective fatigue had gene expression profiles indicative of an altered host response during acute mononucleosis compared to those who recovered uneventfully. Several genes including ISG20 (interferon stimulated gene), DNAJB2 (DnaJ [Hsp40] homolog and CD99), CDK8 (cyclin-dependent kinase 8), E2F2 (E2F transcription factor 2), CDK8 (cyclin-dependent kinase 8), and ACTN2 (actinin, alpha 2), known to be regulated during EBV infection, were differentially expressed in post-infective fatigue cases. Several of the differentially expressed genes affect mitochondrial functions including fatty acid metabolism and the cell cycle. These preliminary data provide insights into alterations in gene transcripts associated with the varied clinical outcomes from acute infectious mononucleosis.

Fulminant anaplastic large cell lymphoma (ALCL) concomitant with primary cytomegalovirus (CMV) infection, and human herpes virus 8 (HHV-8) infection together with Epstein-Barr-virus (EBV) reactivation in a patient with asymptomatic HIV-infection.

PubMed

Grützmeier, Sven; Porwit, Anna; Schmitt, Corinna; Sandström, Eric; Åkerlund, Börje; Ernberg, Ingemar

2016-01-01

Most malignant lymphomas in HIV-patients are caused by reactivation of EBV-infection. Some lymphomas have a very rapid fulminant course. HHV-8 has also been reported to be a cause of lymphoma. The role of CMV in the development of lymphoma is not clear, though both CMV and HHV-8 have been reported in tissues adjacent to the tumour in Burkitt lymphoma patients. Here we present a patient with asymptomatic HIV infection, that contracted a primary cytomegalovirus (CMV) infection and human herpes virus 8 (HHV-8) infection. Three weeks before onset of symptoms the patient had unprotected sex which could be possible source of his CMV and also HHV-8 infection He deteriorated rapidly and died with a generalized anaplastic large cell lymphoma (ALCL). A Caucasian homosexual male with asymptomatic human immunodeficiency virus (HIV) infection contracted a primary cytomegalovirus (CMV) infection and human herpes virus 8 (HHV-8) infection. He deteriorated rapidly and died with a generalized anaplastic large cell lymphoma (ALCL). Clinical and laboratory records were compiled. Immunohistochemistry was performed on lymphoid tissues, a liver biopsy, a bone marrow aspirate and the spleen during the illness and at autopsy. Serology and PCR for HIV, CMV, EBV, HHV-1-3 and 6-8 was performed on blood drawn during the course of disease. The patient presented with an acute primary CMV infection. Biopsies taken 2 weeks before death showed a small focus of ALCL in one lymph node of the neck. Autopsy demonstrated a massive infiltration of ALCL in lymph nodes, liver, spleen and bone marrow. Blood samples confirmed primary CMV- infection, a HHV-8 infection together with reactivation of Epstein- Barr-virus (EBV). Primary CMV-infection and concomitant HHV-8 infection correlated with reactivation of EBV. We propose that these two viruses influenced the development and progression of the lymphoma. Quantitative PCR blood analysis for EBV, CMV and HHV-8 could be valuable in diagnosis and treatment of

Epstein-Barr virus (EBV) in infectious mononucleosis: detection of the virus in tonsillar B lymphocytes but not in desquamated oropharyngeal epithelial cells

PubMed Central

Niedobitek, G; Agathanggelou, A; Steven, N; Young, L S

2000-01-01

Aims—Despite its well established tropism for B cells, the nature of the cellular compartment(s) mediating primary and persistent Epstein-Barr virus (EBV) infection is still a matter of controversy. In view of the association of EBV with several lymphoid and epithelial malignancies, resolution of this issue is important. Methods—Desquamated oropharyngeal epithelial cells from 10 patients with acute infectious mononucleosis and from seven chronic virus carriers were studied for evidence of EBV infection using in situ hybridisation for the detection of the small EBV encoded RNAs (EBERs) and of the viral genome. In addition, immunocytochemistry was used to detect the BZLF1 transactivator protein of EBV. Results—There was no evidence of latent or replicative EBV infection in oropharyngeal epithelial cells in any of the samples. In contrast, EBV infected B cells were readily identified in a tonsil from a patient with infectious mononucleosis. Conclusions—The results suggest that oropharyngeal epithelial cells are not a major site of EBV infection and provide further support for the notion that B cells mediate primary and persistent EBV infection. PMID:10884920

Therapies based on targeting EBV lytic replication for EBV-associated malignancies.

PubMed

Li, Hongde; Hu, Jianmin; Luo, Xiangjian; Bode, Ann M; Dong, Zigang; Cao, Ya

2018-05-11

In recent years, EBV lytic infection has been shown to significantly contribute to carcinogenesis. Thus, therapies aimed at targeting the EBV lytic cycle have been developed as novel strategies for treatment of EBV-associated diseases malignancies. In this review, focusing on the viral lytic proteins, we describe recent advances regarding the involvement of the EBV lytic cycle in carcinogenesis. Moreover, we further discuss two distinct EBV lytic cycle-targeted therapeutic strategies against EBV-induced malignancies: One of the strategies involves inhibition of the EBV lytic cycle by natural compounds known to have anti-EBV properties; another one is to intentionally induce EBV lytic replication in combination with nucleotide analogues. Recent advances in EBV lytic-based strategies are beginning to show promise in the treatment and/or prevention of EBV-related tumors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Characterization of variants in the promoter of BZLF1 gene of EBV in nonmalignant EBV-associated diseases in Chinese children.

PubMed

Jin, Yingkang; Xie, Zhengde; Lu, Gen; Yang, Shuang; Shen, Kunling

2010-05-10

Diseases associated with Epstein-Barr virus (EBV) infections, such as infectious mononucleosis (IM), EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and chronic active EBV infection (CAEBV) are not rare in Chinese children. The association of type 1 or type 2 EBV and variants of the EBV BZLF1 promoter zone (Zp) with these diseases is unclear. The objective of this study was to investigate the relationship between EBV genotypes (Zp variants and EBV type 1 and 2) and the clinical phenotypes of EBV-associated diseases in Chinese children. The Zp region was directly sequenced in 206 EBV-positive DNA samples from the blood of patients with IM, EBV-HLH, CAEBV, and healthy controls. Type 1 or type 2 EBV was examined by PCR for EBNA2 and EBNA3C subtypes. Four polymorphic Zp variants were identified: Zp-P, Zp-V3, Zp-P4 and Zp-V1, a new variant. The Zp-V3 variant was significantly associated with CAEBV (P infection with Zp variants was higher in patients with CAEBV and EBV-HLH, compared with IM and healthy controls, mostly as Zp-P+V3 co-infection. Type 1 EBV was predominant in all categories (81.3-95%) and there was no significant difference in the frequency of the EBV types 1 and 2 in different categories (P > 0.05). Type 1 EBV and BZLF1 Zp-P of EBV were the predominant genotypes in nonmalignant EBV associated diseases in Chinese children and Zp-V3 variant may correlates with the developing of severe EBV infection diseases, such as CAEBV and EBV-HLH.

Characterization of variants in the promoter of BZLF1 gene of EBV in nonmalignant EBV-associated diseases in Chinese children

PubMed Central

2010-01-01

Background Diseases associated with Epstein-Barr virus (EBV) infections, such as infectious mononucleosis (IM), EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and chronic active EBV infection (CAEBV) are not rare in Chinese children. The association of type 1 or type 2 EBV and variants of the EBV BZLF1 promoter zone (Zp) with these diseases is unclear. Results The objective of this study was to investigate the relationship between EBV genotypes (Zp variants and EBV type 1 and 2) and the clinical phenotypes of EBV-associated diseases in Chinese children. The Zp region was directly sequenced in 206 EBV-positive DNA samples from the blood of patients with IM, EBV-HLH, CAEBV, and healthy controls. Type 1 or type 2 EBV was examined by PCR for EBNA2 and EBNA3C subtypes. Four polymorphic Zp variants were identified: Zp-P, Zp-V3, Zp-P4 and Zp-V1, a new variant. The Zp-V3 variant was significantly associated with CAEBV (P ≤ 0.01). The frequency of co-infection with Zp variants was higher in patients with CAEBV and EBV-HLH, compared with IM and healthy controls, mostly as Zp-P+V3 co-infection. Type 1 EBV was predominant in all categories (81.3-95%) and there was no significant difference in the frequency of the EBV types 1 and 2 in different categories (P > 0.05). Conclusions Type 1 EBV and BZLF1 Zp-P of EBV were the predominant genotypes in nonmalignant EBV associated diseases in Chinese children and Zp-V3 variant may correlates with the developing of severe EBV infection diseases, such as CAEBV and EBV-HLH. PMID:20459737

Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr Virus

PubMed Central

Vernon, Suzanne D; Whistler, Toni; Cameron, Barbara; Hickie, Ian B; Reeves, William C; Lloyd, Andrew

2006-01-01

Background Acute infectious diseases are typically accompanied by non-specific symptoms including fever, malaise, irritability and somnolence that usually resolve on recovery. However, in some individuals these symptoms persist in what is commonly termed post-infective fatigue. The objective of this pilot study was to determine the gene expression correlates of post-infective fatigue following acute Epstein Barr virus (EBV) infection. Methods We followed 5 people with acute mononucleosis who developed post-infective fatigue of more than 6 months duration and 5 HLA-matched control subjects who recovered within 3 months. Subjects had peripheral blood mononuclear cell (PBMC) samples collected at varying time points including at diagnosis, then every 2 weeks for 3 months, then every 3 months for a year. Total RNA was extracted from the PBMC samples and hybridized to microarrays spotted with 3,800 oligonucleotides. Results Those who developed post-infective fatigue had gene expression profiles indicative of an altered host response during acute mononucleosis compared to those who recovered uneventfully. Several genes including ISG20 (interferon stimulated gene), DNAJB2 (DnaJ [Hsp40] homolog and CD99), CDK8 (cyclin-dependent kinase 8), E2F2 (E2F transcription factor 2), CDK8 (cyclin-dependent kinase 8), and ACTN2 (actinin, alpha 2), known to be regulated during EBV infection, were differentially expressed in post-infective fatigue cases. Several of the differentially expressed genes affect mitochondrial functions including fatty acid metabolism and the cell cycle. Conclusion These preliminary data provide insights into alterations in gene transcripts associated with the varied clinical outcomes from acute infectious mononucleosis. PMID:16448567

Active CMV and EBV infections in renal transplant recipients with unexplained fever and elevated serum creatinine.

PubMed

Hasannia, Tahereh; Moosavi Movahed, Seyed Majid; Vakili, Rosita; Rafatpanah, Houshang; Hekmat, Reza; Valizadeh, Narges; Rezaee, Seyed Abdolrahim

2016-10-01

Proper identification of active cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections are helpful for monitoring antiviral treatment in transplant recipients. Qualitative and quantitative CMV, EBV DNA PCR techniques in the context of serological tests are performed for early detection and differentiation of active and latent CMV and EBV infections in renal transplantation. Basically, 129 renal transplanted recipients monitored carefully and hospitalized for unexplained elevated creatinine levels or high fever and 21 of their donors were studied. CMV DNA was detected in 63.5% of the febrile episodes following transplantation and in 46.42% of readmitted patients using qualitative PCR method. In the first group, 15% of the patients and in the second group 42.85% of the patients had copy numbers more than cutoff point (900 copies/mL). Cutoff point had 100% sensitivity and 82.5% specificity for active and symptomatic CMV infection. Only 15.5% of the subjects were positive for EBV infection by qualitative PCR method. Among them 5% had >2000 copies/mL and were symptomatic. One subject with a history of three times hospitalization had higher EBV viral load and developed post-transplant lymphoproliferative disorder. CMV load was significantly correlated with elevated creatinine levels (OR = 3.1, p = 0.006), abnormal heart sounds (OR = 4.7; p = 0.02) and hypertension (OR = 3.6; p = 0.03). Only qRT-PCR could differentiate between latent and active infections and might be clinically useful for monitoring symptomatic CMV and EBV infections and initiation of the antiviral therapy. Elevated creatinine levels, hypertension, and abnormal heart sounds could be considered as main manifestations of HCMV infection in kidney recipients.

Acute EBV infection masquerading as "In-situ Follicular Lymphoma": a pitfall in the differential diagnosis of this entity.

PubMed

Gru, Alejandro A; Kreisel, Friederike; Duncavage, Eric; Nguyen, TuDung T; Hassan, Anjum; Frater, John L

2013-06-19

We present the case of a 30 year-old man who was referred for evaluation of diffuse lymphadenopathy. Six weeks prior, he noticed darkening of his urine associated with pale stools, nausea and an eventual 30 lb weight loss within a month. The initial laboratory findings showed elevation of the liver enzymes. A CT scan showed mesenteric and periaortic lymphadenopathy with the largest lymph node measuring 2.8 cm. Other laboratory results were otherwise unremarkable (including a normal LDH) with the exception of positive serum antibodies against Epstein-Barr virus (EBV) associated antigens (IgM+ and IgG+). An excisional biopsy of 4 of the small neck lymph nodes showed a normal architecture with prominent follicles and an intact capsule. But, by immunohistochemistry two of the follicles showed aberrant coexpression of BCL-2, in addition to CD10 and BCL-6. In-situ hybridization for early Epstein-Barr virus mRNA (EBER) and immunohistochemistry for latent membrane protein-1 (LMP-1) stained both scattered positive cells, as well as BCL-2 positive B-cells. Although an original diagnosis of in-situ follicular lymphoma was favored at an outside facility, additional interphase fluorescence in situ hybridization (FISH) studies for t(14;18);(IGH-BCL2) rearrangement (performed on the BCL-2 + follicles microdissected from the tissue block; Abott probe dual colour fusion) and molecular studies (IGH gene rearrangement by PCR, also performed on the microdissected follicles) were negative. Serologic studies (positive EBV antibodies) and immunostains in conjunction with the molecular studies confirmed the reactive nature of the changes. Our case also shows direct immunopathogenic evidence of BCL-2 expression among the EBV-infected cells, which has to our knowledge not been previously documented in vivo. A diagnosis of EBV infection should, therefore, be considered when confronted with BCL-2 expression in germinal centers, particularly in younger individuals, as the diagnosis of FLIS may

The Effect of Antiretroviral Combination Treatment on Epstein-Barr Virus (EBV) Genome Load in HIV-Infected Patients

PubMed Central

Friis, Anna M. C.; Gyllensten, Katarina; Aleman, Anna; Ernberg, Ingemar; Åkerlund, Börje

2010-01-01

We evaluated the effect of combination anti-retroviral treatment (cART) on the host control of EBV infection in moderately immunosuppressed HIV-1 patients. Twenty HIV-1 infected individuals were followed for five years with repeated measurements of EBV DNA load in peripheral blood lymphocytes in relation to HIV-RNA titers and CD4+ cell counts. Individuals with optimal response, i.e. durable non-detectable HIV-RNA, showed a decline of EBV load to the level of healthy controls. Individuals with non-optimal HIV-1 control did not restore their EBV control. Long-lasting suppression of HIV-replication after early initiation of cART is a prerequisite for re-establishing the immune control of EBV. PMID:21994658

[Acute dacryocystitis complicating primary mononucleosis infection].

PubMed

Delbet, C; PhamDang, N; Mondie, J-M; Barthelemy, I

2010-01-01

Infectious mononucleosis may lead to numerous complications. Tonsillar hyperplasia with risk of airway obstruction is well known. Dacryocystitis is a rare but potentially severe complication. A 6-year-old child with primary mononucleosis infectious diagnosed 8 days before, developed acute dacryocystitis, with rapid evolution to orbital cellulitis, despite adequate antibiotherapy. Emergency surgical drainage was required. Dacryocystitis is a rare and little documented complication of EBV infection. Its acute evolution to orbital cellulitis is possible and potentially severe. Its physiopathology is specific. Patients are initially free of chronic stenosis and epiphora, which express acute obstruction of the lachrymal sac due to general lymphoid hyperplasia. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Unusual MRI findings in an immunocompetent patient with EBV encephalitis: a case report

PubMed Central

2011-01-01

Blackground It is well-known that Epstein-Barr virus (EBV) can affect the central nervous system (CNS). Case presentation Herein the authors report unusual timely Magnetic Resonance Imaging (MRI) brain scan findings in an immunocompetent patient with EBV encephalitis. Diffusion weighted MRI sequence performed during the acute phase of the disease was normal, whereas the Fast Relaxation Fast Spin Echo T2 image showed diffuse signal intensity changes in white matter. The enhancement pattern suggested an inflammatory response restricted to the brain microcirculation. Acyclovir and corticosteroid therapy was administered. After three weeks, all signal intensities returned to normal and the patient showed clinical recovery. Conclusion This report demonstrates that EBV in an immunocompetent adult can present with diffuse, reversible brain white matter involvement in the acute phase of mononucleosis. Moreover, our case suggests that a negative DWI sequence is associated with a favorable improvement in severe EBV CNS infection. More extensive studies are needed to assess what other instrumental data can help to distinguish viral lesions from other causes in the acute phase of disease. PMID:21435249

EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

PubMed

Takada, Honami; Imadome, Ken-Ichi; Shibayama, Haruna; Yoshimori, Mayumi; Wang, Ludan; Saitoh, Yasunori; Uota, Shin; Yamaoka, Shoji; Koyama, Takatoshi; Shimizu, Norio; Yamamoto, Kouhei; Fujiwara, Shigeyoshi; Miura, Osamu; Arai, Ayako

2017-01-01

Epstein-Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.

EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells

PubMed Central

Shibayama, Haruna; Yoshimori, Mayumi; Wang, Ludan; Saitoh, Yasunori; Uota, Shin; Yamaoka, Shoji; Koyama, Takatoshi; Shimizu, Norio; Yamamoto, Kouhei; Fujiwara, Shigeyoshi; Miura, Osamu

2017-01-01

Epstein–Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-κB activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-κB activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-κB activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-κB that suppresses NF-κB activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-κB-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells. PMID:28346502

Acute disseminated encephalomyelitis and thrombocytopenia following Epstein-Barr virus infection.

PubMed

Saeed, Muhammad; Dabbagh, Omar; Al-Muhaizae, Muhammad; Dhalaan, Hesham; Chedrawi, Aziza

2014-11-01

Epstein-Barr Virus (EBV) causes a broad spectrum of disease in humans with several clinical syndromes and is ubiquitous, infecting more than 95% of the world's population. Central Nervous System (CNS) disease alone associated with Epstein-Barr virus rarely occurs in previously healthy individuals. Systemic viral illness in children and complications are rare, but may occur. In few cases, it is associated with a variety of CNS and hematological complications like acute disseminated encephalomyelitis, transverse myelitis, neuropsychiatric syndrome, GBS, autoimmune thrombocytopenia and hemolytic anemia and they usually respond to immunotherapy. We report previously healthy boy, who presented with left sided weakness, headache and thrombocytopenia following EBV infection. The thrombocytopenia was resistant to intravenous immunoglobulin and methylprednisolone but responded well to Rituximab.

Epstein-Barr virus (EBV) recombinants: use of positive selection markers to rescue mutants in EBV-negative B-lymphoma cells.

PubMed

Wang, F; Marchini, A; Kieff, E

1991-04-01

The objective of these experiments was to develop strategies for creation and identification of recombinant mutant Epstein-Barr viruses (EBV). EBV recombinant molecular genetics has been limited to mutations within a short DNA segment deleted from a nontransforming EBV and an underlying strategy which relies on growth transformation of primary B lymphocytes for identification of recombinants. Thus, mutations outside the deletion or mutations which affect transformation cannot be easily recovered. In these experiments we investigated whether a toxic drug resistance gene, guanine phosphoribosyltransferase or hygromycin phosphotransferase, driven by the simian virus 40 promoter can be recombined into the EBV genome and can function to identify B-lymphoma cells infected with recombinant virus. Two different strategies were used to recombine the drug resistance marker into the EBV genome. Both utilized transfection of partially permissive, EBV-infected B95-8 cells and positive selection for cells which had incorporated a functional drug resistance gene. In the first series of experiments, B95-8 clones were screened for transfected DNA that had recombined into the EBV genome. In the second series of experiments, the transfected drug resistance marker was linked to the plasmid and lytic EBV origins so that it was maintained as an episome and could recombine with the B95-8 EBV genome during virus replication. The recombinant EBV from either experiment could be recovered by infection and toxic drug selection of EBV-negative B-lymphoma cells. The EBV genome in these B-lymphoma cells is frequently an episome. Virus genes associated with latent infection of primary B lymphocytes are expressed. Expression of Epstein-Barr virus nuclear antigen 2 (EBNA-2) and the EBNA-3 genes is variable relative to that of EBNA-1, as is characteristic of some naturally infected Burkitt tumor cells. Moreover, the EBV-infected B-lymphoma cells are often partially permissive for early replicative

Epstein-Barr virus (EBV) recombinants: use of positive selection markers to rescue mutants in EBV-negative B-lymphoma cells.

PubMed Central

Wang, F; Marchini, A; Kieff, E

1991-01-01

The objective of these experiments was to develop strategies for creation and identification of recombinant mutant Epstein-Barr viruses (EBV). EBV recombinant molecular genetics has been limited to mutations within a short DNA segment deleted from a nontransforming EBV and an underlying strategy which relies on growth transformation of primary B lymphocytes for identification of recombinants. Thus, mutations outside the deletion or mutations which affect transformation cannot be easily recovered. In these experiments we investigated whether a toxic drug resistance gene, guanine phosphoribosyltransferase or hygromycin phosphotransferase, driven by the simian virus 40 promoter can be recombined into the EBV genome and can function to identify B-lymphoma cells infected with recombinant virus. Two different strategies were used to recombine the drug resistance marker into the EBV genome. Both utilized transfection of partially permissive, EBV-infected B95-8 cells and positive selection for cells which had incorporated a functional drug resistance gene. In the first series of experiments, B95-8 clones were screened for transfected DNA that had recombined into the EBV genome. In the second series of experiments, the transfected drug resistance marker was linked to the plasmid and lytic EBV origins so that it was maintained as an episome and could recombine with the B95-8 EBV genome during virus replication. The recombinant EBV from either experiment could be recovered by infection and toxic drug selection of EBV-negative B-lymphoma cells. The EBV genome in these B-lymphoma cells is frequently an episome. Virus genes associated with latent infection of primary B lymphocytes are expressed. Expression of Epstein-Barr virus nuclear antigen 2 (EBNA-2) and the EBNA-3 genes is variable relative to that of EBNA-1, as is characteristic of some naturally infected Burkitt tumor cells. Moreover, the EBV-infected B-lymphoma cells are often partially permissive for early replicative

Hepatocellular apoptosis associated with cytotoxic T/natural killer-cell infiltration in chronic active EBV infection.

PubMed

Nomura, Yuko; Kimura, Hiroshi; Karube, Kennosuke; Yoshida, Shiro; Sugita, Yasuo; Niino, Daisuke; Shimizu, Kei; Kimura, Yoshizo; Aoki, Ryosuke; Kiyasu, Junichi; Takeuchi, Masanori; Hashikawa, Keiko; Hirose, Shinichi; Ohshima, Koichi

2009-07-01

The aim of the present study was to identify the mechanism of hepatocellular apoptosis induced by EBV-infected cytotoxic T/natural killer (NK) cells in chronic active EBV infection (CAEBV). Eight patients with CAEBV were studied, and infected T-cell expansion and NK-cell expansion were detected in four patients each. Biopsy or necropsy was performed on lymph node, liver, or spleen, and each specimen was subjected to immunohistochemical double staining of CD3 plus caspase-3 with the addition of cytotoxic markers of T-cell restricted intracellular antigen-1 (TIA-1), perforin, and granzyme B, as well as EBV in situ hybridization (EBV-ISH). In the liver, some of the infiltrating CD3-positive lymphocytes stained positively for EBV-ISH and cytotoxic markers. Double staining of CD3 plus caspase-3 indicated caspase-3 positive hepatocytes with apoptotic features, accompanied by extensive infiltration of CD3-positive cells, which were directly attached to the apoptotic caspase-3 positive hepatocytes. In contrast, far fewer cells stained positive for caspase-3 in lymph node and spleen than in liver. The present findings suggest that in patients with CAEBV, cytotoxic T/NK cells may directly induce hepatocytes to undergo apoptosis more frequently than they do cells in other organs of the reticulo-endothelial system.

Comprehensive assessment of peripheral blood TCRβ repertoire in infectious mononucleosis and chronic active EBV infection patients.

PubMed

Liu, Shenglin; Zhang, Qian; Huang, Dongli; Zhang, Wenli; Zhong, Fengluan; Feng, Jia; Chen, Xueru; Meng, Qingxiang; Chen, Xiaofan; Zhang, Wei; Zhang, Hongyu

2017-04-01

Epstein-Barr virus (EBV) primary infection is usually asymptomatic, but it sometimes progresses to infectious mononucleosis (IM). Occasionally, some people develop chronic active EBV infection (CAEBV) with underlying immunodeficiency, which belongs to a continuous spectrum of EBV-associated lymphoproliferative disorders (EBV + LPD) with heterogeneous clinical presentations and high mortality. It has been well established that T cell-mediated immune response plays a critical role in the disease evolution of EBV infection. Recently, high-throughput sequencing of the hypervariable complementarity-determining region 3 (CDR3) segments of the T cell receptor (T cell receptor β (TCRβ)) has emerged as a sensitive approach to assess the T cell repertoire. In this study, we fully characterized the diversity of peripheral blood TCRβ repertoire in IM (n = 6) and CAEBV patients (n = 5) and EBV-seropositive controls (n = 5). Compared with the healthy EBV-seropositive controls, both IM and CAEBV patients demonstrate a significant decrease in peripheral blood TCRβ repertoire diversity, basically, including narrowed repertoire breadth, highly expanded clones, and skewed CDR3 length distribution. However, there is no significant difference between IM and CAEBV patients. Furthermore, we observed some disease-related preferences in TRBV/TRBJ usage and combinations, as well as lots of T cell clones shared by different groups (unique or overlapped) involved in public T cell responses, which provide more detailed insights into the divergent disease evolution.

Acute infectious mononucleosis and coincidental measles virus infection.

PubMed

Atrasheuskaya, A V; Kameneva, S N; Neverov, A A; Ignatyev, G M

2004-10-01

Both Epstein-Barr and measles viruses (MV) cause immune suppression, and the association of the two viruses is evaluated as life threatening. The cell immune impairment caused by simultaneous Epstein-Barr and measles viral infections was responsible for the complicated course of the disease in all described previously reports and for unfavorable outcomes in most of the cases. Timely diagnosis of coincidental viral infections could be a useful predictor for the clinical course and complications. Diagnosis must be based on an accurate assessment of clinical, hematologic, serologic manifestations and supported by appropriate laboratory methods. Recognizing the infectious etiology of concomitant infections is important for both clinicians and epidemiologists. To describe a case report of a 20-year-old woman previously vaccinated against measles infected with acute mononucleosis and coincidental measles virus infection. The clinical, routine laboratory, as well as serological and virologic findings of this patient were scrutinized. Special emphasis was placed on the use of RT-PCR/PCR for confirming the involvement of both measles virus and Epstein-Barr virus (EBV) in this patient's illness. Infectious mononucleosis was not suspected at admission to the hospital. The final diagnosis of a concomitant measles virus infection and acute infectious mononucleosis was facilitated using viral serology to detect virus-specific IgG and IgM antibodies and by RT-PCR for the detection of measles virus RNA and EBV DNA from peripheral blood monocyte cells (PBMC). The present report highlights the difficulty of diagnosing two coincidental virus infections on clinical grounds. Serological and molecular laboratory methods, specifically the PCR (RT-PCR) analysis, are found to be useful for confirming the concomitant viral infections and proper identification of the infecting pathogens.

Detection and quantification of Epstein-Barr virus EBER1 in EBV-infected cells by fluorescent in situ hybridization and flow cytometry

NASA Technical Reports Server (NTRS)

Stowe, R. P.; Cubbage, M. L.; Sams, C. F.; Pierson, D. L.; Barrett, A. D.

1998-01-01

A rapid and highly sensitive fluorescent in situ hybridization (FISH) assay was developed to detect Epstein Barr virus (EBV)-infected cells in peripheral blood. Multiple fluorescein-labeled antisense oligonucleotide probes were designed to hybridize to the EBER1 transcript, which is highly expressed in latently infected cells. After a rapid (30 min) hybridization, the cells were analyzed by flow cytometry. EBER1 was detected in several positive control cell lines that have variable numbers of EBV genome copies. No EBER1 was detected in two known EBV-negative cell lines. Northern blot analyses confirmed the presence and quantity of EBER1 transcripts in each cell line. This method was used to quantify the number of EBV-infected cells in peripheral blood from a patient with chronic mononucleosis. These results indicate that EBV-infected cells can be detected at the single cell level, and that this assay can be used to quantify the number of EBV-infected cells in clinical samples.

Epstein-Barr Virus (EBV)-associated Gastric Carcinoma

PubMed Central

Iizasa, Hisashi; Nanbo, Asuka; Nishikawa, Jun; Jinushi, Masahisa; Yoshiyama, Hironori

2012-01-01

The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute to B cell lymphomagenesis. Although the monoclonal proliferation of EBV-infected cells can be observed in epithelial tumors, such as nasopharyngeal carcinoma and EBV-associated gastric carcinoma, the precise role of EBV in the carcinogenic progress is not fully understood. This review features characteristics and current understanding of EBV-associated gastric carcinoma. EBV-associated gastric carcinoma comprises almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I). Firstly, definition, epidemiology, and clinical features are discussed. Then, the route of infection and carcinogenic role of viral genes are presented. Of particular interest, the association with frequent genomic CpG methylation and role of miRNA for carcinogenesis are topically discussed. Finally, the possibility of therapies targeting EBV-associated gastric carcinoma is proposed. PMID:23342366

Antibody producing B lineage cells invade the central nervous system predominantly at the time of and triggered by acute Epstein-Barr virus infection: A hypothesis on the origin of intrathecal immunoglobulin synthesis in multiple sclerosis.

PubMed

Otto, Carolin; Hofmann, Jörg; Ruprecht, Klemens

2016-06-01

Patients with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), typically have an intrathecal synthesis of immunoglobulin (Ig)G. Intrathecal IgG is produced by B lineage cells that entered the CNS, but why and when these cells invade the CNS of patients with MS is unknown. The intrathecal IgG response in patients with MS is polyspecific and part of it is directed against different common viruses (e.g. measles virus, rubella virus, varicella zoster virus). Strong and consistent evidence suggests an association of MS and Epstein-Barr virus (EBV) infection and EBV seroprevalence in patients with MS is practically 100%. However, intriguingly, despite of the universal EBV seroprevalence, the frequency of intrathecally produced IgG to EBV in patients with MS is much lower than that of intrathecally produced IgG to other common viruses. The acute phase of primary EBV infection is characterized by a strong polyclonal B cell activation. As typical for humoral immune responses against viruses, EBV specific IgG is produced only with a temporal delay after acute EBV infection. Aiming to put the above facts into a logical structure, we here propose the hypothesis that in individuals going on to develop MS antibody producing B lineage cells invade the CNS predominantly at the time of and triggered by acute primary EBV infection. Because at the time of acute EBV infection EBV IgG producing B lineage cells have not yet occurred, the hypothesis could explain the universal EBV seroprevalence and the low frequency of intrathecally produced IgG to EBV in patients with MS. Evidence supporting the hypothesis could be provided by large prospective follow-up studies of individuals with symptomatic primary EBV infection (infectious mononucleosis). Furthermore, the clarification of the molecular mechanism underlying an EBV induced invasion of B lineage cells into the CNS of individuals going on to develop MS could corroborate it, too. If true, our

Chronic active EBV infection with features of granulomatosis with polyangiitis.

PubMed

Shimomura, Masaki; Morishita, Hideaki; Meguro, Takaaki; Seto, Shiro; Kimura, Mitsuaki; Hamazaki, Minoru; Hashimoto, Ayako; Sugiyama, Yuka; Kimura, Hiroshi

2016-07-01

Herein, we report the case of a 13-year-old boy with multiple recurrent ulcers on his legs. He developed severe sinusitis at 10 years of age and had significant weight loss (6 kg) in the 2 months prior to admission. Histology of tissue biopsied from the ulcer indicated small vessel vasculitis and granulomatous inflammation. Given that these findings met the diagnostic criteria for granulomatosis with polyangiitis (GPA), he was treated with immunosuppressive agents. Further pathology, however, indicated Epstein-Barr virus (EBV)-encoded RNA (EBER) in most lymphocytes in the same sample. The EBER-positive lymphocytes were mainly CD4-positive T cells. The EBV-DNA load in the peripheral blood was also abnormally increased (1.0 × 10(4) copies/μg DNA). Thus, the diagnosis was established as chronic active EBV infection (CAEBV). This case illustrates the necessity of careful differential diagnosis of CAEBV owing to its clinical resemblance and pathological overlap with GPA. © 2016 Japan Pediatric Society.

Common cytological and cytogenetic features of Epstein-Barr virus (EBV)-positive natural killer (NK) cells and cell lines derived from patients with nasal T/NK-cell lymphomas, chronic active EBV infection and hydroa vacciniforme-like eruptions.

PubMed

Zhang, Yu; Nagata, Hiroshi; Ikeuchi, Tatsuro; Mukai, Hiroyuki; Oyoshi, Michiko K; Demachi, Ayako; Morio, Tomohiro; Wakiguchi, Hiroshi; Kimura, Nobuhiro; Shimizu, Norio; Yamamoto, Kohtaro

2003-06-01

In this study, we describe the cytological and cytogenetic features of six Epstein-Barr virus (EBV)-infected natural killer (NK) cell clones. Three cell clones, SNK-1, -3 and -6, were derived from patients with nasal T/NK-cell lymphomas; two cell clones, SNK-5 and -10, were isolated from patients with chronic active EBV infection (CAEBV); and the other cell clone, SNK-11, was from a patient with hydroa vacciniforme (HV)-like eruptions. An analysis of the number of EBV-terminal repeats showed that the SNK cell clones had monoclonal EBV genomes identical to the original EBV-infected cells of the respective patients, and SNK cells had the type II latency of EBV infection, suggesting that not only the cell clones isolated from nasal T/NK-cell lymphomas but also those isolated from CAEBV and HV-like eruptions had been transformed by EBV to a certain degree. Cytogenetic analysis detected deletions in chromosome 6q in five out of the six SNK cell clones, while 6q was not deleted in four control cell lines of T-cell lineage. This suggested that a 6q deletion is a characteristic feature of EBV-positive NK cells, which proliferated in the diseased individuals. The results showed that EBV-positive NK cells in malignant and non-malignant lymphoproliferative diseases shared common cytological and cytogenetic features.

An overview of the infection of CMV, HSV 1/2 and EBV in Mexican patients with glioblastoma multiforme.

PubMed

Zavala-Vega, Sergio; Castro-Escarpulli, Graciela; Hernández-Santos, Hector; Salinas-Lara, Citlatepetl; Palma, Icela; Mejía-Aranguré, Juan Manuel; Gelista-Herrera, Noemí; Rembao-Bojorquez, Daniel; Ochoa, Sara A; Cruz-Córdova, Ariadnna; Xicohtencatl-Cortes, Juan; Uribe-Gutiérrez, Gabriel; Arellano-Galindo, José

2017-03-01

Several risk factors are involved in glioblastoma, including cytomegalovirus (CMV). This research was carried out to determine the rate of CMV infection, as well as HSV 1/2 and EBV in brain tissue, in patients with glioblastomamultiforme (GBM). The tissues were tested using immunohistochemistry, PCR, in situ hybridization and real-time PCR. At least, one HHV was detected in 21/29 (72%) patients as follows: single infections with HSV-1/2 in 4/21 (19%), EBV in 6/21 (28.6%) and CMV in 1/21 (4.8%). Mixed viral infection, HSV-1/2 and EBV were detected in 4/21 patients (19%), CMV and EBV in 5/21 (23.8%), and HSV-1/2, EBV, and CMV in 1/21. The CMV viral load ranged from 3×10 2 to 4.33×10 5 genome/100ng of tissue. Genotype based on CMV gB was 3/7 where 2/3 was gB1 and 1/3 gB4. HSV, EBV and CMV were frequently found in brain tissues, more in mix in a population reported as highly seropositive. Copyright © 2017 Elsevier GmbH. All rights reserved.

Plasma EBV microRNAs in paediatric renal transplant recipients.

PubMed

Hassan, Jaythoon; Dean, Jonathan; De Gascun, Cillian F; Riordan, Michael; Sweeney, Clodagh; Connell, Jeff; Awan, Atif

2018-06-01

Epstein-Barr virus (EBV) was the first human virus identified to express microRNA (miRNA). To date, 44 mature miRNAs are encoded for within the EBV genome. EBV miRNAs have not been profiled in paediatric renal transplant recipients. In this study, we investigated circulating EBV miRNA profiles as novel biomarkers in paediatric renal transplant patients. Forty-two microRNAs encoded within 2 EBV open reading frames (BART and BHRF) were examined in renal transplant recipients who resolved EBV infection (REI) or maintained chronic high viral loads (CHL), and in non-transplant patients with acute infectious mononucleosis (IM). Plasma EBV-miR-BART2-5p was present in higher numbers of IM (7/8) and CHL (7/10) compared to REI (7/12) patients. A trend was observed between the numbers of plasma EBV miRNAs expressed and EBV viral load (p < 0.07). Several EBV-miRs including BART7-3p, 15, 9-3p, 11-3p, 1-3p and 3-3p were detected in IM and CHL patients only. The lytic EBV-miRs, BHRF1-2-3p and 1-1, indicating active viral replication, were detected in IM patients only. One CHL patient developed post-transplant lymphoproliferative disease (PTLD) after several years and analysis of 10 samples over a 30-month period showed an average 24-fold higher change in plasma EBV-miR-BART2-5p compared to the CHL group and 110-fold higher change compared to the REI group. Our results suggest that EBV-miR-BART2-5p, which targets the stress-induced immune ligand MICB to escape recognition and elimination by NK cells, may have a role in sustaining high EBV viral loads in CHL paediatric kidney transplant recipients.

Novel Mouse Xenograft Models Reveal a Critical Role of CD4+ T Cells in the Proliferation of EBV-Infected T and NK Cells

PubMed Central

Arai, Ayako; Nakazawa, Atsuko; Kawano, Fuyuko; Ichikawa, Sayumi; Shimizu, Norio; Yamamoto, Naoki; Morio, Tomohiro; Ohga, Shouichi; Nakamura, Hiroyuki; Ito, Mamoru; Miura, Osamu; Komano, Jun; Fujiwara, Shigeyoshi

2011-01-01

Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients' PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rγnull strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Expression of the EBV nuclear antigen 1 (EBNA1), the latent membrane protein 1 (LMP1), and LMP2, but not EBNA2, in the engrafted cells is consistent with the latency II program of EBV gene expression known in CAEBV. High levels of human cytokines, including IL-8, IFN-γ, and RANTES, were detected in the peripheral blood of the model mice, mirroring hypercytokinemia characteristic to both CAEBV and EBV-HLH. Transplantation of individual immunophenotypic subsets isolated from patients' PBMC as well as that of various combinations of these subsets revealed a critical role of CD4+ T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases. PMID:22028658

Novel mouse xenograft models reveal a critical role of CD4+ T cells in the proliferation of EBV-infected T and NK cells.

PubMed

Imadome, Ken-ichi; Yajima, Misako; Arai, Ayako; Nakazawa, Atsuko; Kawano, Fuyuko; Ichikawa, Sayumi; Shimizu, Norio; Yamamoto, Naoki; Morio, Tomohiro; Ohga, Shouichi; Nakamura, Hiroyuki; Ito, Mamoru; Miura, Osamu; Komano, Jun; Fujiwara, Shigeyoshi

2011-10-01

Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients' PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rγ(null) strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Expression of the EBV nuclear antigen 1 (EBNA1), the latent membrane protein 1 (LMP1), and LMP2, but not EBNA2, in the engrafted cells is consistent with the latency II program of EBV gene expression known in CAEBV. High levels of human cytokines, including IL-8, IFN-γ, and RANTES, were detected in the peripheral blood of the model mice, mirroring hypercytokinemia characteristic to both CAEBV and EBV-HLH. Transplantation of individual immunophenotypic subsets isolated from patients' PBMC as well as that of various combinations of these subsets revealed a critical role of CD4+ T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases.

Transient immune deficiency in patients with acute Epstein-Barr virus infection.

PubMed

Junker, A K; Ochs, H D; Clark, E A; Puterman, M L; Wedgwood, R J

1986-09-01

To study the effect of primary Epstein-Barr virus (EBV) infection on antigen-specific antibody production, we immunized 17 college students who had developed acute infectious mononucleosis with the T-cell dependent neoantigen bacteriophage phi X174. During the early phase of infectious mononucleosis, the proportion of peripheral blood lymphocytes displaying Ia and T8 (CD8) phenotypes was increased and the T helper/suppressor (T4/T8) ratio was decreased (less than 1). These abnormalities disappeared during the convalescent phase. Correlating with EBV-induced changes in T lymphocytes, we demonstrated depressed humoral immune responses to bacteriophage phi X174 both in vivo and in vitro. In vitro coculture experiments indicated that the Ia+ suppressor T cells could inhibit antibody production and isotype switch. Removal of T8+ lymphocytes from patient T cells normalized in vitro antibody synthesis. In addition, impaired B-cell function was shown to be in part responsible for deficient antibody production. These studies demonstrate that infection with EBV affects both B and T lymphocytes and causes a broad-based transient immune deficiency in patients with uncomplicated infectious mononucleosis.

Chronic active EBV infection: the experience of the Samsung Medical Center in South Korea.

PubMed

Lee, Tae-Hee; Ko, Young-Hyeh

Chronic active EBV infection (CAEBV) of T-cell or NK-cell type is an EBV+ polyclonal, oligoclonal or often monoclonal lymphoproliferative disorder (LPD) recognized as representing the spectrum of EBV-associated T-cell and NK-cell LPD with different clinical presentations; one systemic and two cutaneous disorders including hydroa vacciniforme-like T-cell LPD and mosquito bite hypersensitivity. The systemic form of the disease is characterized by fever, persistent hepatitis, hepatosplenomegaly and lymphadenopathy, which shows varying degrees of clinical severity depending on the immune response of the host and the EBV viral load. We described the clinicopathological findings of two children with CAEBV with a brief review of the literature. Recognition of the disease is important for adequate management of the patient. EBV analysis should be included in the principal diagnostic tests for febrile children. Copyright © 2015 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

Epstein-Barr virus associated acute hepatitis with cross-reacting antibodies to other herpes viruses in immunocompetent patients: report of two cases.

PubMed

Gupta, Ekta; Bhatia, Vikram; Choudhary, Aashish; Rastogi, Archana; Gupta, Naveen L

2013-03-01

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis (IM) which is characterized by the triad of fever, sore throat, and lymphadenopathy. Self-limited, mild liver function test abnormalities are seen in IM. Acute hepatitis in primary EBV infection is uncommon. Serum transaminases are elevated but are less than fivefold the normal levels in most cases and rarely exceed 10 times the normal levels in primary EBV infections especially in elderly. Laboratory diagnosis of acute EBV infection is by serological assays confirming the presence of EBV viral capsid antigen (VCA) IgM antibodies. Due to antigenic cross-reactivity with Herpes viruses, serological assays lack specificity; hence specific molecular diagnostic methods are required for confirmation of the etiology. The present report describes two cases of acute hepatitis caused by infection with EBV which had indistinguishable clinical features and biochemical markers from acute hepatitis caused by hepatotropic viruses such as hepatitis viruses A-E. The diagnosis of infection by EBV was confirmed by detection of EBV DNA in blood of both the patients and EBV DNA in the liver tissue of one of the patients. Copyright © 2013 Wiley Periodicals, Inc.

CUX1/Wnt signaling regulates Epithelial Mesenchymal Transition in EBV infected epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Malizia, Andrea P.; Lacey, Noreen; Walls, Dermot

Idiopathic pulmonary fibrosis (IPF) is a refractory and lethal interstitial lung disease characterized by alveolar epithelial cells apoptosis, fibroblast proliferation and extra-cellular matrix protein deposition. EBV, localised to alveolar epithelial cells of pulmonary fibrosis patients is associated with a poor prognosis. A strategy based on microarray-differential gene expression analysis to identify molecular drivers of EBV-associated lung fibrosis was utilized. Alveolar epithelial cells were infected with EBV to identify genes whose expression was altered following TGF{beta}1-mediated lytic phase. EBV lytic reactivation by TGF{beta}1 drives a selective alteration in CUX1 variant (a) (NCBI accession number NM{sub 1}81552) expression, inducing activation of non-canonicalmore » Wnt pathway mediators, implicating it in Epithelial Mesenchymal Transition (EMT), the molecular event underpinning scar production in tissue fibrosis. The role of EBV in EMT can be attenuated by antiviral strategies and inhibition of Wnt signaling by using All-Trans Retinoic Acids (ATRA). Activation of non-canonical Wnt signaling pathway by EBV in epithelial cells suggests a novel mechanism of EMT via CUX1 signaling. These data present a framework for further description of the link between infectious agents and fibrosis, a significant disease burden.« less

Clinicopathological states of Epstein-Barr virus-associated T/NK-cell lymphoproliferative disorders (severe chronic active EBV infection) of children and young adults.

PubMed

Suzuki, Keiko; Ohshima, Koichi; Karube, Kennosuke; Suzumiya, Junji; Ohga, Shouichi; Ishihara, Shigehiko; Tamura, Kazuo; Kikuchi, Masahiro

2004-05-01

Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disorders (LPD) of children and young adults are sometimes termed as severe chronic active EBV infection (CAEBV), and are associated with an aggressive clinical course. However, these clinicopathological states and the role of EBV have not been clarified. A retrospective study was performed on 43 children and adult patients, who manifested EBV-associated T/NK-cell lymphoproliferative disorders (EBV-T/NK-LPD) and most of whom had experienced general illness with CAEBV for several months or years. Clinicopathologically, 43 patients were classified into four groups: group A (smoldering state) (n=7), morphological non-neoplastic LPD with chronic clinical course (several years); group B (chronic state) (n=10), non-neoplastic LPD with clonal EBV-infected cells and a chronic course; group C (leukemia/lymphoma state) (n=22), neoplastic LPD with a subacute course (years to months); group D (fulminant state) (n=4), neoplastic LPD with a fulminant course (weeks to days). The 43 patients comprised 21 males and 22 females. The median age of group A was 14 years, group B 12 years, group C 17 years, and group D 1 year. Four of 7 patients in group A, 3 of 10 in group B, 12 of 22 in group C, and all 4 in group D have died. Causes of death included hemophagocytic syndrome and/or tumor death. Genotypically and phenotypically, group C was composed of peripheral T-cell lymphoma (PTCL), and NK-cell leukemia/lymphoma (NKLL), and group D comprised cases of PTCL. Groups A and B exhibited increased NK- or T-cells (CD8>CD4), and rare B-cells. Serologic titers of EBV were only modestly elevated or not elevated in almost all cases. EBV early RNA-1 (EBER-1)-expressing EBV-infected cells were frequently encountered in each group, but the number of infected cells varied between the cases. The EBV genotype did not differ between the groups. Our findings support an important pathogenic role for EBV-infected T/NK-cell infection

Successful control of Epstein-Barr virus (EBV)-infected cells by allogeneic nonmyeloablative stem cell transplantation in a patient with the lethal form of chronic active EBV infection.

PubMed

Uehara, Taeko; Nakaseko, Chiaki; Hara, Satoru; Harima, Akane; Ejiri, Megumi; Yokota, Akira; Saito, Yasushi; Nishimura, Miki

2004-08-01

Chronic active Epstein-Barr virus infection (CAEBV) is a heterogeneous EBV-related disorder, ranging from mild/moderate forms to rapidly lethal disorders. The lethal form of CAEBV is characterized by multiple organ failure, hemophagocytic syndrome, and development of lymphomas. Allogeneic stem cell transplantation is considered as the only potentially curative treatment for the lethal form of CAEBV, but it is not always desirable because of the high incidence of regimen-related toxicities. A 17-year-old female with CAEBV, who was refractory to conventional therapies and considered to be unable to receive a myeloablative regimen because of multiple organ dysfunction, underwent allogeneic nonmyeloablative stem cell transplantation (allo-NST) before developing a hematological malignancy. She has been well without any signs of CAEBV for 27 months after allo-NST, and we confirmed that specific cytotoxic T lymphocyte activity against EBV was reconstituted. This outcome suggests that allo-NST can control CAEBV by reconstituting the host immunity against EBV. Copyright 2004 Wiley-Liss, Inc.

On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis

PubMed Central

Hadinoto, Vey; Shapiro, Michael; Greenough, Thomas C.; Sullivan, John L.; Luzuriaga, Katherine

2008-01-01

Memory B cells latently infected with Epstein-Barr virus (mBLats) in the blood disappear rapidly on presentation with acute symptomatic primary infection (acute infectious mononucleosis [AIM]). They undergo a simple exponential decay (average half-life: 7.5 ± 3.7 days) similar to that of normal memory B cells. The cytotoxic T lymphocyte (CTL) response to immediate early (IE) lytic antigens (CTLIEs) also decays over this time period, but no such correlation was observed for the CTL response to lytic or latent antigens or to the levels of virions shed into saliva. We have estimated the average half-life of CTLIEs to be 73 (± 23) days. We propose that cycles of infection and reactivation occur in the initial stages of infection that produce high levels of mBLats in the circulation. Eventually the immune response arises and minimizes these cycles leaving the high levels of mBLats in the blood to decay through simple memory B-cell homeostasis mechanisms. This triggers the cells to reactivate the virus whereupon most are killed by CTLIEs before they can release virus and infect new cells. The release of antigens caused by this large-scale destruction of infected cells may trigger the symptoms of AIM and be a cofactor in other AIM-associated diseases. PMID:17991806

EBV and systemic lupus erythematosus: a new perspective.

PubMed

Gross, Andrew J; Hochberg, Donna; Rand, William M; Thorley-Lawson, David A

2005-06-01

We have proposed that EBV uses mature B cell biology to access memory B cells as a site of persistent infection. A central feature of this model is that EBV adapts its gene expression profile to the state of the B cell it resides in and that the level of infection is stable over time. This led us to question whether changes in the behavior or regulation of mature B cells would alter the state of EBV persistence. To investigate this, we studied the impact of systemic lupus erythematosus (SLE), a disease characterized by immune dysfunction, on EBV infection. We show that patients with SLE have abnormally high frequencies of EBV-infected cells in their blood, and this is associated with the occurrence of SLE disease flares. Although patients with SLE have frequencies of infected cells comparable to those seen in immunosuppressed patients, in SLE the effect was independent of immunosuppressive therapy. Aberrant expression of viral lytic (BZLF1) and latency (latency membrane proteins 1 and 2a) genes was also detected in the blood of SLE patients. We conclude that the abnormal regulation of EBV infection in SLE patients reflects the sensitivity of the virus to perturbation of the immune system.

Acute Epstein-Barr virus infection presenting as severe gastroenteritis without infectious mononucleosis-like manifestations.

PubMed

Fujiwara, Mikio; Miyamoto, Shin'ichi; Iguchi, Kouta; Matsunaka, Toshihiro; Sakashita, Hiromi; Tsuruyama, Tatsuaki; Kanegane, Hirokazu; Marusawa, Hiroyuki; Nakase, Hiroshi; Chiba, Tsutomu

2009-12-01

Primary Epstein-Barr virus (EBV) infection is usually a self-limiting disease. Although it is sometimes accompanied by severe complications such as thrombocytopenia, hemolytic anemia, and splenic rupture, predominantly gastrointestinal complications are rarely reported. We studied an unusual case of primary EBV infection associated with severe hemorrhagic gastroenteritis. EBV infection was confirmed in the biopsy specimen by demonstrating the presence of EBV DNA by polymerase chain reaction, and of EBV-encoded small RNA (EBER)-positive cells by in-situ hybridization. Our patient was suspected of having primary EBV infection from the serological findings-EBV-viral capsid antigen IgM (+) and EBV nuclear antigen (-)-but he did not show typical clinical features of infectious mononucleosis such as lymph node swelling, pharyngitis, liver dysfunction, and splenomegaly. A definite diagnosis of primary EBV infection was made using biopsy specimens by demonstrating the presence of EBV DNA and EBER-positive cells.

Transient widespread cortical and splenial lesions in acute encephalitis/encephalopathy associated with primary Epstein-Barr virus infection.

PubMed

Zhang, Shuo; Feng, Juan; Shi, Yifang

2016-01-01

Infection with Epstein-Barr virus (EBV) is very common and usually occurs in childhood or early adulthood. Encephalitis/encephalopathy is an uncommon but serious neurological complication of EBV. A case of EBV-associated encephalitis/encephalopathy with involvement of reversible widespread cortical and splenial lesions is presented herein. An 8-year-old Chinese girl who presented with fever and headache, followed by seizures and drowsiness, was admitted to the hospital. Magnetic resonance imaging revealed high signal intensities on diffusion-weighted imaging in widespread cortical and splenial lesions. The clinical and laboratory examination results together with the unusual radiology findings suggested acute encephalitis/encephalopathy due to primary EBV infection. After methylprednisolone pulse therapy together with ganciclovir, the patient made a full recovery without any brain lesions. The hallmark clinical-radiological features of this patient included severe encephalitis/encephalopathy at onset, the prompt and complete recovery, and rapidly reversible widespread involvement of the cortex and splenium. Patients with EBV encephalitis/encephalopathy who have multiple lesions, even with the widespread involvement of cortex and splenium of the corpus callosum, may have a favorable outcome with complete disappearance of all brain lesions. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

A gene expression signature that correlates with CD8+T cell expansion in acute Epstein Barr virus infection1

PubMed Central

Greenough, Thomas C.; Straubhaar, Juerg R.; Kamga, Larisa; Weiss, Eric R.; Brody, Robin M.; McManus, Margaret M.; Lambrecht, Linda K.; Somasundaran, Mohan; Luzuriaga, Katherine F.

2015-01-01

Virus specific CD8+ T cells expand dramatically during acute Epstein Barr virus (EBV) infection, and their persistence is important for lifelong control of EBV-related disease. To better define the generation and maintenance of these effective CD8+ T cell responses, we used microarrays to characterize gene expression in total and EBV-specific CD8+ T cells isolated from the peripheral blood of ten individuals followed from acute infectious mononucleosis (AIM) into convalescence (CONV). In total CD8+ T cells, differential expression of genes in AIM and CONV was most pronounced among those encoding proteins important in T cell activation/differentiation, cell division/metabolism, chemokines/cytokines and receptors, signaling and transcription factors (TF), immune effector functions, and negative regulators. Within these categories, we identified 28 genes that correlated with CD8+ T cell expansion in response to an acute EBV infection. In EBV-specific CD8+ T cells, we identified 33 genes that were differentially expressed in AIM and CONV. Two important TF, T-bet and Eomesodermin (Eomes), were upregulated and maintained at similar levels in both AIM and CONV; by contrast, protein expression declined from AIM to CONV. Expression of these TF varied among cells with different epitope specificities. Altogether, gene and protein expression patterns suggest that a large proportion, if not a majority of CD8+ T cells in AIM are virus-specific, activated, dividing, and primed to exert effector activities. High expression of T-bet and Eomes may help to maintain effector mechanisms in activated cells, and to enable proliferation and transition to earlier differentiation states in CONV. PMID:26416268

A heart breaking case of rapidly developing severe hemophagocytic syndrome secondary to chronic active EBV infection; a case report and review of the literature.

PubMed

Tawfik, Khoury; Liron, Yosha; Ayman, Abu Rmieleh; Schneider, Ronen; Wolf, D G; Ronen, Levi

2015-06-01

Epstein-Barr virus (EBV, HHV-4) is a gamma Herpesvirus with a 90% >seroprevalence in adults. Reactivations in non-immuno compromised individuals usually cause mild or no symptoms at all. Rarely, host immunity-virus balance is interrupted, resulting in a chronic active EBV infection. The following case illustrates the rapid development of severe hemophagocytic syndrome during chronic active EBV infection in a 73 year old woman who presented with lower extremity pain and edema, splenomegaly and abnormal liver enzymes. A diagnosis of chronic active EBV infection was made following an extensive investigation and the patient died secondary to rapidly progressive hemophagocytic syndrome. Copyright © 2015 Elsevier B.V. All rights reserved.

[Sequential monitoring of plasma EBV-DNA level in a patient with EBV-positive Hodgkin lymphoma].

PubMed

Uchida, Emi; Honma, Riko; Igarashi, Aiko; Kurata, Morito; Imadome, Ken-Ichi; Omoto, Eijiro; Miura, Osamu; Arai, Ayako

2012-01-01

A 58-year-old woman was admitted to our hospital because of fever, systemic lymphadenopathy with abnormal Epstein-Barr virus (EBV) antibody titers, and a high EBV-DNA load in the serum. She had been diagnosed as possibly having chronic active EBV infection (CAEBV) during a previous hospitalization. The EBV-DNA load of the plasma (pEBV-DNA), examined at our hospital, was elevated to 1.8×10(4) copies/ml, whereas that of the peripheral blood mononuclear cells was 3.4×10(1) copies/μg DNA, which was not clearly elevated, unlike in cases with CAEBV. Biopsy of the cervical lymph node was performed and the diagnosis of mixed cellularity classical Hodgkin lymphoma, Stage4B was made. Hodgkin cells were positive for EBV. COPP therapy was started and pEBV-DNA decreased drastically. The treatment was followed by ABVD therapy and pEBV-DNA turned negative after one course of ABVD therapy. She achieved complete response after 4 courses of the treatment. Reports from abroad indicate that pEBV-DNA parallels the disease state of EBV-positive Hodgkin lymphoma. Our results were consistent with these reports, and demonstrated that, in a Japanese patient, EBV-DNA load and its localization in the peripheral blood fractions could be useful tools for diagnosis as well as evaluating the disease status.

An Animal Model for Human EBV-Associated Hemophagocytic Syndrome

PubMed Central

Hayashi, Kazuhiko; Ohara, Nobuya; Teramoto, Norihiro; Onoda, Sachiyo; Chen, Hong-Li; Oka, Takashi; Kondo, Eisaku; Yoshino, Tadashi; Takahashi, Kiyoshi; Yates, John; Akagi, Tadaatsu

2001-01-01

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) is often associated with fatal infectious mononucleosis. However, the animal model for EBV-AHS has not been developed. We reported the first animal model for EBV-AHS using rabbits infected with EBV-related herpesvirus of baboon (HVP). Eleven of 13 (85%) rabbits inoculated intravenously with HVP-producing cells developed fatal lymphoproliferative disorders (LPD) between 22 and 105 days after inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in nine of these 11 rabbits. The peroral spray of cell-free HVP induced the virus infection with increased anti-EBV-viral capsid antigen-IgG titers in three of five rabbits, and two of these three infected rabbits died of LPD with HPS. Autopsy revealed hepatosplenomegaly and swollen lymph nodes. Atypical lymphoid T cells expressing EBV-encoded small RNA-1 infiltrated diffusely in many organs, frequently involving the lymph nodes, spleen, and liver. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by polymerase chain reaction or Southern blot analysis. Reverse transcriptase-polymerase chain reaction revealed both HVP-EBNA1 and HVP-EBNA2 transcripts, suggesting latency type III infection. These data indicate that the high rate of rabbit LPD with HPS induction is caused by HVP. This system is useful for studying the pathogenesis, prevention, and treatment of human EBV-AHS. PMID:11290571

Spontaneous resolution of hemophagocytic syndrome associated with acute parvovirus B19 infection and concomitant Epstein-Barr virus reactivation in an otherwise healthy adult.

PubMed

Larroche, C; Scieux, C; Honderlick, P; Piette, A M; Morinet, F; Blétry, O

2002-10-01

Reported here is the case of a patient who spontaneously recovered from hemophagocytic syndrome associated with acute B19 infection and concomitant Epstein-Barr virus reactivation. The previously healthy 37-year-old-man was hospitalized after 10 days of high fever, arthralgia and arthritis and was determined to have hemophagocytic syndrome. Immunoglobulin (Ig) M antibodies to Epstein-Barr virus (EBV) capsid antigen, early antigen and parvovirus B19 (B19) were found. B19 DNA and low-level EBV DNA were detected in bone marrow, serum and peripheral blood mononuclear cells. The patient recovered spontaneously without any treatment. Two months later anti-B19 IgG antibodies were detected, while at 9-month follow-up, anti-B19 IgM antibodies were no longer detectable and B19 DNA had disappeared from serum. To the best of our knowledge, this is the first report of spontaneous resolution of hemophagocytic syndrome associated with acute B19 infection and concomitant EBV reactivation in an otherwise healthy adult.

Epstein-Barr Virus (EBV) DNA in plasma is not encapsidated in patients with EBV-related malignancies.

PubMed

Ryan, Julie L; Fan, Hongxin; Swinnen, Lode J; Schichman, Steven A; Raab-Traub, Nancy; Covington, Mary; Elmore, Sandra; Gulley, Margaret L

2004-06-01

Epstein-Barr Virus (EBV), a ubiquitous gamma herpes virus, infects more than 95% of the human population before adulthood. Life-long persistence, usually without adverse health consequences, relies on a balance between viral latency, viral replication, and host immune response. Patients with EBV-related disease often have high levels of EBV DNA in their plasma. This study addresses whether this circulating, cell-free EBV DNA is encapsidated in virions or exists as naked genomes. First, an assay was developed, combining DNase I and quantitative real-time PCR, to discriminate encapsidated from naked EBV DNA. EBV DNA was almost always naked in the plasma of AIDS-related lymphoma patients (n = 11) and immunosuppressed/posttransplantation patients (n = 8). In contrast, infectious mononucleosis patients (n = 30) often had a mixture of encapsidated and naked EBV DNA. These findings may be important in understanding how viral load relates to disease status and in predicting response to nucleoside analogs and other antiviral therapies.

Cutaneous EBV-related lymphoproliferative disorders.

PubMed

Gru, Alejandro A; Jaffe, Elaine S

2017-01-01

This article will focus on the cutaneous lymphoproliferative disorders associated with EBV, with an emphasis on the upcoming changes in the revised 4th Edition of the WHO classification of tumors of the hematopoietic system, many of which deal with cutaneous disorders derived from NK-cells or T-cells. Extranodal NK/T-cell lymphoma usually presents in the upper aerodigestive tract, but can involve the skin secondarily. EBV-associated T- and NK-cell lymphoproliferative disorders (LPD) in the pediatric age group include the systemic diseases, chronic active EBV infection (CAEBV) and systemic EBV+ T-cell lymphoma of childhood. Hydroa vacciniforme (HV)-like LPD is a primarily cutaneous form of CAEBV and encompasses the lesions previously referred to as HV and HV-like lymphoma (HVLL). All the T/NK-cell-EBV-associated diseases occur with higher frequency in Asians, and indigenous populations from Central and South America and Mexico. Among the B-cell EBV-associated LPD two major changes have been introduced in the WHO. The previously designated EBV-positive diffuse large B-cell lymphoma (EBV-DLBCL) of the elderly, has been changed to EBV-DLBCL with 'not otherwise specified' as a modifier (NOS). A new addition to the WHO system is the more recently identified EBV+ mucocutaneous ulcer, which involves skin and mucosal-associated sites. Copyright © 2017 Elsevier Inc. All rights reserved.

Curcuminoids as EBV Lytic Activators for Adjuvant Treatment in EBV-Positive Carcinomas

PubMed Central

Ramayanti, Octavia; Brinkkemper, Mitch; Verkuijlen, Sandra A. W. M.; Ritmaleni, Leni; Go, Mei Lin

2018-01-01

Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA treatment has proven safe in phase-I/II trials with promising clinical responses in patients with recurrent NPC. However, a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, a dietary spice used in Asian countries, is known for its antitumor property and therapeutic potential. Novel curcuminoids that were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvants. We investigated the potential of curcumin and its analogs (curcuminoids) to trigger the EBV lytic cycle in EBVaGC and NPC cells. EBV-reactivating effects were measured by immunoblot and immunofluorescence using monoclonal antibodies specific for EBV lytic proteins. Two of the hit compounds (41, EF24) with high lytic inducing activity were further studied for their synergistic or antagonistic effects when combined with GCb+VPA and analyzed by cytotoxicity and mRNA profiling assays to measure the EBV reactivation. Curcuminoid as a single agent significantly induced EBV reactivation in recombinant GC and NPC lines. The drug effects were dose- and time-dependent. Micromolar concentration of curcuminoid EF24 enhanced the CLVA effect in all cell systems except SNU719, a naturally infected EBVaGC cell that carries a more tightly latent viral genome. These findings indicated that EF24 has potential as EBV lytic activator and may serve as an adjuvant in CLVA treatment. PMID:29565326

Curcuminoids as EBV Lytic Activators for Adjuvant Treatment in EBV-Positive Carcinomas.

PubMed

Ramayanti, Octavia; Brinkkemper, Mitch; Verkuijlen, Sandra A W M; Ritmaleni, Leni; Go, Mei Lin; Middeldorp, Jaap M

2018-03-22

Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA treatment has proven safe in phase-I/II trials with promising clinical responses in patients with recurrent NPC. However, a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, a dietary spice used in Asian countries, is known for its antitumor property and therapeutic potential. Novel curcuminoids that were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvants. We investigated the potential of curcumin and its analogs (curcuminoids) to trigger the EBV lytic cycle in EBVaGC and NPC cells. EBV-reactivating effects were measured by immunoblot and immunofluorescence using monoclonal antibodies specific for EBV lytic proteins. Two of the hit compounds ( 41 , EF24 ) with high lytic inducing activity were further studied for their synergistic or antagonistic effects when combined with GCb+VPA and analyzed by cytotoxicity and mRNA profiling assays to measure the EBV reactivation. Curcuminoid as a single agent significantly induced EBV reactivation in recombinant GC and NPC lines. The drug effects were dose- and time-dependent. Micromolar concentration of curcuminoid EF24 enhanced the CLVA effect in all cell systems except SNU719, a naturally infected EBVaGC cell that carries a more tightly latent viral genome. These findings indicated that EF24 has potential as EBV lytic activator and may serve as an adjuvant in CLVA treatment.

Defective activity of Epstein-Barr virus (EBV) specific cytotoxic T lymphocytes in children with chronic active EBV infection and in their parents.

PubMed

Fujieda, M; Wakiguchi, H; Hisakawa, H; Kubota, H; Kurashige, T

1993-10-01

Antibodies of Epstein-Barr virus (EBV), EBV-specific cytotoxic T lymphocyte (EBVCTL) activity and the lymphocyte subset of CTL were examined in 13 Japanese children with chronic active EBV infection (CAEBV) and their parents (eight fathers and 10 mothers). Anti-virus-capsid antigen (VCA)-IgG antibody titers ranged from 1:640 to 1:5120 in the patients with CAEBV and from 1:40 to 1:640 in the parents. While anti-VCA-IgM antibody was detected in three patients, anti-VCA-IgA antibody in five and anti-early-antigen (EA)-IgG antibody in 11, no antibody was detected in the parents except anti-EA antibody, which was positive in the mothers of cases 5 and 13 (1:10 and 1:40). Anti-EBV-associated nuclear antigen (EBNA) antibody was < or = 1:10 in six out of 13 patients with CAEBV and in 10 out of 18 parents tested. Epstein-Barr virus activity was significantly lower (P < 0.005) both in the children with CAEBV and in their parents than in seropositive age-matched controls. Proportions of a CTL subset (CD8+ CD11- lymphocytes) in the patients with CAEBV were significantly higher (P < 0.005) than in controls, while those in the parents were at the same level as in controls. Defective EBVCTL activity and anti-EBNA-antibody responses were frequently observed both in children with CAEBV and in their parents, which may suggest that the abnormal immune response to EBV may be based on a familial disorder, though no familial involvement has been reported in Japanese children with CAEBV.

Combination of immunoglobulins and natural killer cells in the context of CMV and EBV infection.

PubMed

Frenzel, K; Lehmann, J; Krüger, D H; Martin-Parras, L; Uharek, L; Hofmann, J

2014-04-01

Cytomegalovirus (CMV)-specific hyperimmunoglobulin (CMV-HIG) is used to treat and prevent CMV infection in immunocompromised patients, and anti-CD20 monoclonal antibody is successfully used in the treatment for post-transplant lymphoproliferative disease caused by Epstein-Barr virus (EBV). Two immunological approaches have been suggested to further improve the control of viral reproduction in patients with active disease: first, the use of monoclonal antibodies with specificity against viral epitopes and second, coadministration of cells with the capacity to promote antibody-dependent cell-mediated cytotoxicity. Here, we have evaluated the effectiveness of these strategies in vitro (alone and in combination) with neutralization and cytotoxicity assays. Our results indicate that monoclonal antibodies (in particular SM5-1) can be as effective as CMV-HIG in neutralizing-cell-free CMV. Moreover, our data indicate that antibody-mediated elimination (either by moAb or by HIG) of EBV-infected cells can be significantly enhanced by NK cells. Using human NK cells that have been purified, cultured and expanded under GMP conditions, we were able to demonstrate that the combination of NK cells and antibodies could represent a feasible and highly effective clinical approach to achieve control of EBV infections. Especially in leukopenic patients with low numbers of ADCC-promoting cells, the combination of adoptively transferred NK cells and antiviral antibodies offers a promising strategy that should be tested in clinical trials.

Epstein-Barr Virus (EBV) Latent Protein EBNA3A Directly Targets and Silences the STK39 Gene in B Cells Infected by EBV.

PubMed

Bazot, Quentin; Paschos, Kostas; Allday, Martin J

2018-04-01

Epstein-Barr virus (EBV) establishes latent infection in human B cells and is associated with a wide range of cancers. The EBV nuclear antigen 3 (EBNA3) family proteins are critical for B cell transformation and function as transcriptional regulators. It is well established that EBNA3A and EBNA3C cooperate in the regulation of cellular genes. Here, we demonstrate that the gene STK39 is repressed only by EBNA3A. This is the first example of a gene regulated only by EBNA3A in EBV-transformed lymphoblastoid cell lines (LCLs) without the help of EBNA3C. This was demonstrated using a variety of LCLs carrying either knockout, revertant, or conditional EBNA3 recombinants. Investigating the kinetics of EBNA3A-mediated changes in STK39 expression showed that STK39 becomes derepressed quickly after EBNA3A inactivation. This derepression is reversible as EBNA3A reactivation represses STK39 in the same cells expressing a conditional EBNA3A. STK39 is silenced shortly after primary B cell infection by EBV, and no STK39 -encoded protein (SPAK) is detected 3 weeks postinfection. Chromatin immunoprecipitation (ChIP) analysis indicates that EBNA3A directly binds to a regulatory region downstream of the STK39 transcription start site. For the first time, we demonstrated that the polycomb repressive complex 2 with the deposition of the repressive mark H3K27me3 is not only important for the maintenance of an EBNA3A target gene ( STK39 ) but is also essential for the initial establishment of its silencing. Finally, we showed that DNA methyltransferases are involved in the EBNA3A-mediated repression of STK39 IMPORTANCE EBV is well known for its ability to transform B lymphocytes to continuously proliferating lymphoblastoid cell lines. This is achieved in part by the reprogramming of cellular gene transcription by EBV transcription factors, including the EBNA3 proteins that play a crucial role in this process. In the present study, we found that EBNA3A epigenetically silences STK39 This

Epstein-Barr virus and regulatory T cells in Egyptian paediatric patients with acute B lymphoblastic leukaemia.

PubMed

Ateyah, Mohamed E; Hashem, Mona E; Abdelsalam, Mohamed

2017-02-01

Acute B lymphoblastic leukaemia (B-ALL) is the most common type of childhood malignancy worldwide but little is known of its origin. Recently, many studies showed both a high incidence of Epstein-Barr virus (EBV) infection and high levels of CD4 + CD25 + Foxp3 + (Treg cells) in children with B-ALL. In our study, we investigated the possible relationship between EBV infection and the onset of B-ALL, and its relation to expression of CD4 + , CD25 high+ Foxp3+ T regulatory cells. We analysed expression and mean fluorescence intensity (MFI) of Treg cells in peripheral blood of 45 children with B-ALL and in 40 apparently healthy children as a control, using flow cytometry. Serum anti-EBV viral capsid antigen (VCA) IgG, anti-EBV nuclear antigen (EBNA) IgG (for latent infection) and anti-EBV VCA IgM (for acute infection) were investigated using ELISA. Analysis of the Treg cells population in patients and controls revealed that expression of CD4 + CD25 high+ T lymphocytes was higher in patients than in controls (mean±SD 15.7±4.1 and 10.61±2.6 in patients and controls, respectively, and MFI of Foxp3 was 30.1±7.1 and 16.7±3.7 in patients and controls, respectively (p<0.001)). There was a high incidence of latent EBV infection in patients (31%) compared with controls (10%) while the incidence of acute infection was 12% in patients and 0% in the control group. To study the role of latent EBV infection in the pathogenesis of acute B-ALL, OR was calculated (OR=4.06, coefficient index 1.2-13.6). These findings suggest a possible role for Treg cells and EBV in the pathogenesis of B-ALL. Further studies are needed on the possible mechanisms of tumour genesis related to Treg cells and EBV in children with B-ALL. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Detection of cell-free Epstein-Barr virus DNA in serum during acute infectious mononucleosis.

PubMed

Gan, Y J; Sullivan, J L; Sixbey, J W

1994-08-01

Infectious Epstein-Barr virus (EBV) is shed from the oropharynx of infected hosts intermittently throughout life, but in the peripheral circulation the viral genome characteristically maintains itself in a noninfectious, cell-associated form. Sera from 125 persons with heterophil-positive acute infectious mononucleosis or EBV-associated nasopharyngeal carcinoma or who were healthy virus carriers were examined for evidence of cell-free viral DNA. EBV DNA suggesting viremia was detected in 11 (27%) of 41 infectious mononucleosis patients by polymerase chain reaction analysis but infrequently in healthy seropositive carriers and patients with nasopharyngeal carcinoma. In serial samples examined from 2 patients, serum EBV DNA was detected over a 3-day interval. Viral DNA was found in concert with one serologic marker of acute infection, EBV-specific polymeric IgA, that could affect patterns of viral spread and clinical symptomatology.

[Epstein-Barr virus infection with severe consequences. EBV, haemophagocytic lymphohistiocytosis and Hodgkin lymphoma with Down syndrome].

PubMed

Kuitert, Pieter C J; Abbink, Floor C H; Broers, Chantal J M; van der Valk, Paul; van Furth, A Marceline; van der Kuip, Martijn

2014-01-01

Over 90% of the population is infected with the Epstein-Barr virus (EBV). Following primary infection, the virus remains latent in B-lymphocytes. In isolated cases, especially in immunocompromised patients, the Epstein-Barr virus can result in a chronic active infection (CAEBV). We describe an 11-year-old boy with Down syndrome who was admitted because of fever of unknown origin during several periods. Serological findings (high VCA-IgG and absent EBNA-IgG) were suggestive of CAEBV, which was confirmed by the high circulating EBV viral load. During admission the clinical picture worsened and our patient developed pancytopenia, which led us to diagnose concurrent haemophagocytic lymphohistiocytosis and Hodgkin lymphoma. CAEBV is the result of deficiency in cellular immunity, which in this patient could possibly be attributed to deficiencies in the immune system associated with Down syndrome. CAEBV is difficult to treat, and it can come with life-threatening complications such as haemophagocytic lymphohistiocytosis.

EBV, HCMV, HHV6, and HHV7 Screening in Bone Marrow Samples from Children with Acute Lymphoblastic Leukemia

PubMed Central

Morales-Sánchez, A.; Pompa-Mera, E. N.; Fajardo-Gutiérrez, A.; Alvarez-Rodríguez, F. J.; Bekker-Méndez, V. C.; Flores-Chapa, J. de Diego; Flores-Lujano, J.; Jiménez-Hernández, E.; Peñaloza-González, J. G.; Rodríguez-Zepeda, M. C.; Torres-Nava, J. R.; Velázquez-Aviña, M. M.; Amador-Sánchez, R.; Alvarado-Ibarra, M.; Reyes-Zepeda, N.; Espinosa-Elizondo, R. M.; Pérez-Saldivar, M. L.; Núñez-Enríquez, J. C.; Mejía-Aranguré, J. M.; Fuentes-Pananá, E. M.

2014-01-01

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood worldwide and Mexico has reported one of the highest incidence rates. An infectious etiology has been suggested and supported by epidemiological evidences; however, the identity of the involved agent(s) is not known. We considered that early transmitted lymphotropic herpes viruses were good candidates, since transforming mechanisms have been described for them and some are already associated with human cancers. In this study we interrogated the direct role of EBV, HCMV, HHV6, and HHV7 human herpes viruses in childhood ALL. Viral genomes were screened in 70 bone marrow samples from ALL patients through standard and a more sensitive nested PCR. Positive samples were detected only by nested PCR indicating a low level of infection. Our result argues that viral genomes were not present in all leukemic cells, and, hence, infection most likely was not part of the initial genetic lesions leading to ALL. The high statistical power of the study suggested that these agents are not involved in the genesis of ALL in Mexican children. Additional analysis showed that detected infections or coinfections were not associated with prognosis. PMID:25309913

EBV, HCMV, HHV6, and HHV7 screening in bone marrow samples from children with acute lymphoblastic leukemia.

PubMed

Morales-Sánchez, A; Pompa-Mera, E N; Fajardo-Gutiérrez, A; Alvarez-Rodríguez, F J; Bekker-Méndez, V C; Flores-Chapa, J de Diego; Flores-Lujano, J; Jiménez-Hernández, E; Peñaloza-González, J G; Rodríguez-Zepeda, M C; Torres-Nava, J R; Velázquez-Aviña, M M; Amador-Sánchez, R; Alvarado-Ibarra, M; Reyes-Zepeda, N; Espinosa-Elizondo, R M; Pérez-Saldivar, M L; Núñez-Enríquez, J C; Mejía-Aranguré, J M; Fuentes-Pananá, E M

2014-01-01

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood worldwide and Mexico has reported one of the highest incidence rates. An infectious etiology has been suggested and supported by epidemiological evidences; however, the identity of the involved agent(s) is not known. We considered that early transmitted lymphotropic herpes viruses were good candidates, since transforming mechanisms have been described for them and some are already associated with human cancers. In this study we interrogated the direct role of EBV, HCMV, HHV6, and HHV7 human herpes viruses in childhood ALL. Viral genomes were screened in 70 bone marrow samples from ALL patients through standard and a more sensitive nested PCR. Positive samples were detected only by nested PCR indicating a low level of infection. Our result argues that viral genomes were not present in all leukemic cells, and, hence, infection most likely was not part of the initial genetic lesions leading to ALL. The high statistical power of the study suggested that these agents are not involved in the genesis of ALL in Mexican children. Additional analysis showed that detected infections or coinfections were not associated with prognosis.

Animal in vivo models of EBV-associated lymphoproliferative diseases: special references to rabbit models.

PubMed

Hayashi, K; Teramoto, N; Akagi, T

2002-10-01

Animal models of human EBV-associated diseases are essential to elucidate the pathogenesis of EBV-associated diseases. Here we review those previous models using EBV or EBV-like herpesviruses and describe the details on our two newly-developed rabbit models of lymphoproliferative diseases (LPD) induced by simian EBV-like viruses. The first is Cynomolgus-EBV-induced T-cell lymphomas in rabbits inoculated intravenously (77-90%) and orally (82-89%) during 2-5 months. EBV-DNA was detected in peripheral blood by PCR from 2 days after oral inoculation, while anti-EBV-VCA IgG was raised 3 weeks later. Rabbit lymphomas and their cell lines contained EBV-DNA and expressed EBV-encoded RNA-1 (EBER-1). Rabbit lymphoma cell lines, most of which have specific chromosomal abnormality, showed tumorigenicity in nude mice. The second is the first animal model for EBV-infected T-cell LPD with virus-associated hemophagocytic syndrome (VAHS), using rabbits infected with an EBV-like herpesvirus, Herpesvirus papio (HVP). Rabbits inoculated intravenously with HVP-producing cells showed increased anti-EBV-VCA-IgG titers, and most (85%) subsequently died of fatal LPD and VAHS, with bleeding and hepatosplenomegaly, during 22-105 days. Peroral spray of cell-free HVP induced viral infection with seroconversion in 3 out of 5 rabbits, with 2 of the 3 infected rabbits dying of LPD with VAHS. Atypical T lymphocytes containing HVP-DNA and expressing EBER-1 were observed in many organs. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. These rabbit models are also useful and inexpensive alternative experimental model systems for studying the biology and pathogenesis of EBV, and prophylactic and therapeutic regimens.

Obstructive sleep apnea (OSA): a complication of acute infectious mononucleosis infection in a child.

PubMed

Cheng, Jeffrey

2014-03-01

Independently, obstructive sleep apnea (OSA) and infectious mononucleosis are not uncommon in the pediatric population, but acute onset of OSA, as a respiratory complication in the setting of acute EBV infection is extremely uncommon. Previous reports of this clinical entity are sparse and from nearly two decades ago. Urgent adenotonsillectomy was commonly advocated. This complication may be managed medically with systemic corticosteroids and non-invasive continuous positive airway pressure (CPAP), and a case is presented to highlight an updated management approach to this rarely encountered clinical problem in children. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Nominal dysphasia and euphoria caused by EBV encephalitis

PubMed Central

Carman, Kursat Bora; Yakut, Ayten; Ekici, Arzu; Isikay, Sedat

2013-01-01

Encephalitis is an uncommon neurological complication of Ebstein-Barr virus (EBV) infection and usually presents with confusion, decreased level of consciousness, fever, epileptic seizure, emotional instability and chorea. We present a patient with EBV encephalitis, characterised by nominal dysphasia, euphoria and personality changes. PMID:23307455

Interaction of Epstein-Barr virus (EBV) with human B-lymphocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klein, George, E-mail: Georg.Klein@ki.se; Klein, Eva; Kashuba, Elena

Epstein-Barr virus, EBV, and humans have a common history that reaches back to our primate ancestors. The virus co-evolved with man and has established a largely harmless and highly complex co-existence. It is carried as silent infection by almost all human adults. A serendipitous discovery established that it is the causative agent of infectious mononucleosis. Still, EBV became known first in 1964, in a rare, geographically prevalent malignant lymphoma of B-cell origin, Burkitt lymphoma BL. Its association with a malignancy prompted intensive studies and its capacity to immortalize B-lymphocytes in vitro was soon demonstrated. Consequently EBV was classified therefore asmore » a potentially tumorigenic virus. Despite of this property however, the virus carrier state itself does not lead to malignancies because the transformed cells are recognized by the immune response. Consequently the EBV induced proliferation of EBV carrying B-lymphocytes is manifested only under immunosuppressive conditions. The expression of EBV encoded genes is regulated by the cell phenotype. The virus genome can be found in malignancies originating from cell types other than the B-lymphocyte. Even in the EBV infected B-cell, the direct transforming capacity is restricted to a defined window of differentiation. A complex interaction between virally encoded proteins and B-cell specific cellular proteins constitute the proliferation inducing program. In this short review we touch upon aspects which are the subject of our present work. We describe the mechanisms of some of the functional interactions between EBV encoded and cellular proteins that determine the phenotype of latently infected B-cells. The growth promoting EBV encoded genes are not expressed in the virus carrying BL cells. Still, EBV seems to contribute to the etiology of this tumor by modifying events that influence cell survival and proliferation. We describe a possible growth promoting mechanism in the genesis of Burkitt

Unveiling Another Missing Piece in EBV-Driven Lymphomagenesis: EBV-Encoded MicroRNAs Expression in EBER-Negative Burkitt Lymphoma Cases.

PubMed

Mundo, Lucia; Ambrosio, Maria R; Picciolini, Matteo; Lo Bello, Giuseppe; Gazaneo, Sara; Del Porro, Leonardo; Lazzi, Stefano; Navari, Mohsen; Onyango, Noel; Granai, Massimo; Bellan, Cristiana; De Falco, Giulia; Gibellini, Davide; Piccaluga, Pier P; Leoncini, Lorenzo

2017-01-01

Epstein-Barr virus (EBV) is a gammaherpesvirus linked to a number of lymphoid and epithelial malignancies, including Burkitt lymphoma (BL) in which its frequency ranges from 30% in sporadic cases to 100% in the endemic ones. The possible contribution of EBV to BL pathogenesis is largely unknown. It has been suggested that EBV may be associated with all of the cases, including those diagnosed as EBV negative by a mechanism of hit-and-run . Early during oncogenesis, viral genes are essential for initiating disease. Progressively, viral genome is lost to escape the immune system and host mutations accumulate in proto-oncogenic cell. The main problem with the hit-and-run hypothesis is the lack of evidence in primary tumors. The routine methods applied to detect the virus [i.e., immunohistochemistry and EBV-encoded RNAs (EBER) in situ hybridization (ISH)] have a low specificity and accuracy. The aim of this study was to identify the most suitable method to detect EBV infection in pathology samples by applying conventional and non-conventional methods (i.e., EBV-microRNAs detection and EBV viral load measurement). We investigated a total of 10 cases and we found that all the samples ( n = 6) diagnosed as EBV negative by immunohistochemistry and EBER-ISH demonstrated the presence of EBV-microRNAs and EBV genome. This points at the possibility that EBV might have contributed to lymphomagenesis in all our patients, and propose microRNAs detection as the most specific and sensitive tool to recognize EBV vestiges. It is worth noting that our data would have considerable implications for EBV-related diseases control. By using anti-EBV vaccines, one could potentially prevent also some cancers less suspected of a viral origin because of viral genome loss.

Unveiling Another Missing Piece in EBV-Driven Lymphomagenesis: EBV-Encoded MicroRNAs Expression in EBER-Negative Burkitt Lymphoma Cases

PubMed Central

Mundo, Lucia; Ambrosio, Maria R.; Picciolini, Matteo; Lo Bello, Giuseppe; Gazaneo, Sara; Del Porro, Leonardo; Lazzi, Stefano; Navari, Mohsen; Onyango, Noel; Granai, Massimo; Bellan, Cristiana; De Falco, Giulia; Gibellini, Davide; Piccaluga, Pier P.; Leoncini, Lorenzo

2017-01-01

Epstein–Barr virus (EBV) is a gammaherpesvirus linked to a number of lymphoid and epithelial malignancies, including Burkitt lymphoma (BL) in which its frequency ranges from 30% in sporadic cases to 100% in the endemic ones. The possible contribution of EBV to BL pathogenesis is largely unknown. It has been suggested that EBV may be associated with all of the cases, including those diagnosed as EBV negative by a mechanism of hit-and-run. Early during oncogenesis, viral genes are essential for initiating disease. Progressively, viral genome is lost to escape the immune system and host mutations accumulate in proto-oncogenic cell. The main problem with the hit-and-run hypothesis is the lack of evidence in primary tumors. The routine methods applied to detect the virus [i.e., immunohistochemistry and EBV-encoded RNAs (EBER) in situ hybridization (ISH)] have a low specificity and accuracy. The aim of this study was to identify the most suitable method to detect EBV infection in pathology samples by applying conventional and non-conventional methods (i.e., EBV-microRNAs detection and EBV viral load measurement). We investigated a total of 10 cases and we found that all the samples (n = 6) diagnosed as EBV negative by immunohistochemistry and EBER-ISH demonstrated the presence of EBV-microRNAs and EBV genome. This points at the possibility that EBV might have contributed to lymphomagenesis in all our patients, and propose microRNAs detection as the most specific and sensitive tool to recognize EBV vestiges. It is worth noting that our data would have considerable implications for EBV-related diseases control. By using anti-EBV vaccines, one could potentially prevent also some cancers less suspected of a viral origin because of viral genome loss. PMID:28298901

Maribavir Inhibits Epstein-Barr Virus Transcription through the EBV Protein Kinase

PubMed Central

Whitehurst, Christopher B.; Sanders, Marcia K.; Law, Mankit; Wang, Fu-Zhang; Xiong, Jie; Dittmer, Dirk P.

2013-01-01

Maribavir (MBV) inhibits Epstein-Barr virus (EBV) replication and the enzymatic activity of the viral protein kinase BGLF4. MBV also inhibits expression of multiple EBV transcripts during EBV lytic infection. Here we demonstrate, with the use of a BGLF4 knockout virus, that effects of MBV on transcription take place primarily through inhibition of BGLF4. MBV inhibits viral genome copy numbers and infectivity to levels similar to and exceeding levels produced by BGLF4 knockout virus. PMID:23449792

Cholecystitis and nephrotic syndrome complicating Epstein-Barr virus primary infection.

PubMed

Rodà, Diana; Huici, Malka; Ricart, Sílvia; Vila, Jordi; Fortuny, Clàudia; Alsina, Laia

2017-02-01

Epstein-Barr virus (EBV) infection results in a spectrum of clinical manifestations. The host immune response to EBV plays a key role in the extent and degree of clinical features, which in children under 4 years of age are usually mild, non-specific and self-limiting. A 2-year-old boy in whom no known immune disorder could be found presented with acute acalculous cholecystitis, renal dysfunction with massive proteinuria, ascites, pleural effusion, minimal peripheral oedema and a severe systemic inflammatory response. Improvement occurred after initiation of corticosteroids and antiviral treatment with gancyclovir. In severely symptomatic or complicated EBV infection, a primary immunodeficiency must be suspected. If a primary immunodeficiency has been ruled out, the correct management of severe EBV infection in the immunocompetent host remains controversial.

Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity

PubMed Central

Matar, Caline G.; Anthony, Neil R.; O’Flaherty, Brigid M.; Jacobs, Nathan T.; Priyamvada, Lalita; Engwerda, Christian R.; Speck, Samuel H.; Lamb, Tracey J.

2015-01-01

Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV) by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primary Plasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68) infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i) suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii) plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2-null mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodium transmission. PMID:25996913

Seroprevalence of Anti-EBV IgG among Various Age Groups from Khon Kaen Province, Thailand.

PubMed

Suntornlohanakul, Rabporn; Wanlapakorn, Nasamon; Vongpunsawad, Sompong; Thongmee, Thanunrat; Chansaenroj, Jira; Poovorawan, Yong

2015-01-01

Epstein-Barr virus (EBV) is an extremely common herpesvirus that may cause asymptomatic infection or various diseases, including infectious mononucleosis, certain lymphoproliferative diseases and several types of neoplasms. Vaccine development is an important strategy to reduce the burden of EBV-associated diseases and the timing of vaccinations should be before primary infection occurs. In the past, more than 90% of Thai children were infected with EBV in early childhood. Now, due to the improved healthcare system in Thailand, we aim to determine current prevalence of EBV infection among people in different age groups. A total of 538 sera were collected from residents of Khon Kaen province in northeastern Thailand for detecting anti-EBV IgG. Sera of infants under 2-years-old were also tested for anti-EBV IgM and EBV-DNA. The prevalence of anti-EBV IgG was 47.1% (95% CI: 23.3-70.8) in infants aged 0-6 months, 34.9% (95% CI: 23.1-46.7) in those aged 6-24 months, 87.9% (95% CI: 79.5-96.3) in children aged 3-5 years and then maintained at above 95% through adulthood. These seropositivity rates among Thai children remain similar to those found in a previous study conducted 20 years ago. Thai children are still exposed to EBV from an early age. Therefore, a prophylactic vaccine should be given within the first two years of life.

Aggressive Peripheral CD70-positive T-cell Lymphoma Associated with Severe Chronic Active EBV Infection

PubMed Central

Shaffer, Donald R.; Sheehan, Andrea M.; Yi, Zhongzhen; Rodgers, Cheryl C; Bollard, Catherine M; Brenner, Malcolm K; Rooney, Cliona M; Heslop, Helen E; Gottschalk, Stephen

2011-01-01

Severe chronic active Epstein-Barr virus infection (CAEBV) in T or NK cells is a rare complication of latent EBV infection. CAEBV associated T-cell lymphoproliferative disease (LPD) consists of polyclonal lesions as well as aggressive lymphomas. Here we report such a patient. In addition, we show that this primary CAEBV associated T-cell lymphoma expresses CD70 and is sensitive to killing by CD70-specific T cells, identifying CD70 as a potential immunotherapeutic target for CAEBV-associated T-cell lymphoma. PMID:21994111

Clinical guidelines for the management of acute viral infections in patients with systemic lupus erythematosus.

PubMed

Ramos-Casals, M; Cuadrado, M J; Alba, P; Sanna, G; Brito-Zerón, P; Bertolaccini, L; Babini, A; Moreno, A; D'Cruz, D; Khamashta, M A

2009-12-01

In recent decades, many research groups have focused on the role of viral infections in the etiopathogenesis of systemic lupus erythematosus (SLE), the so-called "viral hypothesis". The main candidates are herpes viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), which have a high seroprevalence in the general population. However, a viral causal agent of SLE has not yet been discovered, although many interesting clinical findings on the complex interactions between viruses and SLE have been made. This review analyzes 88 cases of acute viral infections in adult patients with SLE and identifies situations in which viral infections influenced the diagnosis, prognosis or treatment of SLE. We also propose clinical guidelines for the management of these infections in patients with SLE.

Efficient Translation of Epstein-Barr Virus (EBV) DNA Polymerase Contributes to the Enhanced Lytic Replication Phenotype of M81 EBV.

PubMed

Church, Trenton Mel; Verma, Dinesh; Thompson, Jacob; Swaminathan, Sankar

2018-03-15

Epstein-Barr virus (EBV) is linked to the development of both lymphoid and epithelial malignancies worldwide. The M81 strain of EBV, isolated from a Chinese patient with nasopharyngeal carcinoma (NPC), demonstrates spontaneous lytic replication and high-titer virus production in comparison to the prototype B95-8 EBV strain. Genetic comparisons of M81 and B95-8 EBVs were previously been performed in order to determine if the hyperlytic property of M81 is associated with sequence differences in essential lytic genes. EBV SM is an RNA-binding protein expressed during early lytic replication that is essential for virus production. We compared the functions of M81 SM and B95-8 SM and demonstrate that polymorphisms in SM do not contribute to the lytic phenotype of M81 EBV. However, the expression level of the EBV DNA polymerase protein was much higher in M81- than in B95-8-infected cells. The relative deficiency in the expression of B95-8 DNA polymerase was related to the B95-8 genome deletion, which truncates the BALF5 3' untranslated region (UTR). Similarly, the insertion of bacmid DNA into the widely used recombinant B95-8 bacmid creates an inefficient BALF5 3' UTR. We further showed that the while SM is required for and facilitates the efficient expression of both M81 and B95-8 mRNAs regardless of the 3' UTR, the BALF5 3' UTR sequence is important for BALF5 protein translation. These data indicate that the enhanced lytic replication and virus production of M81 compared to those of B95-8 are partly due to the robust translation of EBV DNA polymerase required for viral DNA replication due to a more efficient BALF5 3' UTR in M81. IMPORTANCE Epstein-Barr virus (EBV) infects more than 90% of the human population, but the incidence of EBV-associated tumors varies greatly in different parts of the world. Thus, understanding the connection between genetic polymorphisms from patient isolates of EBV, gene expression phenotypes, and disease is important and may help in

A novel mouse xenotransplantation model of EBV-T/NK-LPD and the application of the mouse model.

PubMed

Imadome, Ken-Ichi

2013-01-01

Chronic active Epstein-Barr virus (EBV) infection (CAEBV), characterized by proliferation of EBV-infected T or NK cells, is a disease of unknown pathogenesis and requires hematopoietic stem cell transplantation for curative treatment. Here we show that intravenous injection of peripheral blood mononuclear cells (PBMCs) isolated from patients with CAEBV to NOD/Shi-scid/IL-2R γ(null) (NOG) mice leads to engraftment of EBV-infected T or NK cells. Analysis of TCR repertoire identified an identical predominant EBV-infected T-cell clone both in a patient and a mouse transplanted with his PBMCs. EBV-infected T or NK cells infiltrated to most major organs including the liver, spleen, lungs, kidneys, adrenal glands, and intestine, showing histological characteristics of CAEBV. Expression of EBNA1, LMP1, and LMP2A, but not EBNA2, in these cells indicated the latency II program of EBV gene characteristic to CAEBV. High levels of TNF-α, IFN-γ, and RANTES were detected in the peripheral blood of these mice. EBV-containing fractions of either CD8(+), γδT, or NK cell lineages failed to engraft, once they were isolated from PBMCs ; they could engraft only when CD4(+) cell fraction was transplanted in parallel. Isolated EBV-containing CD4(+) T cells, in contrast, did engraft on their own. This is the first report of an animal model of CAEBV and suggest that EBV-infected T or NK cells in CAEBV are not truly neoplastic but are dependent on CD4(+) T cells for their proliferation in vivo.

Acute Hepatitis E Virus infection with coincident reactivation of Epstein-Barr virus infection in an immunosuppressed patient with rheumatoid arthritis: a case report.

PubMed

Schultze, Detlev; Mani, Bernhard; Dollenmaier, Günter; Sahli, Roland; Zbinden, Andrea; Krayenbühl, Pierre Alexandre

2015-10-29

Hepatitis E virus (HEV) is the most recently discovered of the hepatotropic viruses, and is considered an emerging pathogen in developed countries with the possibility of fulminant hepatitis in immunocompromised patients. Especially in the latter elevated transaminases should be taken as a clue to consider HEV infection, as it can be treated by discontinuation of immunosuppression and/or ribavirin therapy. To our best knowledge, this is a unique case of autochthonous HEV infection with coincident reactivation of Epstein-Barr virus (EBV) infection in an immunosuppressed patient with rheumatoid arthritis (RA). A 68-year-old Swiss woman with RA developed hepatitis initially diagnosed as methotrexate-induced liver injury, but later diagnosed as autochthonous HEV infection accompanied by reactivation of her latent EBV infection. She showed confounding serological results pointing to three hepatotropic viruses (HEV, Hepatitis B virus (HBV) and EBV) that could be resolved by detection of HEV and EBV viraemia. The patient recovered by temporary discontinuation of immunosuppressive therapy. In immunosuppressed patients with RA and signs of liver injury, HEV infection should be considered, as infection can be treated by discontinuation of immunosuppression. Although anti-HEV-IgM antibody assays can be used as first line virological tools, nucleic acid amplification tests (NAAT) for detection of HEV RNA are recommended--as in our case--if confounding serological results from other hepatotropic viruses are obtained. After discontinuation of immunosuppressive therapy, our patient recovered from both HEV infection and reactivation of latent EBV infection without sequelae.

A multiplex calibrated real-time PCR assay for quantitation of DNA of EBV-1 and 2.

PubMed

Gatto, Francesca; Cassina, Giulia; Broccolo, Francesco; Morreale, Giuseppe; Lanino, Edoardo; Di Marco, Eddi; Vardas, Efthiya; Bernasconi, Daniela; Buttò, Stefano; Principi, Nicola; Esposito, Susanna; Scarlatti, Gabriella; Lusso, Paolo; Malnati, Mauro S

2011-12-01

Accurate and highly sensitive tests for the diagnosis of active Epstein-Barr virus (EBV) infection are essential for the clinical management of individuals infected with EBV. A calibrated quantitative real-time PCR assay for the measurement of EBV DNA of both EBV-1 and 2 subtypes was developed, combining the detection of the EBV DNA and a synthetic DNA calibrator in a multiplex PCR format. The assay displays a wide dynamic range and a high degree of accuracy even in the presence of 1μg of human genomic DNA. This assay measures with the same efficiency EBV DNA from strains prevalent in different geographic areas. The clinical sensitivity and specificity of the system were evaluated by testing 181 peripheral blood mononuclear cell (PBMCs) and plasma specimens obtained from 21 patients subjected to bone marrow transplantation, 70 HIV-seropositive subjects and 23 healthy controls. Patients affected by EBV-associated post-transplant lymphoprolipherative disorders had the highest frequency of EBV detection and the highest viral load. Persons infected with HIV had higher levels of EBV DNA load in PBMCs and a higher frequency of EBV plasma viremia compared to healthy controls. In conclusion, this new assay provides a reliable high-throughput method for the quantitation of EBV DNA in clinical samples. Copyright © 2011 Elsevier B.V. All rights reserved.

Systemic Epstein-Barr virus infection associated with membranous nephropathy in children.

PubMed

Araya, C E; González-Peralta, R P; Skoda-Smith, S; Dharnidharka, V R

2006-03-01

Epstein-Barr virus (EBV) infection can cause diverse renal manifestations ranging from microscopic hematuria to acute renal failure. Membranous nephropathy (MN) is an uncommon and usually secondary cause of nephrotic syndrome in children, and has been reported after chronic infections and antigenemia. We report two pediatric cases of secondary MN associated with acute and chronic systemic EBV infection. Patient 1 had a liver transplant for cirrhosis due to biliary atresia and developed chronic EB viremia. Membranous nephropathy occurred 3 years later and with aggressive therapy has partially subsided, in temporal association with a drop in blood EBV PCR levels. The other patient had a primary immunodeficiency and developed a lymphoproliferative disorder attributed to EBV. Nephrotic syndrome developed at initial presentation and was associated with MN on biopsy. The patient cleared the virus from blood, which was associated with eventual resolution of the MN. We postulate that EB viremia in patients lacking a fully competent immune system, but without a renal allograft, may create a susceptible environment for chronic systemic EB antigenemia that can then lead to immune-complex MN in the kidney. The association of EBV with renal histological changes consistent with MN has been suggested but not directly described before.

Aggressive peripheral CD70-positive T-cell lymphoma associated with severe chronic active EBV infection.

PubMed

Shaffer, Donald R; Sheehan, Andrea M; Yi, Zhongzhen; Rodgers, Cheryl C; Bollard, Catherine M; Brenner, Malcolm K; Rooney, Cliona M; Heslop, Helen E; Gottschalk, Stephen

2012-10-01

Severe chronic active Epstein-Barr virus infection (CAEBV) in T or NK cells is a rare complication of latent EBV infection. CAEBV associated T-cell lymphoproliferative disease (LPD) consists of polyclonal lesions as well as aggressive lymphomas. Here, we report such a patient. In addition, we show that this primary CAEBV associated T-cell lymphoma expresses CD70 and is sensitive to killing by CD70-specific T cells, identifying CD70 as a potential immunotherapeutic target for CAEBV-associated T-cell lymphoma. Copyright © 2011 Wiley Periodicals, Inc.

Productive infection of Epstein-Barr virus (EBV) in EBV-genome-positive epithelial cell lines (GT38 and GT39) derived from gastric tissues.

PubMed

Takasaka, N; Tajima, M; Okinaga, K; Satoh, Y; Hoshikawa, Y; Katsumoto, T; Kurata, T; Sairenji, T

1998-08-01

We characterized the expression of Epstein-Barr virus (EBV) on two epithelial cell lines, GT38 and GT39, derived from human gastric tissues. The EBV nuclear antigen (EBNA) was detected in all cells of both cell lines. The EBV immediate-early BZLF 1 protein (ZEBRA), the early antigen diffuse component (EA-D), and one of the EBV envelope proteins (gp350/220) were expressed spontaneously in small proportions in the cells. EBNA 1, EBNA2, latent membrane protein 1, ZEBRA, and EA-D molecules were then observed by Western blotting in the cells. The lytic cycle was enhanced with treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) or n-butyrate. The virus particles were observed in the TPA treated GT38 cells by electron microscopy. Infectious EBV was detected with the transformation of cord blood lymphocytes and also with the induction of early antigen to Raji cells by the supernatants of both cells lines. A major single and minor multiple fused terminal fragments and a ladder of smaller fragments of the EBV genome were detected with a Xhol probe in both cell lines. These epithelial cells lines and viruses will be useful in studying their association with EBV in gastric epithelial cells.

EBV and Apoptosis: The Viral Master Regulator of Cell Fate?

PubMed Central

Kelly, Gemma L.

2017-01-01

Epstein–Barr virus (EBV) was first discovered in cells from a patient with Burkitt lymphoma (BL), and is now known to be a contributory factor in 1–2% of all cancers, for which there are as yet, no EBV-targeted therapies available. Like other herpesviruses, EBV adopts a persistent latent infection in vivo and only rarely reactivates into replicative lytic cycle. Although latency is associated with restricted patterns of gene expression, genes are never expressed in isolation; always in groups. Here, we discuss (1) the ways in which the latent genes of EBV are known to modulate cell death, (2) how these mechanisms relate to growth transformation and lymphomagenesis, and (3) how EBV genes cooperate to coordinately regulate key cell death pathways in BL and lymphoblastoid cell lines (LCLs). Since manipulation of the cell death machinery is critical in EBV pathogenesis, understanding the mechanisms that underpin EBV regulation of apoptosis therefore provides opportunities for novel therapeutic interventions. PMID:29137176

Methylation of Epstein-Barr virus Rta promoter in EBV primary infection, reactivation and lymphoproliferation.

PubMed

Germi, Raphaële; Guigue, Nicolas; Lupo, Julien; Semenova, Touyana; Grossi, Laurence; Vermeulen, Odile; Epaulard, Olivier; de Fraipont, Florence; Morand, Patrice

2016-10-01

During Epstein-Barr virus (EBV) latency, the EBV genome is largely silenced by methylation. This silencing is overturned during the switch to the lytic cycle. A key event is the production of the viral protein Zta which binds to three Zta-response elements (ZRE) from the Rta promoter (Rp), two of which (ZRE2 and ZRE3) include three CpG motifs methylated in the latent genome. The bisulphite pyrosequencing reaction was used to quantify the methylation of ZRE2, ZRE3a, and ZRE3b in EBV-positive cell lines and in ex vivo samples of EBV-related diseases, in order to assess whether the level of methylation in these ZREs could provide additional information to viral DNA load and serology in the characterization of EBV-associated diseases. In PBMC from two patients with infectious mononucleosis, over time Rp became increasingly methylated whereas EBV load decreased. In tonsil from patients with chronic tonsillitis, the methylation was less than in EBV-associated tumors, regardless of the viral load. This was even more striking when only the ZRE3a and ZRE3b were considered since some samples presented unbalanced profiles on ZRE2. EBV reactivation in cell culture showed that the reduction in the overall level of methylation was closely related to the production of unmethylated virions. Thus, an assessment of the level of methylation may help to better characterize EBV replication in PBMC and in biopsies with high EBV load, during infectious mononucleosis and EBV-associated cancers. J. Med. Virol. 88:1814-1820, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Performance of the Architect EBV Antibody Panel for Determination of Epstein-Barr Virus Infection Stage in Immunocompetent Adolescents and Young Adults with Clinical Suspicion of Infectious Mononucleosis

PubMed Central

Patel, Mauli; Kadakia, Kinjal; Haque, Tanzina

2014-01-01

The Architect EBV antibody panel is a new chemiluminescence immunoassay system used to determine the stage of Epstein-Barr virus (EBV) infection based on the detection of IgM and IgG antibodies to viral capsid antigen (VCA) and IgG antibodies against Epstein-Barr nuclear antigen 1 (EBNA-1). We evaluated its diagnostic accuracy in immunocompetent adolescents and young adults with clinical suspicion of infectious mononucleosis (IM) using the RecomLine EBV IgM and IgG immunoblots as the reference standard. In addition, the use of the antibody panel in a sequential testing algorithm based on initial EBNA-1 IgG analysis was assessed for cost-effectiveness. Finally, we investigated the degree of cross-reactivity of the VCA IgM marker during other primary viral infections that may present with an EBV IM-like picture. High sensitivity (98.3% [95% confidence interval {CI}, 90.7 to 99.7%]) and specificity (94.2% [95% CI, 87.9 to 97.8%]) were found after testing 162 precharacterized archived serum samples. There was perfect agreement between the use of the antibody panel in sequential and parallel testing algorithms, but substantial cost savings (23%) were obtained with the sequential strategy. A high rate of reactive VCA IgM results was found in primary cytomegalovirus (CMV) infections (60.7%). In summary, the Architect EBV antibody panel performs satisfactorily in the investigation of EBV IM in immunocompetent adolescents and young adults, and the application of an EBNA-1 IgG-based sequential testing algorithm is cost-effective in this diagnostic setting. Concomitant testing for CMV is strongly recommended to aid in the interpretation of EBV serological patterns. PMID:24695777

Acute Gastritis and Splenic Infarction Caused by Epstein-Barr Virus

PubMed Central

Jeong, Ji Eun; Kim, Kyung Moon; Shim, Jae Won; Kim, Deok Soo; Shim, Jung Yeon; Park, Moon Soo; Park, Soo Kyung

2018-01-01

Epstein-Barr virus (EBV) infection can be presented with various clinical manifestations and different levels of severity when infected. Infectious mononucleosis, which is most commonly caused by EBV infection in children and adolescents, is a clinical syndrome characterized by fatigue, malaise, fever, sore throat, and generalized lymphadenopathy. But rarely, patients with infectious mononucleosis may present with gastrointestinal symptoms and complicated by gastritis, splenic infarction, and splenic rupture. We encountered a 16-year-old girl who presented with fever, fatigue, and epigastric pain. Splenic infarction and EBV-associated gastritis were diagnosed by using esophagogastroduodenoscopy and abdominal computed tomography. Endoscopy revealed a generalized hyperemic nodular lesion in the stomach, and the biopsy findings were chronic gastritis with erosion and positive in situ hybridization for EBV. As splenic infarction and acute gastritis are rare in infectious mononucleosis and are prone to be overlooked, we must consider these complications when an infectious mononucleosis patient presents with gastrointestinal symptom. PMID:29713613

Viral Carcinogenesis Beyond Malignant Transformation: EBV in the Progression of Human Cancers

PubMed Central

Müller-Coan, Bárbara G.; Pagano, Joseph S.

2017-01-01

Cancer progression begins when malignant cells colonize adjacent sites, and it is characterized by increasing tumor heterogeneity, invasion and dissemination of cancer cells. Clinically, progression is the most relevant stage in the natural history of cancers. A given virus is usually regarded as oncogenic because of its ability to induce malignant transformation of cells. Nonetheless, oncogenic viruses may also be important for the progression of infection-associated cancers. Recently this hypothesis has been addressed because of studies on the contribution of the Epstein–Barr virus (EBV) to the aggressiveness of nasopharyngeal carcinoma (NPC). Several EBV products modulate cancer progression phenomena, such as the epithelial–mesenchymal transition, cell motility, invasiveness, angiogenesis, and metastasis. In this regard, there are compelling data about the effects of EBV latent membrane proteins (LMPs) and EBV nuclear antigens (EBNAs), as well as nontranslated viral RNAs, such as the EBV-encoded small nonpolyadenylated RNAs (EBERs) and viral microRNAs, notably EBV miR-BARTs. The available data on the mechanisms and players involved in the contribution of EBV infection to the aggressiveness of NPC are discussed in this review. Overall, this conceptual framework may be valuable for the understanding of the contribution of some infectious agents in the progression of cancers. PMID:27068530

Gene expression analysis of hypersensitivity to mosquito bite, chronic active EBV infection and NK/T-lymphoma/leukemia.

PubMed

Washio, Kana; Oka, Takashi; Abdalkader, Lamia; Muraoka, Michiko; Shimada, Akira; Oda, Megumi; Sato, Hiaki; Takata, Katsuyoshi; Kagami, Yoshitoyo; Shimizu, Norio; Kato, Seiichi; Kimura, Hiroshi; Nishizaki, Kazunori; Yoshino, Tadashi; Tsukahara, Hirokazu

2017-11-01

The human herpes virus, Epstein-Barr virus (EBV), is a known oncogenic virus and plays important roles in life-threatening T/NK-cell lymphoproliferative disorders (T/NK-cell LPD) such as hypersensitivity to mosquito bite (HMB), chronic active EBV infection (CAEBV), and NK/T-cell lymphoma/leukemia. During the clinical courses of HMB and CAEBV, patients frequently develop malignant lymphomas and the diseases passively progress sequentially. In the present study, gene expression of CD16 (-) CD56 (+) -, EBV (+) HMB, CAEBV, NK-lymphoma, and NK-leukemia cell lines, which were established from patients, was analyzed using oligonucleotide microarrays and compared to that of CD56 bright CD16 dim/- NK cells from healthy donors. Principal components analysis showed that CAEBV and NK-lymphoma cells were relatively closely located, indicating that they had similar expression profiles. Unsupervised hierarchal clustering analyses of microarray data and gene ontology analysis revealed specific gene clusters and identified several candidate genes responsible for disease that can be used to discriminate each category of NK-LPD and NK-cell lymphoma/leukemia.

Detection of autoimmunity in early primary Epstein-Barr virus infection by Western blot analysis.

PubMed

Mascia, M T; Sandri, G; Guerzoni, C; Roncaglia, R; Mantovani, G; Ferri, C

2008-01-01

The Epstein-Barr virus (EBV) represents a potentially important factor in the pathogenesis of certain autoimmune disorders such as systemic lupus erythematosus (SLE), and Sjögren's syndrome, probably through a molecular mimicry mechanism. Several studies have focused on the relationship between previous EBV infection and clinically overt connective tissue diseases (CTDs), while the aim of this study was to investigate the immunological alterations during the early phase of primary acute EBV infection by means of ENA Western blotting (WB) analysis. This technique is able to detect a wide spectrum of anti-ENA autoantibodies, potentially directed against diverse epitopes of the same antigen. Sera from 54 subjects (F/M=24/30, mean age 17+/-6 SD years) with primary acute EBV infection were analysed using indirect immunofluorescence (IF) on Hep-2 cells for ANA, and both ELISA and WB for ENA. Only 8 ANA+ and no ENA+ were found by means of IF and ELISA techniques, respectively; however, one or more ENA autoantibodies were detected in 24/54 (44%) sera using WB. The autoantibodies were no longer present at the second evaluation. Subjects with immunological alterations had not developed any significant clinical manifestations at a 5-year follow-up. This study demonstrated the appearance of autoantibody production in a high proportion of individuals with primary acute EBV infection; interestingly, the observed serological subsets are quite similar to clinical SLE clusters. Moreover, the absence of immunological disorders during the follow-up reinforces the role of multiple genetic and/or environmental co-factors in the pathogenesis of CTDs.

Serological diagnosis of Epstein-Barr virus infection: Problems and solutions

PubMed Central

De Paschale, Massimo; Clerici, Pierangelo

2012-01-01

Serological tests for antibodies specific for Epstein-Barr virus (EBV) antigens are frequently used to define infection status and for the differential diagnosis of other pathogens responsible for mononucleosis syndrome. Using only three parameters [viral capsid antigen (VCA) IgG, VCA IgM and EBV nuclear antigen (EBNA)-1 IgG],it is normally possible to distinguish acute from past infection: the presence of VCA IgM and VCA IgG without EBNA-1 IgG indicates acute infection, whereas the presence of VCA IgG and EBNA-1 IgG without VCA IgM is typical of past infection. However, serological findings may sometimes be difficult to interpret as VCA IgG can be present without VCA IgM or EBNA-1 IgG in cases of acute or past infection, or all the three parameters may be detected simultaneously in the case of recent infection or during the course of reactivation. A profile of isolated EBNA-1 IgG may also create some doubts. In order to interpret these patterns correctly, it is necessary to determine IgG avidity, identify anti-EBV IgG and IgM antibodies by immunoblotting, and look for heterophile antibodies, anti-EA (D) antibodies or viral genome using molecular biology methods. These tests make it possible to define the status of the infection and solve any problems that may arise in routine laboratory practice. PMID:24175209

KSHV LANA and EBV LMP1 induce the expression of UCH-L1 following viral transformation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bentz, Gretchen L.; Bheda-Malge, Anjali; Wang, Ling

Ubiquitin C-terminal Hydrolase L1 (UCH-L1) has oncogenic properties and is highly expressed during malignancies. We recently documented that Epstein-Barr virus (EBV) infection induces uch-l1 expression. Here we show that Kaposi's Sarcoma-associated herpesvirus (KSHV) infection induced UCH-L1 expression, via cooperation of KSHV Latency-Associated Nuclear Antigen (LANA) and RBP-Jκ and activation of the uch-l1 promoter. UCH-L1 expression was also increased in Primary Effusion Lymphoma (PEL) cells co-infected with KSHV and EBV compared with PEL cells infected only with KSHV, suggesting EBV augments the effect of LANA on uch-l1. EBV latent membrane protein 1 (LMP1) is one of the few EBV products expressedmore » in PEL cells. Results showed that LMP1 was sufficient to induce uch-l1 expression, and co-expression of LMP1 and LANA had an additive effect on uch-l1 expression. These results indicate that viral latency products of both human γ-herpesviruses contribute to uch-l1 expression, which may contribute to the progression of lymphoid malignancies. - Highlights: • Infection of endothelial cells with KSHV induced UCH-L1 expression. • KSHV LANA is sufficient for the induction of uch-l1. • Co-infection with KSHV and EBV (observed in some PELs) results in the additive induction of uch-l1. • EBV LMP1 also induced UCH-L1 expression. • LANA- and LMP1-mediated activation of the uch-l1 promoter is in part through RBP-Jκ.« less

Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication.

PubMed

Bilger, Andrea; Plowshay, Julie; Ma, Shidong; Nawandar, Dhananjay; Barlow, Elizabeth A; Romero-Masters, James C; Bristol, Jillian A; Li, Zhe; Tsai, Ming-Han; Delecluse, Henri-Jacques; Kenney, Shannon C

2017-07-04

EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both "on target" and "off target" mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.

[Acute inflammatory polyradiculoneuropathy and membranous glomerulonephritis following Epbstein-Barr virus primary infection in a 12-year-old girl].

PubMed

Meyer, P; Soëte, S; Raynaud, P; Henry, V; Morin, D; Rodière, M; Rivier, F; Roubertie, A

2010-11-01

Acute inflammatory polyradiculoneuropathy, or Guillain-Barré syndrome (GBS), is characterized by peripheral nerve demyelination, which leads to rapidly progressive weakness, loss of sensation, and loss of deep tendon reflexes. It is a prototype of postinfectious autoimmune disease, whose pathophysiology is well described in the forms provoked by certain bacteria (molecular mimicry with Campylobacter jejuni), but remains unclear for the forms related to other organisms (cytomegalovirus, Epstein-Barr virus and other herpes group viruses, Mycoplasma pneumoniae). Glomerular lesions can be associated with the neurological symptoms and have also been described after various infections, independently of any signs of polyradiculoneuropathy. We report the observation of a 12-year-old girl who presented with Guillain-Barré syndrome with facial diplegia, ataxia, and intracranial hypertension following Epstein-Barr virus (EBV) primary infection. During the course of the neurological disease, membranous glomerulonephritis (MGN) was diagnosed. The neurological impairment was regressive within 6 months after intravenous immunoglobulin treatment followed by intravenous then oral corticosteroid administration. Viremia remained high more than 6 months after the onset of symptoms. Glomerulopathy progressed independently and finally required immunosuppressant medication with cyclosporine. EBV might be the factor that triggered the autoimmune disorders, as previously reported for systemic lupus erythematosus and multiple sclerosis in children. To the best of our knowledge, this association of 3 conditions (GBS, MGN, and EBV primary infection) has never been reported in the literature. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Acute and chronic symptoms of mononucleosis.

PubMed

Lambore, S; McSherry, J; Kraus, A S

1991-07-01

The clinical symptoms and durations of illness of patients with infectious mononucleosis (IM) are variable and are poorly documented in the scientific literature. Patients who presented for care at the Student Health Service of a Canadian university between September 1985 and May 1988 and had been diagnosed as having IM were surveyed. Health experience during the acute and convalescent phases of IM was compared with that of a group of patients matched for age, sex, date of diagnosis, and year of study, who had suffered acute upper respiratory tract infections (URI), other than Epstein-Barr virus (EBV)-induced, during the same period. Students were sicker for longer after IM than after non-EBV-induced URI. During the acute phase of illness, the symptoms of fatigue (P = less than .000001), night sweats (P = .000001), and painful neck swelling (P = .00003) were seen significantly more often in the IM group. The severity and duration of these symptoms were also significantly worse in IM patients. Getting tired easily (P = .002), diurnal somnolence (P = .002), and depression (P = .002) were significantly more common postacute symptoms. Eleven percent of IM patients reported persistence of symptoms longer than 100 days, and in 6% of patients the symptoms had persisted after 1 year. Convalescent cases showed a trend toward reduced alcohol intake and, perhaps, reduced alcohol tolerance. IM involves excessive morbidity in a student community compared with URI that was other than EBV-induced, during both the acute and the postacute phases of infection.

Performance of the architect EBV antibody panel for determination of Epstein-Barr virus infection stage in immunocompetent adolescents and young adults with clinical suspicion of infectious mononucleosis.

PubMed

Guerrero-Ramos, Alvaro; Patel, Mauli; Kadakia, Kinjal; Haque, Tanzina

2014-06-01

The Architect EBV antibody panel is a new chemiluminescence immunoassay system used to determine the stage of Epstein-Barr virus (EBV) infection based on the detection of IgM and IgG antibodies to viral capsid antigen (VCA) and IgG antibodies against Epstein-Barr nuclear antigen 1 (EBNA-1). We evaluated its diagnostic accuracy in immunocompetent adolescents and young adults with clinical suspicion of infectious mononucleosis (IM) using the RecomLine EBV IgM and IgG immunoblots as the reference standard. In addition, the use of the antibody panel in a sequential testing algorithm based on initial EBNA-1 IgG analysis was assessed for cost-effectiveness. Finally, we investigated the degree of cross-reactivity of the VCA IgM marker during other primary viral infections that may present with an EBV IM-like picture. High sensitivity (98.3% [95% confidence interval {CI}, 90.7 to 99.7%]) and specificity (94.2% [95% CI, 87.9 to 97.8%]) were found after testing 162 precharacterized archived serum samples. There was perfect agreement between the use of the antibody panel in sequential and parallel testing algorithms, but substantial cost savings (23%) were obtained with the sequential strategy. A high rate of reactive VCA IgM results was found in primary cytomegalovirus (CMV) infections (60.7%). In summary, the Architect EBV antibody panel performs satisfactorily in the investigation of EBV IM in immunocompetent adolescents and young adults, and the application of an EBNA-1 IgG-based sequential testing algorithm is cost-effective in this diagnostic setting. Concomitant testing for CMV is strongly recommended to aid in the interpretation of EBV serological patterns. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

An atypical pattern of Epstein-Barr virus infection in a case with idiopathic tubulointerstitial nephritis.

PubMed

Okada, Hirokazu; Ikeda, Naofumi; Kobayashi, Tatsuya; Inoue, Tsutomu; Kanno, Yoshihiko; Sugahara, Souichi; Nakamoto, Hidetomo; Yamamoto, Takako; Suzuki, Hiromichi

2002-10-01

Recently, Epstein-Barr virus (EBV) received attention because a latent form of its infection in renal proximal tubular epithelial cells was found to cause idiopathic, chronic tubulointerstitial nephritis. In this report, we describe the case of a patient with a replicative form of EBV infection, chronic active EBV infection (CAEBV), who developed acute tubulointerstitial nephritis and minimal change nephrotic syndrome. A renal biopsy revealed papillary infoldings of atypical tubular epithelium and adjacent dense infiltration of lymphocytes. Using in situ polymerase chain reaction methods, we detected the EBV genome in some of the infiltrating lymphocytes, but not in the tubular epithelial cells. EBV-infected T cells are thought to activate other educated T cells, as well as secrete an unrestricted variety of cytokines, thus playing a pivotal role in CAEBV and its end organ disease. Therefore, in our case, the CAEBV activated, educated T cells may have followed the EBV-infected lymphocytes as they infiltrated into the peritubular interstitium, and promoted focal tubular epithelial atypia and minimal change nephrotic syndrome. The long-term observation of such patients is important because CAEBV may progress into lymphoproliferative diseases. Copyright 2002 S. Karger AG, Basel

The Epstein-Barr Virus (EBV) in T Cell and NK Cell Lymphomas: Time for a Reassessment

PubMed Central

Gru, A. A.; Haverkos, B. H.; Freud, A. G.; Hastings, J.; Nowacki, N. B.; Barrionuevo, C.; Vigil, C. E.; Rochford, R.; Natkunam, Y.; Baiocchi, R. A.

2015-01-01

While Epstein-Barr virus (EBV) was initially discovered and characterized as an oncogenic virus in B cell neoplasms, it also plays a complex and multifaceted role in T/NK cell lymphomas. In B cell lymphomas, EBV-encoded proteins have been shown to directly promote immortalization and proliferation through stimulation of the NF-κB pathway and increased expression of anti-apoptotic genes. In the context of mature T/NK lymphomas (MTNKL), with the possible exception on extranodal NK/T cell lymphoma (ENKTL), the virus likely plays a more diverse and nuanced role. EBV has been shown to shape the tumor microenvironment by promoting Th2-skewed T cell responses and by increasing the expression of the immune checkpoint ligand PD-L1. The type of cell infected, the amount of plasma EBV DNA, and the degree of viral lytic replication have all been proposed to have prognostic value in T/NK cell lymphomas. Latency patterns of EBV infection have been defined using EBV-infected B cell models and have not been definitively established in T/NK cell lymphomas. Identifying the expression profile of EBV lytic proteins could allow for individualized therapy with the use of antiviral medications. More work needs to be done to determine whether EBV-associated MTNKL have distinct biological and clinical features, which can be leveraged for risk stratification, disease monitoring, and therapeutic purposes. PMID:26449716

Co-infection with cytomegalovirus and Epstein-Barr virus in mononucleosis: case report and review of literature.

PubMed

Olson, Douglas; Huntington, Mark K

2009-09-01

A 25-year-old woman presented with infectious mononucleosis. Serological studies demonstrated elevated IgM titres to both cytomegalovirus (CMV) and Epstein-Barr virus (EBV). The role of each of these agents in infectious mononucleosis is reviewed, as are literature reports of co-infection by these two viruses. Both near-simultaneous infections and temporally remote sequential infections with acute CMV triggering an immunoreactivation of EBV are reported in the literature. We believe the current case is most consistent with the latter. Infectious mononucleosis is a common infection of childhood and young adulthood. Although a variety of agents may be associated with infectious mononucleosis, EBV is the most common etiology. We encountered a patient with serological findings that were suggestive of the simultaneous presence of two etiological agents of infectious mononucleosis: EBV and CMV. This prompted an inquiry into how commonly dual infections are encountered and their significance.

Studies of EBV-lymphoid cell interactions in two patients with the X-linked lymphoproliferative syndrome: normal EBV-specific HLA-restricted cytotoxicity.

PubMed

Rousset, F; Souillet, G; Roncarolo, M G; Lamelin, J P

1986-02-01

Two X-linked lymphoproliferative syndrome (XLP) patients with the hypogammaglobulinemia phenotype were investigated at a time remote from their primary infection with the Epstein-Barr virus (EBV). The lymphoblastoid cell lines derived from these patients expressed the phenotypic markers characteristic of normal mature B lymphocytes and produced normal levels of immunoglobulins (Ig). These observations imply that at least some of their B cells are phenotypically normal. The natural killer (NK) activity of the two patients was low. In one patient, activated lymphocyte killer (ALK) activity was inefficient. These two XLP patients expressed a normal EBV-specific, HLA-restricted cytotoxic activity. It thus appears, from the present findings and those in cases published previously (6/11 patients expressing normal EBV-specific cytotoxic activity), that the notion of poor specific T cell memory for EBV may not be as pivotal ass suggested or, alternatively, that this defect may not be common in hypogammaglobulinemic survivors.

Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases.

PubMed

Abbott, Rachel J; Pachnio, Annette; Pedroza-Pacheco, Isabela; Leese, Alison M; Begum, Jusnara; Long, Heather M; Croom-Carter, Debbie; Stacey, Andrea; Moss, Paul A H; Hislop, Andrew D; Borrow, Persephone; Rickinson, Alan B; Bell, Andrew I

2017-11-01

Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. In contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterized by anti-EBV IgM antibody positivity, high loads of circulating latently infected B cells, and a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8 + T cells plus a milder expansion of CD56 dim NKG2A + KIR - natural killer (NK) cells. How the two situations compare is unclear due to the paucity of studies on clinically silent infection. Here we describe five prospectively studied patients with asymptomatic infections identified in a seroepidemiologic survey of university entrants. In each case, the key blood sample had high cell-associated viral loads without a marked CD8 lymphocytosis or NK cell disturbance like those seen in patients during the acute phase of IM. Two of the cases with the highest viral loads showed a coincident expansion of activated EBV-specific CD8 + T cells, but overall CD8 + T cell numbers were either unaffected or only mildly increased. Two cases with slightly lower loads, in whom serology suggests the infection may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another case with a higher viral load, in which T and NK cell responses were undetectable in the primary blood sample in which infection was detected, EBV-specific T cell responses did not appear until several months later, by which time the viral loads in the blood had already fallen. Thus, some patients with asymptomatic primary infections have very high circulating viral loads similar to those in patients during the acute phase of IM and a cell-mediated immune response that is qualitatively similar to that in IM patients but of a lower magnitude. However, other patients may have quite different immune responses that ultimately could reveal novel mechanisms of host control. IMPORTANCE Epstein-Barr virus

Therapeutic trials for a rabbit model of EBV-associated Hemophagocytic Syndrome (HPS): effects of vidarabine or CHOP, and development of Herpesvirus papio (HVP)-negative lymphomas surrounded by HVP-infected lymphoproliferative disease.

PubMed

Hayashi, K; Joko, H; Koirala, T R; Onoda, S; Jin, Z-S; Munemasa, M; Ohara, N; Oda, W; Tanaka, T; Oka, T; Kondo, E; Yoshino, T; Takahashi, K; Yamada, M; Akagi, T

2003-10-01

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS), which is often associated with fatal infectious mononucleosis or T-cell lymphoproliferative diseases (LPD), is a distinct disease characterized by high mortality. Treatment of patients with EBV-AHS has proved challenging. To develop some therapeutic interventions for EBV-AHS, we examined the effectiveness of an antiviral agent (vidarabine) or chemotherapy (CHOP), using a rabbit model for EBV-AHS. Fourteen untreated rabbits were inoculated intravenously with cell-free virions of the EBV-like virus Herpesvirus papio (HVP). All of the rabbits died of HVP-associated (LPD) and hemophagocytic syndrome (HPS) between 21 and 31 days after inoculation. Furthermore, three HVP-infected rabbits treated with vidarabine died between days 23 and 28 after inoculation, and their clinicopathological features were no different from those of untreated rabbits, indicating that this drug is not effective at all to treat HVP-induced rabbit LPD and HPS. Three of the infected rabbits that were treated with one course, with an incomplete set of three courses, or with three full courses of CHOP treatment died of HVP-induced LPD and HPS with a bleeding tendency and/or with opportunistic infections. They died on the 26th, 62nd and 105th day after virus inoculation, respectively. CHOP treatment transiently suppressed the HVP-induced LPD and contributed to the prolonged survival time of two infected rabbits. However, it did not remove all of the HVP-infected cells from the infected rabbits, and residual HVP-infected lymphocytes caused recurrences of rabbit LPD and HPS. The most interesting finding of this experiment was observed in the infected rabbit with the longest survival time of 105 days: HVP-negative lymphomas surrounded by HVP-induced LPD developed in the larynx and ileum of this rabbit, causing an obstruction of the lumen. We concluded that these were not secondary lymphomas caused by CHOP treatment, because no suspicious

A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis.

PubMed

Balfour, Henry H; Holman, Carol J; Hokanson, Kristin M; Lelonek, Meghan M; Giesbrecht, Jill E; White, Dana R; Schmeling, David O; Webb, Chiu-Ho; Cavert, Winston; Wang, David H; Brundage, Richard C

2005-11-01

Characterizing virus-host interactions during self-limited infectious mononucleosis could explain how Epstein-Barr virus (EBV) replication is normally controlled and provide insight into why certain immunocompromised patients fail to contain it. University students had an average of 7 clinical and virologic evaluations during acute infectious mononucleosis. EBV was quantified in 697 samples of oral wash fluid, whole blood, peripheral blood mononuclear cells (PBMCs), and plasma by a real-time (TaqMan) polymerase chain reaction (qEBV) assay developed in our laboratory. Twenty of 25 subjects had serologically confirmed primary EBV infection. EBV was cleared from whole blood by a first-order process with a median half-life of 3 days, and its quantity was associated with severity of illness (r2=0.82). Oral shedding persisted at a median of >or=1x104 copies/mL for 32 weeks and was unrelated to severity of illness. Subjects with nonprimary EBV infection shed virus intermittently, and median quantities for all samples became undetectable within 4 weeks. Using a novel qEBV assay, we demonstrated that young adults with primary EBV infection rapidly cleared virus from blood but not from the oropharynx. High oral concentrations of EBV in asymptomatic persons who have resumed normal activities support the concept that infectious mononucleosis is most likely acquired by kissing.

Heterogeneity of the Epstein-Barr Virus (EBV) Major Internal Repeat Reveals Evolutionary Mechanisms of EBV and a Functional Defect in the Prototype EBV Strain B95-8.

PubMed

Ba Abdullah, Mohammed M; Palermo, Richard D; Palser, Anne L; Grayson, Nicholas E; Kellam, Paul; Correia, Samantha; Szymula, Agnieszka; White, Robert E

2017-12-01

Epstein-Barr virus (EBV) is a ubiquitous pathogen of humans that can cause several types of lymphoma and carcinoma. Like other herpesviruses, EBV has diversified through both coevolution with its host and genetic exchange between virus strains. Sequence analysis of the EBV genome is unusually challenging because of the large number and lengths of repeat regions within the virus. Here we describe the sequence assembly and analysis of the large internal repeat 1 of EBV (IR1; also known as the BamW repeats) for more than 70 strains. The diversity of the latency protein EBV nuclear antigen leader protein (EBNA-LP) resides predominantly within the exons downstream of IR1. The integrity of the putative BWRF1 open reading frame (ORF) is retained in over 80% of strains, and deletions truncating IR1 always spare BWRF1. Conserved regions include the IR1 latency promoter (Wp) and one zone upstream of and two within BWRF1. IR1 is heterogeneous in 70% of strains, and this heterogeneity arises from sequence exchange between strains as well as from spontaneous mutation, with interstrain recombination being more common in tumor-derived viruses. This genetic exchange often incorporates regions of <1 kb, and allelic gene conversion changes the frequency of small regions within the repeat but not close to the flanks. These observations suggest that IR1-and, by extension, EBV-diversifies through both recombination and breakpoint repair, while concerted evolution of IR1 is driven by gene conversion of small regions. Finally, the prototype EBV strain B95-8 contains four nonconsensus variants within a single IR1 repeat unit, including a stop codon in the EBNA-LP gene. Repairing IR1 improves EBNA-LP levels and the quality of transformation by the B95-8 bacterial artificial chromosome (BAC). IMPORTANCE Epstein-Barr virus (EBV) infects the majority of the world population but causes illness in only a small minority of people. Nevertheless, over 1% of cancers worldwide are attributable to

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation, function and EBV immunity.

PubMed

Edwards, Emily S J; Bier, Julia; Cole, Theresa S; Wong, Melanie; Hsu, Peter; Berglund, Lucinda J; Boztug, Kaan; Lau, Anthony; Gostick, Emma; Price, David A; O'Sullivan, Michael; Meyts, Isabelle; Choo, Sharon; Gray, Paul; Holland, Steven M; Deenick, Elissa K; Uzel, Gulbu; Tangye, Stuart G

2018-05-22

Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphatidylinositol-3 kinase, result in hyperactivation of the PI3K-AKT-mTOR pathway and underlie a novel inborn error of immunity. Affected individuals exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or CMV infection, and an increased incidence of B-cell lymphoproliferation and/or lymphoma. Mechanisms underlying disease pathogenesis remain unknown. Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in individuals with PIK3CD GOF mutations, identify key molecules required for cell mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this as well as other EBV-opathies. We studied the consequences of PIK3CD GOF mutations on the generation, differentiation and function of CD8 + T cells and NK cells, which are implicated in host defense against infection with herpesviruses including EBV. PIK3CD GOF total and EBV-specific CD8 + T cells were skewed towards an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion, and increased susceptibility to re-activation induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF. NK cells in PIK3CD GOF individuals also exhibited perturbed expression of differentiation-associated molecules. Both CD8 + T cells and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, PDL-1/2 and CD70. PIK3CD GOF mutations aberrantly induce exhaustion and/or senescence and impair cytotoxicity of CD8+ T and NK cells. These defects may contribute to clinical features of affected individuals, such as impaired immunity to herpesviruses and tumor surveillance. Copyright © 2018. Published by

[Exceptional etiology of acute renal: Burkitt's lymphoma].

PubMed

Dial, Cherif; Doh, Kwame; Thiam, Ibou; Faye, Mariam; Woto-Gaye, Gisèle

2018-02-05

Burkitt's lymphoma (BL) is an exceptional cause of acute renal failure (ARF). The origin of the tumor clone may be lymphoid follicles secondary to renal Epstein-Barr virus (EBV) infection. With the presentation of this clinical case, the pathogenesis, diagnostic criteria and evolution of this extremely rare affection will be discussed. A 4-year-old patient with a recent history of acute osteomyelitis of the right thigh presented an ARF without indications of post-infectious glomerulonephritis. Ultrasound showed enlarged kidneys without dilation of the excretory cavities. Diffuse interstitial infiltration of atypical lymphoid cells of medium size were noted upon renal biopsy. The tumor cells expressed antibodies against CD20, CD10, Bcl6, and Ki67 but not against Bcl2 or CD3. The search for an EBV infection was positive. A few days after diagnosis, the evolution was spontaneously fatal. BL of the kidney is a rare condition that accounts for less than 1 % of kidney tumors, associated almost invariably with EBV infection. The diagnosis is confirmed histologically by renal biopsy and the criteria of Malbrain affirms the primitive character of the lymphoma. BL of the kidney is a diagnostic and therapeutic emergency and may be fatal. Copyright © 2018 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.

A rare case of acute pancreatitis and life-threatening hemolytic anemia associated with Epstein-Barr virus infection in a young healthy adult.

PubMed

Singh, Sukhchain; Khosla, Pam

2016-01-01

Epstein-Barr virus (EBV) is a common infection that affects 95% of adults worldwide at some point during life. It is usually asymptomatic or causes a self-limiting clinical syndrome known as infectious mononucleosis. It rarely causes complications. Here, we present a case of a healthy 21-year-old female college student who suffered from severe pancreatitis and life-threatening autoimmune hemolytic anemia in association with EBV infection, and we also discuss the common presentation of EBV infection and the diagnosis and treatment of simple and complicated EBV infection. Copyright © 2015 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

A Virtual Look at Epstein–Barr Virus Infection: Biological Interpretations

PubMed Central

Delgado-Eckert, Edgar; Hadinoto, Vey; Jarrah, Abdul S; Laubenbacher, Reinhard; Lee, Kichol; Luzuriaga, Katherine; Polys, Nicholas F; Thorley-Lawson, David A

2007-01-01

The possibility of using computer simulation and mathematical modeling to gain insight into biological and other complex systems is receiving increased attention. However, it is as yet unclear to what extent these techniques will provide useful biological insights or even what the best approach is. Epstein–Barr virus (EBV) provides a good candidate to address these issues. It persistently infects most humans and is associated with several important diseases. In addition, a detailed biological model has been developed that provides an intricate understanding of EBV infection in the naturally infected human host and accounts for most of the virus' diverse and peculiar properties. We have developed an agent-based computer model/simulation (PathSim, Pathogen Simulation) of this biological model. The simulation is performed on a virtual grid that represents the anatomy of the tonsils of the nasopharyngeal cavity (Waldeyer ring) and the peripheral circulation—the sites of EBV infection and persistence. The simulation is presented via a user friendly visual interface and reproduces quantitative and qualitative aspects of acute and persistent EBV infection. The simulation also had predictive power in validation experiments involving certain aspects of viral infection dynamics. Moreover, it allows us to identify switch points in the infection process that direct the disease course towards the end points of persistence, clearance, or death. Lastly, we were able to identify parameter sets that reproduced aspects of EBV-associated diseases. These investigations indicate that such simulations, combined with laboratory and clinical studies and animal models, will provide a powerful approach to investigating and controlling EBV infection, including the design of targeted anti-viral therapies. PMID:17953479

Quantification of Epstein-Barr virus DNA is helpful for evaluation of chronic active Epstein-Barr virus infection.

PubMed

Sakamoto, Yuichi; Mariya, Yasushi; Kubo, Kohmei

2012-08-01

Chronic active Epstein-Barr virus infection (CAEBV) presents with chronic or recurrent infectious mononucleosis-like symptoms, such as low-grade fever, liver dysfunction, lymphadenopathy, and hepatosplenomegaly. Immunological methods are useful for the diagnosis of viral infections. However, CAEBV patients do not necessarily have high titers of Epstein-Barr virus (EBV)-specific antibodies. Hosts that are immunocompromised after hematopoietic stem cell transplantations sometimes suffer from systemic EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and EBV-positive lymphoma. Patients with EBV-associated diseases are often diagnosed by analyses of bone marrow. Cytomegalovirus (CMV) can cause serious pneumonia or retinitis in immunocompromised hosts. In order to noninvasively understand the clinical status of patients with EBV-associated diseases, we conducted real-time polymerase chain reaction (PCR) methods in their peripheral blood in order to quantify EBV and CMV DNA levels, which reflect viral activity. Here, we describe a 30-year-old Japanese female patient with CAEBV. The patient had repeated fever, fatigue, and liver dysfunction. The histopathological results of liver biopsies were positive for EBV-encoded RNA-1. Acute hepatitis was associated with the EBV infection. The whole-blood EBV DNA levels were high and above 1.0 × 10⁷ copies/mL. After immunosuppressive and antiviral therapies, EBV DNA levels lowered. However, she had to receive bone marrow transplantation because of her EBV-HLH. As the number of lymphocytes increased in the post-transplantation period, EBV DNA levels gradually increased again. The simultaneous detection of CMV DNA was more sensitive than the CMV antigenemia test that is often used to diagnose CMV infections. Unfortunately, the patient died due to a fungal infection. Observing EBV DNA levels closely with real-time quantitative PCR methods is helpful for evaluating the changes in the clinical course.

Detection of EBV-DNA in serum samples of an immunosuppressed child during a three years follow-up: association of clinical and PCR data with active infection.

PubMed

Okay, Thelma Suely; Del Negro, Gilda Maria Barbaro; Yamamoto, Lídia; Raiz Júnior, Roberto

2005-01-01

Twenty-four whole blood and serum samples were drawn from an eight year-old heart transplant child during a 36 months follow-up. EBV serology was positive for VCA-IgM and IgG, and negative for EBNA-IgG at the age of five years old when the child presented with signs and symptoms suggestive of acute infectious mononucleosis. After 14 months, serological parameters were: positive VCA-IgG, EBNA-IgG and negative VCA-IgM. This serological pattern has been maintained since then even during episodes suggestive of EBV reactivation. PCR amplified a specific DNA fragment from the EBV gp220 (detection limit of 100 viral copies). All twenty-four whole blood samples yielded positive results by PCR, while 12 out of 24 serum samples were positive. We aimed at analyzing whether detection of EBV-DNA in serum samples by PCR was associated with overt disease as stated by the need of antiviral treatment and hospitalization. Statistical analysis showed agreement between the two parameters evidenced by the Kappa test (value 0.750; p < 0.001). We concluded that detection of EBV-DNA in serum samples of immunosuppressed patients might be used as a laboratory marker of active EBV disease when a Real-Time PCR or another quantitative method is not available.

EBV+ lymphoepithelial carcinoma of the parotid gland in Mexican Mestizo patients with chronic autoimmune diseases.

PubMed

Saqui-Salces, Milena; Martinez-Benitez, Braulio; Gamboa-Dominguez, Armando

2006-01-01

Lymphoepithelial carcinomas of the salivary gland are rare tumors constantly associated with Epstein-Barr virus (EBV) and mainly identified in Asiatic and Greenlander population. Four cases have been described in Caucasians, only two with EBV infection. We describe two cases of parotid gland lymphoepithelial carcinomas in Mexican mestizo women in which chronic latent EBV infection was documented by immunohistochemistry and in situ hybridization. One patient had primary Sjögren's syndrome and the other systemic lupus erythematosus of six and three years of evolution, respectively. Epithelial neoplastic cells showed latency pattern II (LMP1+, EBNA-2-, EBER+) with a dense inflammatory infiltrate composed mainly by CD8+ T lymphocytes. Follow-up excluded nasopharyngeal involvement in both patients. This report expands the ethnic groups in which salivary lymphoepithelial carcinomas associated with chronic latent EBV infection have been described, and illustrates for the first time its association with autoimmune diseases in two women living in a region non-endemic for this unusual neoplasm.

Ataxia and Encephalitis in a Young Adult with EBV Mononucleosis: A Case Report.

PubMed

Hussain, Rashid S; Hussain, Naaz A

2013-01-01

Neurological manifestations of mononucleosis are extremely rare, occurring in about 1% of all cases. However, when they occur, appropriate treatment must be undertaken to ensure appropriate symptomatic management and reduce morbidity. We present the case of a 25-year-old graduate student with weeklong complaints of fever, sore throat, fatigue, nausea, and "dizziness." She later developed increased sleep requirements, ataxia, vertigo, and nystagmus with a positive EBV IgM titer confirming acute infectious mononucleosis. The patient was clinically diagnosed with EBV-associated cerebellitis and encephalitis, displaying neurological and psychiatric impairment commonly seen in postconcussion syndrome. MRI showed no acute changes. She was started on valacyclovir and a prednisone taper, recovering by the end of twelve weeks. Though corticosteroids and acyclovir are not recommended therapy in patients presenting with EBV-associated ataxia, clinicians may want to keep a low threshold to start these medications in case more serious neurological sequelae develop.

EBV seroepidemiology in married and unmarried women and men in Iran.

PubMed

Pourahamad, Morteza; Hooshmand, Farhang; Olyaee Nezhad, Sara; Sepidkar, Abdolali

2014-04-01

Among the eight known human herpes viruses, Epstein- Barr virus (EBV) is considered to be sexually transmissible. This study was conducted to evaluate the seroepidemiology of this infection in married and unmarried Iranian couples. In this comparative observational and cross-sectional study, 160 men and women were divided into married and unmarried groups. Serum IgG and IgM antibodies to the EBV viral capsid antigen were analyzed by Enzyme-linked Immunosorbent Assays (ELISAs). In this study 78 men and 82 women were enrolled. Ninety percent of the married and 76.2% of the unmarried women were anti-EBV IgG positive (P = 0.08), while 80% of the married and 94% of the unmarried men were antiEBV IgG positive (P = 0.052). Seroepidemiology of EBV is not significantly different in married vs. unmarried women and men in Iran; therefore, sexual contact may not be the primary mechanism of EBV transmission in Iran and other developing countries. Attention to other possible routes of transmission is recommended.

HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma

PubMed Central

Hjalgrim, Henrik; Rostgaard, Klaus; Johnson, Paul C. D.; Lake, Annette; Shield, Lesley; Little, Ann-Margaret; Ekstrom-Smedby, Karin; Adami, Hans-Olov; Glimelius, Bengt; Hamilton-Dutoit, Stephen; Kane, Eleanor; Taylor, G. Malcolm; McConnachie, Alex; Ryder, Lars P.; Sundstrom, Christer; Andersen, Paal Skytt; Chang, Ellen T.; Alexander, Freda E.; Melbye, Mads; Jarrett, Ruth F.

2010-01-01

A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60–2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51–0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74–6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL. PMID:20308568

Epstein-Barr virus DNA is detected in peripheral blood mononuclear cells of EBV-seronegative infants with infectious mononucleosis-like symptoms.

PubMed

Ikuta, Kazufumi; Saiga, Kyoko; Deguchi, Masanori; Sairenji, Takeshi

2003-01-01

We demonstrated Epstein-Barr virus (EBV) DNA in peripheral blood mononuclear cells (PBMCs) from infants with infectious mononucleosis- (IM) like symptoms. Thirteen of the 17 patients did not have EBV antibodies; however, EBV DNA was detected in 8 PBMC from the 13 seronegative patients by PCR. The 4 patients were retested in 6-12 months later. Three patients were still seronegative; however EBV DNA wasnot detected. One patient seroconverted and EBV DNA could still be detected. The transcript of EBNA1 was detected in one patient, but neither EBNA2 nor LMP2A were detected in all PBMC from the 4 tested patients. Type 1 EBV DNA was detected in 5 PBMC of 7 tested patients, and type 2 EBV DNA was detected in type 1 positive PBMC of one patient as well. The IL-1 beta polymorphism that is reported to be one of the immunological factors of EBV seronegativity revealed no difference in IM-like patients. These results indicated that EBV infection occurs in EBV-seronegative IM-like infants; however, the modes of infection are clearly different from IM.

Quantitative multi-target RNA profiling in Epstein-Barr virus infected tumor cells.

PubMed

Greijer, A E; Ramayanti, O; Verkuijlen, S A W M; Novalić, Z; Juwana, H; Middeldorp, J M

2017-03-01

Epstein-Barr virus (EBV) is etiologically linked to multiple acute, chronic and malignant diseases. Detection of EBV-RNA transcripts in tissues or biofluids besides EBV-DNA can help in diagnosing EBV related syndromes. Sensitive EBV transcription profiling yields new insights on its pathogenic role and may be useful for monitoring virus targeted therapy. Here we describe a multi-gene quantitative RT-PCR profiling method that simultaneously detects a broad spectrum (n=16) of crucial latent and lytic EBV transcripts. These transcripts include (but are not restricted to), EBNA1, EBNA2, LMP1, LMP2, BARTs, EBER1, BARF1 and ZEBRA, Rta, BGLF4 (PK), BXLF1 (TK) and BFRF3 (VCAp18) all of which have been implicated in EBV-driven oncogenesis and viral replication. With this method we determine the amount of RNA copies per infected (tumor) cell in bulk populations of various origin. While we confirm the expected RNA profiles within classic EBV latency programs, this sensitive quantitative approach revealed the presence of rare cells undergoing lytic replication. Inducing lytic replication in EBV tumor cells supports apoptosis and is considered as therapeutic approach to treat EBV-driven malignancies. This sensitive multi-primed quantitative RT-PCR approach can provide broader understanding of transcriptional activity in latent and lytic EBV infection and is suitable for monitoring virus-specific therapy responses in patients with EBV associated cancers. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts

PubMed Central

Fend, Falko

2018-01-01

The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored. PMID:29518976

Performance of the Epstein-Barr Virus and Herpes Simplex Virus Immunoglobulin M Assays on the Liaison Platform with Sera from Patients Displaying Acute Parvovirus B19 Infection▿

PubMed Central

Costa, Elisa; Tormo, Nuria; Clari, María Ángeles; Bravo, Dayana; Muñoz-Cobo, Beatriz; Navarro, David

2009-01-01

Acute parvovirus B19 infection has been reported to cause false-positive results frequently in the Epstein-Barr (EBV) and herpes simplex virus (HSV) immunoglobulin M (IgM) assays from DiaSorin performed on the Liaison platform. We tested 65 sera from patients with a presumptive or conclusive diagnosis of acute parvovirus B19 infection in both assays and obtained no false-positive results in the EBV IgM test and 10.4% nonspecific reactivities in the HSV IgM assay. Our data support the specificity of both assays in this clinical setting. PMID:19571110

Genetic factors affecting EBV copy number in lymphoblastoid cell lines derived from the 1000 Genome Project samples.

PubMed

Mandage, Rajendra; Telford, Marco; Rodríguez, Juan Antonio; Farré, Xavier; Layouni, Hafid; Marigorta, Urko M; Cundiff, Caitlin; Heredia-Genestar, Jose Maria; Navarro, Arcadi; Santpere, Gabriel

2017-01-01

Epstein-Barr virus (EBV), human herpes virus 4, has been classically associated with infectious mononucleosis, multiple sclerosis and several types of cancers. Many of these diseases show marked geographical differences in prevalence, which points to underlying genetic and/or environmental factors. Those factors may include a different susceptibility to EBV infection and viral copy number among human populations. Since EBV is commonly used to transform B-cells into lymphoblastoid cell lines (LCLs) we hypothesize that differences in EBV copy number among individual LCLs may reflect differential susceptibility to EBV infection. To test this hypothesis, we retrieved whole-genome sequenced EBV-mapping reads from 1,753 LCL samples derived from 19 populations worldwide that were sequenced within the context of the 1000 Genomes Project. An in silico methodology was developed to estimate the number of EBV copy number in LCLs and validated these estimations by real-time PCR. After experimentally confirming that EBV relative copy number remains stable over cell passages, we performed a genome wide association analysis (GWAS) to try detecting genetic variants of the host that may be associated with EBV copy number. Our GWAS has yielded several genomic regions suggestively associated with the number of EBV genomes per cell in LCLs, unraveling promising candidate genes such as CAND1, a known inhibitor of EBV replication. While this GWAS does not unequivocally establish the degree to which genetic makeup of individuals determine viral levels within their derived LCLs, for which a larger sample size will be needed, it potentially highlighted human genes affecting EBV-related processes, which constitute interesting candidates to follow up in the context of EBV related pathologies.

Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray.

PubMed

Loebel, Madlen; Eckey, Maren; Sotzny, Franziska; Hahn, Elisabeth; Bauer, Sandra; Grabowski, Patricia; Zerweck, Johannes; Holenya, Pavlo; Hanitsch, Leif G; Wittke, Kirsten; Borchmann, Peter; Rüffer, Jens-Ulrich; Hiepe, Falk; Ruprecht, Klemens; Behrends, Uta; Meindl, Carola; Volk, Hans-Dieter; Reimer, Ulf; Scheibenbogen, Carmen

2017-01-01

Epstein-Barr-Virus (EBV) plays an important role as trigger or cofactor for various autoimmune diseases. In a subset of patients with Chronic Fatigue Syndrome (CFS) disease starts with infectious mononucleosis as late primary EBV-infection, whereby altered levels of EBV-specific antibodies can be observed in another subset of patients. We performed a comprehensive mapping of the IgG response against EBV comparing 50 healthy controls with 92 CFS patients using a microarray platform. Patients with multiple sclerosis (MS), systemic lupus erythematosus (SLE) and cancer-related fatigue served as controls. 3054 overlapping peptides were synthesised as 15-mers from 14 different EBV proteins. Array data was validated by ELISA for selected peptides. Prevalence of EBV serotypes was determined by qPCR from throat washing samples. EBV type 1 infections were found in patients and controls. EBV seroarray profiles between healthy controls and CFS were less divergent than that observed for MS or SLE. We found significantly enhanced IgG responses to several EBNA-6 peptides containing a repeat sequence in CFS patients compared to controls. EBNA-6 peptide IgG responses correlated well with EBNA-6 protein responses. The EBNA-6 repeat region showed sequence homologies to various human proteins. Patients with CFS had a quite similar EBV IgG antibody response pattern as healthy controls. Enhanced IgG reactivity against an EBNA-6 repeat sequence and against EBNA-6 protein is found in CFS patients. Homologous sequences of various human proteins with this EBNA-6 repeat sequence might be potential targets for antigenic mimicry.

Development of Epstein-Barr virus-specific memory T cell receptor clonotypes in acute infectious mononucleosis

PubMed Central

1996-01-01

The importance of cytotoxic T lymphocytes (CTLs) in the immunosurveillance of Epstein-Barr virus (EBV)-infected B cells is firmly established, and the viral antigens of CTL recognition in latent infection are well defined. The epitopes targeted by CTLs during primary infection have not been identified, however, and there is only limited information about T cell receptor (TCR) selection. In the present report, we have monitored the development of memory TCR-beta clonotypes selected in response to natural EBV infection in a longitudinal study of an HLA-B8+ individual with acute infectious mononucleosis (IM). By stimulating peripheral blood lymphocytes with HLA-B8+ EBV-transformed B lymphoblastoid cells, the primary virus- specific CTL response was shown to include specificities for two HLA-B8- restricted antigenic determinants, FLRGRAYGL and QAKWRLQTL, which are encoded within the latent EBV nuclear antigen EBNA-3. TCR-beta sequence analysis of CTL clones specific for each epitope showed polyclonal TCR- beta repertoire selection, with structural restrictions on recognition that indicated antigen-driven selection. Furthermore, longitudinal repertoire analysis revealed long-term preservation of a multiclonal effector response throughout convalescence, with the reemergence of distinct memory T cell clonotypes sharing similar structural restrictions. Tracking the progression of specific TCR-beta clonotypes and antigen-specific TCR-V beta family gene expression in the peripheral repertoire ex vivo using semiquantitative PCR strongly suggested that selective TCR-beta expansions were present at the clonotype level, but not at the TCR-V beta family level. Overall, in this first analysis of antigen-specific TCR development in IM, a picture of polyclonal TCR stimulation is apparent. This diversity may be especially important in the establishment of an effective CTL control during acute EBV infection and in recovery from disease. PMID:8920869

Epstein-Barr Virus nuclear antigen 1 (EBNA1) confers resistance to apoptosis in EBV-positive B-lymphoma cells through up-regulation of survivin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu Jie; Murakami, Masanao; Verma, Subhash C.

Resistance to apoptosis is an important component of the overall mechanism which drives the tumorigenic process. EBV is a ubiquitous human gamma-herpesvirus which preferentially establishes latent infection in viral infected B-lymphocytes. EBNA1 is typically expressed in most forms of EBV-positive malignancies and is important for replication of the latent episome in concert with replication of the host cells. Here, we investigate the effects of EBNA1 on survivin up-regulation in EBV-infected human B-lymphoma cells. We present evidence which demonstrates that EBNA1 forms a complex with Sp1 or Sp1-like proteins bound to their cis-element at the survivin promoter. This enhances the activitymore » of the complex and up-regulates survivin. Knockdown of survivin and EBNA1 showed enhanced apoptosis in infected cells and thus supports a role for EBNA1 in suppressing apoptosis in EBV-infected cells. Here, we suggest that EBV encoded EBNA1 can contribute to the oncogenic process by up-regulating the apoptosis suppressor protein, survivin in EBV-associated B-lymphoma cells.« less

Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations

PubMed Central

Glaser, Sally L.; Gulley, Margaret L.; Clarke, Christina A.; Keegan, Theresa H.; Chang, Ellen T.; Shema, Sarah J.; Craig, Fiona E.; DiGiuseppe, Joseph A.; Dorfman, Ronald F.; Mann, Risa B.; Anton-Culver, Hoda; Ambinder, Richard F.

2009-01-01

Epstein-Barr virus (EBV) is detected in the tumor cells of some but not all Hodgkin lymphoma (HL) patients, and evidence indicates that EBV-positive and –negative HL are distinct entities. Racial/ethnic variation in EBV-positive HL in international comparisons suggests etiologic roles for environmental and genetic factors, but these studies used clinical series and evaluated EBV presence by differing protocols. Therefore, we evaluated EBV presence in the tumors of a large (n=1,032), racially and sociodemographically diverse series of California incident classical HL cases with uniform pathology re-review and EBV detection methods. Tumor EBV-positivity was associated with Hispanic and Asian/Pacific Islander (API) but not black race/ethnicity, irrespective of demographic and clinical factors. Complex race-specific associations were observed between EBV-positive HL and age, sex, histology, stage, neighborhood socioeconomic status (SES), and birth place. In Hispanics, EBV-positive HL was associated not only with young and older age, male sex, and mixed cellularity histology, but also with foreign birth and lower SES in females, suggesting immune function responses to correlates of early childhood experience and later environmental exposures, respectively, as well as of pregnancy. For APIs, a lack of association with birth place may reflect the higher SES of API than Hispanic immigrants. In blacks, EBV-positive HL was associated with later-stage disease, consistent with racial/ethnic variation in certain cytokine polymorphisms. The racial/ethnic variation in our findings suggests that EBV-positive HL results from an intricate interplay of early- and later-life environmental, hormonal, and genetic factors leading to depressed immune function and poorly controlled EBV infection. PMID:18646185

Immediate-Early Transactivator Rta of Epstein-Barr Virus (EBV) Shows Multiple Epitopes Recognized by EBV-Specific Cytotoxic T Lymphocytes

PubMed Central

Pepperl, Sandra; Benninger-Döring, Gerlinde; Modrow, Susanne; Wolf, Hans; Jilg, Wolfgang

1998-01-01

We analyzed the immediate-early transactivator Rta of Epstein-Barr virus (EBV) for its role as a target for specific cytotoxic T lymphocytes (CTL). Panels of overlapping peptides covering the entire amino acid sequence of Rta were synthesized and used to induce and analyze specific CTL responses in EBV-positive donors. Using peptide-pulsed target cells, we found nine different CTL epitopes that are distributed over the entire protein sequence. One epitope restricted by HLA-A24 could be mapped to the decameric sequence DYCNVLNKEF between amino acid positions 28 and 37 of the Rta protein. A second epitope could be assigned to the same region of Rta (residues 25 to 39) and was shown to be restricted by HLA-B18. Another, minimal epitope could be mapped to the nonameric sequence ATIGTAMYK between amino acid positions 134 and 142; this peptide was restricted by HLA-A11. Another four epitopes were proven to be restricted by HLA-A2, -A3, -B61, and -Cw4 and were located between Rta residues 225 and 239, 145 and 159, 529 and 543, and 393 and 407, respectively. For two other epitopes, only the location within the Rta protein is known so far (residues 121 to 135 and 441 to 455); their exact HLA restriction patterns have not yet been identified. Using target cells infected with recombinant vaccinia virus containing the gene for Rta, we showed that six of eight Rta-specific CTL lines recognized the corresponding peptides also after endogenous processing. These data suggest that Rta comprises an important target for EBV-specific cellular cytotoxicity. Together with recent findings of other immediate-early and early proteins also acting as CTL targets, they reveal the role of proteins of the lytic cycle in the immune recognition of EBV-infected cells. PMID:9765404

Acute viral infections in patients with systemic lupus erythematosus: description of 23 cases and review of the literature.

PubMed

Ramos-Casals, Manuel; Cuadrado, María José; Alba, Paula; Sanna, Giovanni; Brito-Zerón, Pilar; Bertolaccini, Laura; Babini, Alejandra; Moreno, Asunción; D'Cruz, David; Khamashta, Munther A

2008-11-01

Few studies have evaluated the impact of viral infections on the daily management of patients with systemic lupus erythematosus (SLE). We analyzed the etiology and clinical features of acute viral infections arising in patients with SLE and their influence on the diagnosis, prognosis, and treatment of SLE. Cases occurring within the last 5 years were selected from the databases of 3 large teaching hospitals. Acute viral infections were confirmed by the identification of specific antiviral IgM antibodies and subsequent seroconversion with detection of specific IgG antibodies. In autopsy studies, macroscopic findings suggestive of viral infection were confirmed by direct identification of the virus or viruses in tissue samples. We performed a MEDLINE search for additional cases reported between January 1985 and March 2008. We included 88 cases (23 from our clinics and 65 from the literature review) of acute viral infections in patients with SLE. Twenty-five patients were diagnosed with new-onset SLE (fulfillment of the 1997 SLE criteria) associated with infection by human parvovirus B19 (n = 15), cytomegalovirus (CMV; n = 6), Epstein-Barr virus (EBV; n = 3), and hepatitis A virus (n = 1). The remaining 63 cases of acute viral infections arose in patients already diagnosed with SLE: in 18 patients, symptoms related to infection mimicked a lupus flare, 36 patients, including 1 patient from the former group who presented with both conditions, presented organ-specific viral infections (mainly pneumonitis, colitis, retinitis, and hepatitis), and 10 patients presented a severe, multiorgan process similar to that described in catastrophic antiphospholipid syndrome-the final diagnosis was hemophagocytic syndrome in 5 cases and disseminated viral infection in 5. Twelve patients died due to infection caused by CMV (n = 5), herpes simplex virus (n = 4), EBV (n = 2), and varicella zoster virus (n = 1). Autopsies were performed in 9 patients and disclosed disseminated herpetic

Graves' disease associated with infectious mononucleosis due to primary Epstein-Barr virus infection: report of 3 cases.

PubMed

Akahori, Hiroshi; Takeshita, Yumie; Saito, Reina; Kaneko, Shuichi; Takamura, Toshinari

2010-01-01

Although the etiology of Graves' disease is still not clear, it is generally suggested that environmental factors such as infections contribute to the development of Graves' disease. We report here three cases of Graves' disease which presented simultaneously with infectious mononucleosis due to primary EBV infection. Acute EBV infection might play an important role in the onset of Graves' disease. These three women complained of a sore throat or neck pain, resembling subacute thyroiditis. In the case of thyrotoxicosis accompanied by sore throat or neck pain, Graves' disease must be distinguished from subacute thyroiditis.

Prevalence and molecular profiling of Epstein Barr virus (EBV) among healthy blood donors from different nationalities in Qatar.

PubMed

Smatti, Maria K; Yassine, Hadi M; AbuOdeh, Raed; AlMarawani, Asmaa; Taleb, Sara A; Althani, Asmaa A; Nasrallah, Gheyath K

2017-01-01

The Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis. EBV is highly prevalent lymphotropic herpesvirus and has been linked to several malignancies. Transmission is generally by oral secretions, but can be through blood transfusions and organ transplantations. This study aimed to determine the seroprevalence, viremia rates, and circulating genotypes of EBV in healthy blood donors in Qatar. Blood samples from 673 blood donors of different nationalities residing in Qatar (mainly Qatar, Egypt, Syria, Jordan, Pakistan, and India) were collected and tested for anti-EBV capsid (VCA; IgG & IgM), nuclear (EBNA; IgG), and early (EA-D; IgG) antigens. Avidity testing was determined when active infection was suspected. DNA was extracted from the buffy coat and subjected to EBV-DNA quantification using qRT-PCR. Genotyping was performed using nested-PCR targeting EBV-EBNA2 gene, and phylogeny by sequence analysis of the LMP-1 gene. 97.9% (673/659) of the samples were seropositive as indicated by the presence VCA-IgG, while 52.6% (354/673) had detectible EBV-DNA. EBV seroprevalence and viremia rates increased significantly with age. Genotyping of 51 randomly selected samples showed predominance of Genotype 1 (72.5%, 37/51) as compared to genotype 2 (3.5%), and mixed infections were detected in 4% of the samples. Sub-genotyping for these samples revealed that the Mediterranean strain was predominant (65.3%), followed by B95.8 prototype and North Carolina strains (12.2% each), and China1 strain (6%). As a first study to evaluate EBV infection in highly diverse population in Qatar, where expatriates represent more than 85% of the population, our results indicated high seroprevalence and viremia rate of EBV in different nationalities, with genotype 1 and Mediterranean strain being predominant. Clinical significance of these finding have not been investigated and shall be evaluated in future studies.

An animal model for human EBV-associated hemophagocytic syndrome: herpesvirus papio frequently induces fatal lymphoproliferative disorders with hemophagocytic syndrome in rabbits.

PubMed

Hayashi, K; Ohara, N; Teramoto, N; Onoda, S; Chen, H L; Oka, T; Kondo, E; Yoshino, T; Takahashi, K; Yates, J; Akagi, T

2001-04-01

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) is often associated with fatal infectious mononucleosis. However, the animal model for EBV-AHS has not been developed. We reported the first animal model for EBV-AHS using rabbits infected with EBV-related herpesvirus of baboon (HVP). Eleven of 13 (85%) rabbits inoculated intravenously with HVP-producing cells developed fatal lymphoproliferative disorders (LPD) between 22 and 105 days after inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in nine of these 11 rabbits. The peroral spray of cell-free HVP induced the virus infection with increased anti-EBV-viral capsid antigen-IgG titers in three of five rabbits, and two of these three infected rabbits died of LPD with HPS. Autopsy revealed hepatosplenomegaly and swollen lymph nodes. Atypical lymphoid T cells expressing EBV-encoded small RNA-1 infiltrated diffusely in many organs, frequently involving the lymph nodes, spleen, and liver. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by polymerase chain reaction or Southern blot analysis. Reverse transcriptase-polymerase chain reaction revealed both HVP-EBNA1 and HVP-EBNA2 transcripts, suggesting latency type III infection. These data indicate that the high rate of rabbit LPD with HPS induction is caused by HVP. This system is useful for studying the pathogenesis, prevention, and treatment of human EBV-AHS.

Chronic active Epstein-Barr virus infection with marked pericardial effusion successfully treated with allogeneic peripheral blood stem cell transplantation.

PubMed

Matsui, Shinichiro; Takeda, Yusuke; Isshiki, Yusuke; Yamazaki, Atsuko; Nakao, Sanshiro; Takaishi, Koji; Nagao, Yuhei; Hasegawa, Nagisa; Togasaki, Emi; Shimizu, Ryoh; Kawajiri, Chika; Sakai, Shio; Mimura, Naoya; Takeuchi, Masahiro; Ohwada, Chikako; Sakaida, Emiko; Iseki, Tohru; Imadome, Ken-Ichi; Nakaseko, Chiaki

2016-05-01

A 23-year-old woman presented with a persistent fever and shortness of breath. Computed tomography showed marked pericardial effusion, hepatosplenomegaly, and cervical and mediastinal lymph node swelling. Epstein-Barr virus (EBV) antibody titers were abnormally elevated, and the copy number of EBV-DNA was increased in peripheral blood. Based on these observations, she was diagnosed with chronic active EBV infection (CAEBV). The EBV-infected cells in her peripheral blood were CD4(+)T lymphocytes. Fever and pericardial effusion improved following treatment with a combination of prednisolone, etoposide, and cyclosporine; however, peripheral blood EBV-DNA levels remained high. The patient underwent allogeneic peripheral blood stem cell transplantation from an EBV-seronegative, HLA-matched sibling donor, with fludarabine and melphalan conditioning. The post-transplantation course was uneventful, except for mild skin acute graft-versus-host disease (grade 2). EBV-DNA became undetectable in peripheral blood 98 days post transplantation. She has since been in good health without disease recurrence. CAEBV is a potentially fatal disease caused by persistent EBV infection of T lymphocytes or natural killer cells, thus requiring prompt treatment and allogeneic transplantation. Pericardial effusion is rarely observed in CAEBV and can impede its diagnosis. Therefore, we should be aware that patients may present with marked pericardial effusion as an initial manifestation of CAEBV.

Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children

PubMed Central

Jayasooriya, Shamanthi; de Silva, Thushan I.; Njie-jobe, Jainaba; Sanyang, Chilel; Leese, Alison M.; Bell, Andrew I.; McAulay, Karen A.; Yanchun, Peng; Long, Heather M.; Dong, Tao; Whittle, Hilton C.; Rickinson, Alan B.; Rowland-Jones, Sarah L.; Hislop, Andrew D.; Flanagan, Katie L.

2015-01-01

Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14–18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms. PMID:25816224

Epstein-Barr virus (EBV) provides survival factors to EBV+ diffuse large B-cell lymphoma (DLBCL) lines and modulates cytokine induced specific chemotaxis in EBV+  DLBCL.

PubMed

Wu, Liang; Ehlin-Henriksson, Barbro; Zhou, Xiaoying; Zhu, Hong; Ernberg, Ingemar; Kis, Lorand L; Klein, George

2017-12-01

Diffuse large B-cell lymphoma (DLBCL), the most common type of malignant lymphoma, accounts for 30% of adult non-Hodgkin lymphomas. Epstein-Barr virus (EBV) -positive DLBCL of the elderly is a newly recognized subtype that accounts for 8-10% of DLBCLs in Asian countries, but is less common in Western populations. Five DLBCL-derived cell lines were employed to characterize patterns of EBV latent gene expression, as well as response to cytokines and chemotaxis. Interleukin-4 and interleukin-21 modified LMP1, EBNA1 and EBNA2 expression depending on cell phenotype and type of EBV latent programme (type I, II or III). These cytokines also affected CXCR4- or CCR7-mediated chemotaxis in two of the cell lines, Farage (type III) and Val (type II). Further, we investigated the effect of EBV by using dominant-negative EBV nuclear antigen 1(dnEBNA1) to eliminate EBV genomes. This resulted in decreased chemotaxis. By employing an alternative way to eliminate EBV genomes, Roscovitine, we show an increase of apoptosis in the EBV-positive lines. These results show that EBV plays an important role in EBV-positive DLBCL lines with regard to survival and chemotactic response. Our findings provide evidence for the impact of microenvironment on EBV-carrying DLBCL cells and might have therapeutic implications. © 2017 John Wiley & Sons Ltd.

Clinicopathological study of severe chronic active Epstein-Barr virus infection that developed in association with lymphoproliferative disorder and/or hemophagocytic syndrome.

PubMed

Ohshima, K; Suzumiya, J; Sugihara, M; Nagafuchi, S; Ohga, S; Kikuchi, M

1998-12-01

Chronic active Epstein-Barr virus (CAEBV) infection has been previously reported to be sometimes associated with an aggressive clinical course. However, the role of EBV in the CAEBV is not well clarified. A retrospective study was performed on nine adult and five child patients (eight males and six females). Histologically, at first admission, the presence of neoplastic lesions could not be confirmed. The lymph nodes in half of all cases revealed paracortical hyperplasia with transformed lymphocytes (hyperplastic type). Half of the cases showed non-suppurative necrosis and an increased number of histiocytes with phagocytosis (histiocytic type). Activated histiocytes with lymphokine positivity were frequently detected in the histiocytic type. In the phenotypical study, 10 of the examined 11 cases showed increased numbers of natural killer (NK) cells and/or CD8-positive T lymphocytes. In situ hybridization (ISH) showed EBV-infected lymphoid cells, but the number of EBV-infected cells varied. Double-labeling immunochemistry/ISH demonstrated EBV-infected T cells, including NK cells, but not B cells. In addition, three cases showed a monoclonal dissemination of EBV terminal repetitive sequence (TR), and two cases showed oligoclonal dissemination. From those findings, monoclonal, oligoclonal and polyclonal populations of EBV-infected T or NK cells were considered to be present in CAEBV states. During the clinical course, 12 of the 14 cases died within 5 years. Six cases died from EBV-associated hematopoietic tumors (histiocytic tumor, T cell lymphoma, B cell lymphoma, plasmacytoma, and NK cell leukemia); one from non-EBV-associated acute myelogenous leukemia, and five due to hemophagocytic syndrome. The examined EBV-associated hematopoietic tumors showed monoclonal EBV terminal repetitive sequences. There is a possibility that the monoclonal dissemination of EBV-infected cells develops from oligoclonal or polyclonal EBV-infected cells. And active histiocytes with

EBV, HSV, CMV and HPV in laryngeal and oropharyngeal carcinoma in Polish patients.

PubMed

Polz-Gruszka, Dorota; Stec, Agnieszka; Dworzański, Jakub; Polz-Dacewicz, Małgorzata

2015-03-01

The role of viruses in the etiology of oral cancer has been proposed in many studies. The aim of the present study was to analyze the prevalence of Epstein-Barr virus, Human Herpes virus type 1, Cytomegalovirus and Human Papilloma virus among patients with oral squamous cell carcinoma in a Polish population. We investigated fresh-frozen tumor tissue fragments obtained from 80 patients with OSCC using the polymerase chain reaction assay. HPV was detected in 32.5% (22.5% were HPV 16), more often in laryngeal (36%) than in oropharyngeal carcinoma (26.6%). EBV was identified in 57.5%, HHV-1 in 7.5%, and CMV in 10% of patients. Co-infection with one or more viruses was detected in 30% of cases and most frequently it was co-infection with EBV and HPV (15%). Further studies are necessary to determine the potential role of EBV and the possible importance of HHV-1 as an infection co-factor in oropharyngeal cancer. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Epstein-Barr virus infection and nasopharyngeal carcinoma.

PubMed

Tsao, Sai Wah; Tsang, Chi Man; Lo, Kwok Wai

2017-10-19

Epstein-Barr virus (EBV) is associated with multiple types of human cancer, including lymphoid and epithelial cancers. The closest association with EBV infection is seen in undifferentiated nasopharyngeal carcinoma (NPC), which is endemic in the southern Chinese population. A strong association between NPC risk and the HLA locus at chromosome 6p has been identified, indicating a link between the presentation of EBV antigens to host immune cells and NPC risk. EBV infection in NPC is clonal in origin, strongly suggesting that NPC develops from the clonal expansion of a single EBV-infected cell. In epithelial cells, the default program of EBV infection is lytic replication. However, latent infection is the predominant mode of EBV infection in NPC. The establishment of latent EBV infection in pre-invasive nasopharyngeal epithelium is believed to be an early stage of NPC pathogenesis. Recent genomic study of NPC has identified multiple somatic mutations in the upstream negative regulators of NF-κB signalling. Dysregulated NF-κB signalling may contribute to the establishment of latent EBV infection in NPC. Stable EBV infection and the expression of latent EBV genes are postulated to drive the transformation of pre-invasive nasopharyngeal epithelial cells to cancer cells through multiple pathways.This article is part of the themed issue 'Human oncogenic viruses'. © 2017 The Author(s).

CD4(+) T-cell responses to Epstein-Barr virus (EBV) latent membrane protein 1 in infectious mononucleosis and EBV-associated non-Hodgkin lymphoma: Th1 in active disease but Tr1 in remission.

PubMed

Marshall, Neil A; Culligan, Dominic J; Johnston, Peter W; Millar, Colin; Barker, Robert N; Vickers, Mark A

2007-10-01

Primary infection with Epstein-Barr virus (EBV) in childhood is usually asymptomatic, whereas infection in adolescence may result in infectious mononucleosis (IM) often followed by a fatigue syndrome. EBV latent membrane protein 1 (LMP1) is expressed in latency and in many EBV-associated tumours, including non-Hodgkin lymphoma (NHL). Given the regulatory nature of the CD4(+) T-cell response against LMP1 previously reported in healthy donors, we investigated whether patients with active EBV-driven disease can nevertheless mount effector [T-helper cell, type 1 (Th1)] anti-LMP1 responses. We therefore performed a longitudinal study of the nature of CD4(+) T-cell responses to LMP1 in four patients with IM, and five patients with NHL. In both groups, responses changed with time. During symptomatic infection or active tumour growth, responses were dominated by a Th1 effector phenotype, but switched to a regulatory interleukin-10 response upon recovery. In addition, the fine specificities of the T cells driving these responses evolved. This study showed the dynamic nature of CD4(+) T-cell responses to LMP1, and demonstrated that, although patients can mount Th1 effector responses, recovery from IM and NHL is associated with regulatory responses.

Evidence of shared Epstein-Barr viral isolates between sexual partners, and low level EBV in genital secretions.

PubMed

Thomas, Ranjit; Macsween, Karen F; McAulay, Karen; Clutterbuck, Daniel; Anderson, Richard; Reid, Stuart; Higgins, Craig D; Swerdlow, Anthony J; Harrison, Nadine; Williams, Hilary; Crawford, Dorothy H

2006-09-01

Epstein-Barr virus is present in the saliva of most persistently infected individuals and is generally thought to be spread by close oral contact. However, there are now several reports of EBV in genital secretions, suggesting the possibility of sexual transmission between adults. The present study was undertaken to investigate the risk of sexual transmission of EBV. PCR analysis was used to examined the degree to which a group (n = 11) of patients with infectious mononucleosis (IM) shared the same viral isolates as their sexual partners, and compare this to the extent of isolate sharing among a different group (n = 18) of IM patients and their non-sexual contacts. There was significantly more sharing of EBV isolates among the IM/sexual-contact pairs than among the IM/non-sexual-contact pairs (P = 0.0012). Female cervical (n = 84), male urethral (n = 55), and semen (n = 30) samples from asymptomatic, unselected volunteers were analyzed for the presence of EBV DNA, revealing 7%, 5%, and 3% to be EBV positive, respectively. Fractionation of cervical and urethral samples into cellular and supernatant fluid components showed EBV to be mainly cell-associated. Quantitation of EBV in these samples gave levels of below 10 EBV genomes per microg of DNA. Overall the findings support the possibility that EBV could on occasions be transmitted sexually, however, the low levels detected in genital secretions compared to saliva suggest that this is not a major transmission route. The finding of small quantities of cell-associated virus suggests a latent infection; thus EBV is probably in the B lymphocyte rather than in the epithelial cell component of the secretions.

The role of oxidative stress in EBV lytic reactivation, radioresistance and the potential preventive and therapeutic implications.

PubMed

Hu, Jianmin; Li, Hongde; Luo, Xiangjian; Li, Yueshuo; Bode, Ann; Cao, Ya

2017-11-01

Epstein-Barr virus (EBV) is an important cancer causing virus. Cancer associated with EBV account for approximately 1.5% of all cancers, and represent 1.8% of all cancer deaths worldwide. EBV reactivation plays an important role in the development of EBV-related diseases and is closely related with patients' survival and clinical stages of EBV-related cancers. The therapy regarding to EBV-related cancers is very urgent, especially in endemic areas. Generating oxidative stress is a critical mechanism by which host cells defend against infection by virus. In addition, ROS-mediated oxidative stress plays a significant but paradoxical role acting as a "double-edged sword" to regulate cellular response to radiation, which is the main therapy strategy for EBV-related cancers, especially nasopharyngeal carcinoma. Therefore, in this review we primarily discuss the possible interplay among the oxidative stress, EBV lytic reactivation and radioresistance. Understanding the role of oxidative stress in EBV lytic reactivation and radioresistance will assist in the development of effective strategies for prevention and treatment of EBV-related cancers. © 2017 UICC.

Prevalence and molecular profiling of Epstein Barr virus (EBV) among healthy blood donors from different nationalities in Qatar

PubMed Central

Smatti, Maria K.; Yassine, Hadi M.; AbuOdeh, Raed; AlMarawani, Asmaa; Taleb, Sara A.; Althani, Asmaa A.

2017-01-01

Background The Epstein–Barr virus (EBV) is the causative agent of infectious mononucleosis. EBV is highly prevalent lymphotropic herpesvirus and has been linked to several malignancies. Transmission is generally by oral secretions, but can be through blood transfusions and organ transplantations. This study aimed to determine the seroprevalence, viremia rates, and circulating genotypes of EBV in healthy blood donors in Qatar. Methods Blood samples from 673 blood donors of different nationalities residing in Qatar (mainly Qatar, Egypt, Syria, Jordan, Pakistan, and India) were collected and tested for anti-EBV capsid (VCA; IgG & IgM), nuclear (EBNA; IgG), and early (EA-D; IgG) antigens. Avidity testing was determined when active infection was suspected. DNA was extracted from the buffy coat and subjected to EBV-DNA quantification using qRT-PCR. Genotyping was performed using nested-PCR targeting EBV-EBNA2 gene, and phylogeny by sequence analysis of the LMP-1 gene. Results 97.9% (673/659) of the samples were seropositive as indicated by the presence VCA-IgG, while 52.6% (354/673) had detectible EBV-DNA. EBV seroprevalence and viremia rates increased significantly with age. Genotyping of 51 randomly selected samples showed predominance of Genotype 1 (72.5%, 37/51) as compared to genotype 2 (3.5%), and mixed infections were detected in 4% of the samples. Sub-genotyping for these samples revealed that the Mediterranean strain was predominant (65.3%), followed by B95.8 prototype and North Carolina strains (12.2% each), and China1 strain (6%). Conclusion As a first study to evaluate EBV infection in highly diverse population in Qatar, where expatriates represent more than 85% of the population, our results indicated high seroprevalence and viremia rate of EBV in different nationalities, with genotype 1 and Mediterranean strain being predominant. Clinical significance of these finding have not been investigated and shall be evaluated in future studies. PMID:29228016

The Epstein-Barr virus (EBV) nuclear antigen 1 BamHI F promoter is activated on entry of EBV-transformed B cells into the lytic cycle.

PubMed Central

Lear, A L; Rowe, M; Kurilla, M G; Lee, S; Henderson, S; Kieff, E; Rickinson, A B

1992-01-01

In Epstein-Barr virus (EBV)-positive Burkitt's lymphoma cell lines exhibiting the latency I form of infection (i.e., EBV nuclear antigen 1 [EBNA1] positive in the absence of other latent proteins), the EBNA1 mRNA has a unique BamHI Q/U/K splice structure and is expressed from a novel promoter, Fp, located near the BamHI FQ boundary. This contrasts with the situation in EBV-transformed lymphoblastoid cell lines (LCLs) exhibiting the latency III form of infection (i.e., positive for all latent proteins), in which transcription from the upstream Cp or Wp promoters is the principal source of EBNA mRNAs. We carried out cDNA amplifications with oligonucleotide primer-probe combinations to determine whether Fp is ever active in an LCL environment. The results clearly showed that some LCLs express a Q/U/K-spliced EBNA1 mRNA in addition to the expected Cp/Wp-initiated transcripts; this seemed inconsistent with the concept of Cp/Wp and Fp as mutually exclusive promoters. Here we show that Fp is indeed silent in latency III cells but is activated at an early stage following the switch from latency III into the virus lytic cycle. Four pieces of evidence support this conclusion: (i) examples of coincident Cp/Wp and Fp usage in LCLs are restricted to those lines in which a small subpopulation of cells have spontaneously entered the lytic cycle; (ii) transcripts initiating from Fp can readily be demonstrated in spontaneously productive lines by S1 nuclease protection; (iii) the presence of Fp-initiated transcripts is not affected by acyclovir blockade of the late lytic cycle; and (iv) infection of latently infected LCLs with a recombinant vaccinia virus encoding the EBV immediate-early protein BZLF1, a transcriptional transactivator which normally initiates the lytic cycle, results in the appearance of the diagnostic Q/U/K-spliced transcripts. Images PMID:1331531

A phase I-II trial to examine the toxicity of CMV- and EBV-specific cytotoxic T lymphocytes when used for prophylaxis against EBV and CMV disease in recipients of CD34-selected/T cell-depleted stem cell transplants.

PubMed

Lucas, K G; Sun, Q; Burton, R L; Tilden, A; Vaughan, W P; Carabasi, M; Salzman, D; Ship, A

2000-07-01

Epstein-Barr virus (EBV)-induced lymphoproliferative disease and cytomegalovirus (CMV) infection are major causes of morbidity and mortality in individuals with compromised cellular immunity. Although anti-viral pharmacological agents exist, severe side effects such as myelosuppression often limit the application of these medications. Infusion of ex vivo-expanded, virus-specific cytotoxic T-lymphocytes (CTL) has been proven to be safe and efficacious for the prophylaxis and treatment of EBV and CMV complications. While EBV-specific CTL can be readily and reliably produced with EBV-immortalized B-lymphoblastoid cell lines (BLCL) as stimulators, current protocols for CMV-specific CTL, which use CMV-infected fibroblasts as stimulators, may be associated with alloreactivity and the need for cloning, as well as the potential for exposure to human blood-born infectious agents. Our laboratory has developed a novel system to generate EBV/CMV-bi-specific CTL by co-culturing PBMC with autologous BLCL expressing a CMV protein pp65 (BLCLpp65) (Sun et al., 1999). pp65, an immunodominant CMV antigen, is transduced into BLCL by a recombinant retrovirus MSCVpp65. While low in alloreactivity, BLCLpp65-stimulated CTL are cytolytic to autologous cells infected with EBV or CMV, and this cytotoxicity is mediated by polyclonal, CD8+, MHC Class I-restricted T-cells. Further experiments revealed that retroviral transduction and expression of pp65 do not compromise the capacity of presenting EBV antigens, and T cells stimulated by BLCLpp65 recognize clinical strains of CMV (Sun et al., 2000). These data indicated that BLCLpp65 could substitute for BLCL as antigen presenting cells in adoptive immunotherapy against EBV-LPD, with the benefit of providing protection against CMV reactivation. This protocol is a Phase I/II study to examine the toxicity associated with and the immunologic effects of ex vivo simultaneously expanded EBV- and CMV-specific CTL for prophylaxis against EBV and CMV

Prevalence of Polyoma BK Virus (BKPyV), Epstein-Barr Virus (EBV) and Human Papilloma Virus (HPV) in Oropharyngeal Cancer.

PubMed

Polz-Gruszka, Dorota; Morshed, Kamal; Jarzyński, Adrian; Polz-Dacewicz, Małgorzata

2015-01-01

The aim of this study was to analyze the prevalence of BK virus, Human Papillomavirus and Epstein-Barr virus in oropharyngeal cancer, and to test our hypothesis that BKV/HPV/EBV co-infection plays a role in oropharyngeal squamous cell carcinoma. The correlation between viral infection, OSCC, anatomic location, pre-treatment staging, evidence of metastases to lymph nodes, and grading was also investigated. The examination samples were collected from 62 patients from paraffin tissue blocks. Males (90.3%) with, smoking (83.9%) and alcohol abuse (67.7%) problems prevailed in the studied group. G2 histological type was recognized in 80.6% cases. T4 (77.4%) and N2 (56.5%) traits occurred in the majority of patients. No cases of metastasis were observed (M0 100%). HPV - 24.2%, EBV - 27.4% and BKV 17.7% were detected in the studied samples. We observed co-infection EBV/BKV in 8% of cases, HPV/BKV in 4.8%, and HPV/EBV in 9% cases. Only in two cases co-infection of all three viruses was found.

[Effect of the Epstein-Barr virus on the nervous system].

PubMed

Kononenko, V V

2001-01-01

On the basis of a comprehensive examination of 12 patients with verified Epstein-Barr virus (EBV) infection it has been shown that this infection can be accompanied by acute and chronic affections of the central and peripheral nervous system. The pathogenesis of chronic EBV-infection involves autoimmune disorders, neurosensitization, a hazard of an injury to the muscular tissue. Chronic EBV-infection calls for differential diagnosis with other slow virus infections, systemic tumor afflictions, systemic diseases of the connective tissue. Acyclovir or valacyclovir can be recommended as treatment of acute and chronic EBV-infection.

In-cell infection: a novel pathway for Epstein-Barr virus infection mediated by cell-in-cell structures

PubMed Central

Ni, Chao; Chen, Yuhui; Zeng, Musheng; Pei, Rongjuan; Du, Yong; Tang, Linquan; Wang, Mengyi; Hu, Yazhuo; Zhu, Hanyu; He, Meifang; Wei, Xiawei; Wang, Shan; Ning, Xiangkai; Wang, Manna; Wang, Jufang; Ma, Li; Chen, Xinwen; Sun, Qiang; Tang, Hong; Wang, Ying; Wang, Xiaoning

2015-01-01

Epstein-Barr virus (EBV) can infect both susceptible B lymphocytes and non-susceptible epithelial cells (ECs). Viral tropism analyses have revealed two intriguing means of EBV infection, either by a receptor-mediated infection of B cells or by a cell-to-cell contact-mediated infection of non-susceptible ECs. Herein, we report a novel “in-cell infection” mechanism for EBV infection of non-susceptible ECs through the formation of cell-in-cell structures. Epithelial CNE-2 cells were invaded by EBV-infected Akata B cells to form cell-in-cell structures in vitro. Such unique cellular structures could be readily observed in the specimens of nasopharyngeal carcinoma. Importantly, the formation of cell-in-cell structures led to the autonomous activation of EBV within Akata cells and subsequent viral transmission to CNE-2 cells, as evidenced by the expression of viral genes and the presence of virion particles in CNE-2 cells. Significantly, EBV generated from in-cell infected ECs displayed altered tropism with higher infection efficacy to both B cells and ECs. In addition to CNE-2 tumor cells, cell-in-cell structure formation could also mediate EBV infection of NPEC1-Bmi1 cells, an immortalized nasopharyngeal epithelial cell line. Furthermore, efficient infection by this mechanism involved the activation of the PI3K/AKT signaling pathway. Thus, our study identified “in-cell infection” as a novel mechanism for EBV infection. Given the diversity of virus-infected cells and the prevalence of cell-in-cell structures during chronic infection, we speculate that “in-cell infection” is likely a general mechanism for EBV and other viruses to infect non-susceptible ECs. PMID:25916549

Splenic infarction associated with acute infectious mononucleosis due to Epstein-Barr virus infection.

PubMed

Heo, Dae-Hyuk; Baek, Dae-Youb; Oh, Sang-Min; Hwang, Joo-Hee; Lee, Chang-Seop; Hwang, Jeong-Hwan

2017-02-01

The purpose of this study was to report a case of a previously healthy 20-year-old woman diagnosed with splenic infarction following infectious mononucleosis (IM) by Epstein-Barr virus (EBV) infection and to perform the first systematic review of the clinical characteristics of splenic infarction associated with IM. A systematic review was conducted using English, French, and Japanese literatures of splenic infarction associated with IM due to EBV infection published between 1961 and 2015 in PubMed Medline. A total of 19 cases were extracted from the collected articles. Left upper quadrant (LUQ) pain was observed in 15 (79%) patients. Splenectomy was performed in five (26%) cases, among which four patients presented with stable vital signs. Splenic rupture was accompanied in two (10%) patients. The median time from the onset of IM symptoms to the diagnosis of splenic infarction was 5 days (range, 1-25 days). Fourteen (74%) of 19 patients experienced improvement through medical treatment, and there were no deaths. Splenic infarction associated with IM due to EBV infection can show a favorable clinical outcome after medical treatment. Clinicians should consider the possibility of splenic infarction when patients with IM experience LUQ pain. J. Med. Virol. 89:332-336, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Molecular Pathogenesis of EBV Susceptibility in XLP as Revealed by Analysis of Female Carriers with Heterozygous Expression of SAP

PubMed Central

Palendira, Umaimainthan; Low, Carol; Chan, Anna; Hislop, Andrew D.; Ho, Edwin; Phan, Tri Giang; Deenick, Elissa; Cook, Matthew C.; Riminton, D. Sean; Choo, Sharon; Loh, Richard; Alvaro, Frank; Booth, Claire; Gaspar, H. Bobby; Moretta, Alessandro; Khanna, Rajiv; Rickinson, Alan B.; Tangye, Stuart G.

2011-01-01

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP+ and SAP− cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8+ T cells specific for CMV and influenza were distributed across SAP+ and SAP− populations, EBV-specific cells were exclusively SAP+. The preferential recruitment of SAP+ cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8+ T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP− clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP− CD8+ T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited. PMID:22069374

[A Case of Severe Chronic Active Epstein-Barr Virus Infection with Aplastic Anemia and Hepatitis].

PubMed

Lee, Ja In; Lee, Sung Won; Han, Nam Ik; Ro, Sang Mi; Noh, Yong-Sun; Jang, Jeong Won; Bae, Si Hyun; Choi, Jong Young; Yoon, Seung Kew

2016-01-25

Epstein-Barr virus (EBV) causes various acute and chronic diseases. Chronic active EBV infection (CAEBV) is characterized by infectious mononucleosis-like symptoms that persist for more than 6 months with high viral loads in peripheral blood and/or an unusual pattern of anti-EBV antibodies. Severe CAEBV is associated with poor prognosis with severe symptoms, an extremely high EBV-related antibody titer, and hematologic complications that often include hemophagocytic lymphohistiocytosis. However, CAEBV which led to the development of aplastic anemia (AA) has not been reported yet. A 73-year-old woman was admitted to our hospital with intermittent fever, general weakness and elevated liver enzymes. In the serologic test, EBV-related antibody titer was elevated, and real-time quantitative-PCR in peripheral blood showed viral loads exceeding 10(4) copies/μg DNA. Liver biopsy showed characteristic histopathological changes of EBV hepatitis and in situ hybridization with EBV-encoded RNA-1 was positive for EBV. Pancytopenia was detected in peripheral blood, and the bone marrow aspiration biopsy showed hypocellularity with replacement by adipocytes. AA progressed and the patient was treated with prednisolone but deceased 8 months after the diagnosis due to multiple organ failure and opportunistic infection. Herein, we report a rare case of severe CAEBV in an adult patient accompanied by AA and persistent hepatitis.

Pathogenic Role of Exosomes in Epstein-Barr Virus (EBV)-Associated Cancers

PubMed Central

Teow, Sin-Yeang; Liew, Kitson; Khoo, Alan Soo-Beng; Peh, Suat-Cheng

2017-01-01

Exosomes are 40- to 100-nm membrane-bound small vesicles that carry a great variety of cellular cargoes including proteins, DNA, messenger RNAs (mRNAs), and microRNAs (miRNAs). These nanovesicles are detected in various biological fluids such as serum, urine, saliva, and seminal fluids. Exosomes serve as key mediators in intercellular communication by facilitating the transfer and exchange of cellular components from cells to cells. They contain various pathogenic factors whereby their adverse effects have been implicated in multiple viral infections and cancers. Interestingly, accumulating evidences showed that exosomes derived from tumour viruses or oncoviruses, exacerbate virus-associated cancers by remodelling the tumour microenvironment. In this review, we summarize the contributing factors of Epstein-Barr virus (EBV) products-containing exosomes in viral pathogenesis and their potential implications in EBV-driven malignancies. Understanding the biological role of these exosomes in the disease would undoubtedly boost the development of a more comprehensive strategy to combat EBV-associated cancers and to better predict the therapeutic outcomes. Furthermore, we also highlight the potentials and challenges of EBV products-containing exosomes being employed as diagnostic markers and therapeutic targets for EBV-related cancers. Since these aspects are rather underexplored, we attempt to underline interesting areas that warrant further investigations in the future. PMID:29104494

Biopsy-proven case of Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system.

PubMed

Kano, Kohei; Katayama, Takayuki; Takeguchi, Shiori; Asanome, Asuka; Takahashi, Kae; Saito, Tsukasa; Sawada, Jun; Saito, Masato; Anei, Ryogo; Kamada, Kyousuke; Miyokawa, Naoyuki; Nishihara, Hiroshi; Hasebe, Naoyuki

2017-06-01

A 75-year-old woman was admitted to our hospital with rapidly deteriorating consciousness disturbance. She had a 7-year history of rheumatoid arthritis (RA), which had been treated with methotrexate (MTX) and prednisolone. Brain T2-weighted MRI showed diffuse high-intensity lesions in the cerebral subcortical and deep white matter, bilateral basal ganglia and thalamus. A cerebrospinal fluid examination revealed elevated protein levels and positive Epstein-Barr virus (EBV) DNA. Human immunodeficiency virus was negative. Brain biopsy showed perivascular lymphocytic infiltration in the parenchyma and meninx with EBV-encoded small RNA (EBER). Since this case did not fulfill the criteria for chronic active EBV infection (CAEBV), she was diagnosed with Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system. High-dose methylprednisolone, acyclovir, ganciclovir and foscarnet were not effective. Although EBV is a causative agent of infectious mononucleosis (IM), lymphomas and nasopharyngeal carcinomas, vasculitic pathology of the central nervous system with EBV reactivation in the elderly is rare. Immunosuppressive drugs such as steroids and MTX are widely used to treat autoimmune disorders, but may exacerbate the reactivation of EBV. This is the first case of biopsy-proven EBV-positive/HIV-negative vasculitis during the treatment of RA with MTX and steroids. This case indicates that EBV-associated vasculitis needs to be considered as a differential diagnosis of CNS vasculitis. © 2016 Japanese Society of Neuropathology.

A Novel Persistence Associated EBV miRNA Expression Profile Is Disrupted in Neoplasia

PubMed Central

Qiu, Jin; Cosmopoulos, Katherine; Pegtel, Michiel; Hopmans, Erik; Murray, Paul; Middeldorp, Jaap; Shapiro, Michael; Thorley-Lawson, David A.

2011-01-01

We have performed the first extensive profiling of Epstein-Barr virus (EBV) miRNAs on in vivo derived normal and neoplastic infected tissues. We describe a unique pattern of viral miRNA expression by normal infected cells in vivo expressing restricted viral latency programs (germinal center: Latency II and memory B: Latency I/0). This includes the complete absence of 15 of the 34 miRNAs profiled. These consist of 12 BART miRNAs (including approximately half of Cluster 2) and 3 of the 4 BHRF1 miRNAs. All but 2 of these absent miRNAs become expressed during EBV driven growth (Latency III). Furthermore, EBV driven growth is accompanied by a 5–10 fold down regulation in the level of the BART miRNAs expressed in germinal center and memory B cells. Therefore, Latency III also expresses a unique pattern of viral miRNAs. We refer to the miRNAs that are specifically expressed in EBV driven growth as the Latency III associated miRNAs. In EBV associated tumors that employ Latency I or II (Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and gastric carcinoma), the Latency III associated BART but not BHRF1 miRNAs are up regulated. Thus BART miRNA expression is deregulated in the EBV associated tumors. This is the first demonstration that Latency III specific genes (the Latency III associated BARTs) can be expressed in these tumors. The EBV associated tumors demonstrate very similar patterns of miRNA expression yet were readily distinguished when the expression data were analyzed either by heat-map/clustering or principal component analysis. Systematic analysis revealed that the information distinguishing the tumor types was redundant and distributed across all the miRNAs. This resembles “secret sharing” algorithms where information can be distributed among a large number of recipients in such a way that any combination of a small number of recipients is able to understand the message. Biologically, this may be a consequence of functional redundancy between

Epstein-Barr virus (EBV)-encoded dUTPase and chronic restraint induce impaired learning and memory and sickness responses.

PubMed

Aubrecht, Taryn G; Weil, Zachary M; Ariza, Maria Eugenia; Williams, Marshall; Reader, Brenda F; Glaser, Ronald; Sheridan, John F; Nelson, Randy J

2014-10-01

Most adult humans have been infected with Epstein-Barr virus (EBV) and carry the latent virus. The EBV genome codes for several proteins that form an early antigen complex important for viral replication; one of these proteins is deoxyuridine triphosphate nucleotidohydrolase (dUTPase). The EBV-encoded dUTPase can induce sickness responses in mice. Because stress can increase latent virus reactivation, we hypothesized that chronic restraint would exacerbate sickness behaviors elicited by EBV-encoded dUTPase. Male Swiss-Webster mice were injected daily for 15 days with either saline or EBV-encoded dUTPase. Additionally, half of the mice from each condition were either restrained for 3h daily or left undisturbed. Restraint stress impaired learning and memory in the passive avoidance chamber; impaired learning and memory was due to EBV-encoded dUTPase injected into restrained mice. EBV-encoded dUTPase induced sickness responses and restraint stress interacts with EBV-encoded dUTPase to exacerbate the sickness response. These data support a role for EBV-encoded dUTPase and restraint stress in altering the pathophysiology of EBV independent of viral replication. Copyright © 2014 Elsevier Inc. All rights reserved.

B-cell polyclonal activation and Epstein-Barr viral abortive lytic cycle are two key features in acute infectious mononucleosis.

PubMed

Al Tabaa, Yassine; Tuaillon, Edouard; Jeziorski, Eric; Ouedraogo, David Eric; Bolloré, Karine; Rubbo, Pierre-Alain; Foulongne, Vincent; Rodière, Michel; Vendrell, Jean-Pierre

2011-09-01

Acute infectious mononucleosis (AIM) is generally associated with a large EBV B cell reservoir cells and an intense B-cell polyclonal activation whereas the number of quiescent EBV-infected memory B cells in chronically EBV-infected healthy controls is very low. To evaluate the extent and functionality of ex vivo B-cell polyclonal activation, quantify the EBV DNA integrated in B cells, enumerate the functional EBV DNA reservoir in B cells and circulating B cells spontaneously secreting EBV antigens in AIM. Circulating B cells and B cells differentiating into plamablasts and plasma cells, early (BZLF1)- and late viral antigen (gp350)-secreting-cells (SCs) were enumerated in six AIM patients and seven healthy EBV carriers. In vitro B-cell polyclonal activation induced 8000-24,000 BZLF1- and 1000-3000gp350-SCs/10(6) B cells, respectively. These data suggest that only 11.1-19.5% of cells expressing BZLF1 synthesized gp350 and so completed the EBV-lytic cycle. Furthermore, circulating spontaneous BZLF1- and gp350-SCs that reflect ongoing viral replication were rare (20-120 and 10-30/10(6) B cells, respectively), and their low numbers contrasted with the high levels of circulating plasma cells (1.1-10.2% of CD19(+) B cells). The in vivo terminal-B-cell differentiation into plasma cells could unmask EBV B-cell reservoir to specific cytotoxic T-cell response and combined with a predominant abortive functional-EBV-reservoir, strongly contribute to rapid decay of cellular EBV reservoir in AIM. Copyright © 2011 Elsevier B.V. All rights reserved.

Epstein-Barr Virus Type 2 Infects T Cells in Healthy Kenyan Children.

PubMed

Coleman, Carrie B; Daud, Ibrahim I; Ogolla, Sidney O; Ritchie, Julie A; Smith, Nicholas A; Sumba, Peter O; Dent, Arlene E; Rochford, Rosemary

2017-09-15

The 2 strains of Epstein-Barr virus (EBV), EBV type 1 (EBV-1) and EBV-2, differ in latency genes, suggesting that they use distinct mechanisms to establish latency. We previously reported that EBV-2 infects T cells in vitro. In this study, we tested the possibility that EBV-2 infects T cells in vivo. Purified T-cell fractions isolated from children positive for EBV-1 or EBV-2 and their mothers were examined for the presence of EBV and for EBV type. We detected EBV-2 in all T-cell samples obtained from EBV-2-infected children at 12 months of age, with some children retaining EBV-2-positive T cells through 24 months of age, suggesting that EBV-2 persists in T cells. We were unable to detect EBV-2 in T-cell samples from mothers but could detect EBV-2 in samples of their breast milk and saliva. These data suggest that EBV-2 uses T cells as an additional latency reservoir but that, over time, the frequency of infected T cells may drop below detectable levels. Alternatively, EBV-2 may establish a prolonged transient infection in the T-cell compartment. Collectively, these novel findings demonstrate that EBV-2 infects T cells in vivo and suggest EBV-2 may use the T-cell compartment to establish latency. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Infectious mononucleosis hepatitis in young adults: two case reports.

PubMed

Kang, Min-Jung; Kim, Tae-Hun; Shim, Ki-Nam; Jung, Sung-Ae; Cho, Min-Sun; Yoo, Kwon; Chung, Kyu Won

2009-12-01

Infectious mononucleosis due to Epstein-Barr virus (EBV) infection sometimes causes acute hepatitis, which is usually self-limiting with mildly elevated transaminases, but rarely with jaundice. Primary EBV infection in children is usually asymptomatic, but in a small number of healthy individuals, typically young adults, EBV infection results in a clinical syndrome of infectious mononucleosis with hepatitis, with typical symptoms of fever, pharyngitis, lymphadenopathy, and hepatosplenomegaly. EBV is rather uncommonly confirmed as an etiologic agent of acute hepatitis in adults. Here, we report two cases: the first case with acute hepatitis secondary to infectious mononucleosis and a second case, with acute hepatitis secondary to infectious mononucleosis concomitantly infected with hepatitis A. Both cases involved young adults presenting with fever, pharyngitis, lymphadenopathy, hepatosplenomegaly, and atypical lymphocytosis confirmed by serologic tests, liver biopsy and electron microscopic study.

Whole transcriptome profiling reveals major cell types in the cellular immune response against acute and chronic active Epstein-Barr virus infection.

PubMed

Zhong, Huaqing; Hu, Xinran; Janowski, Andrew B; Storch, Gregory A; Su, Liyun; Cao, Lingfeng; Yu, Jinsheng; Xu, Jin

2017-12-19

Epstein-Barr virus (EBV) is a common human pathogen that infects over 95% of the population worldwide. In the present study, the whole transcriptome microarray data were generated from peripheral blood mononuclear cells from Chinese children with acute infectious mononucleosis (AIM) and chronic active EBV infection (CAEBV) that were also compared with a publicly available microarray dataset from a study of American college students with AIM. Our study characterized for the first time a broad spectrum of molecular signatures in AIM and CAEBV. The key findings from the transcriptome profiling were validated with qPCR and flow cytometry assays. The most important finding in our study is the discovery of predominant γδ TCR expression and γδ T cell expansion in AIM. This finding, in combination with the striking up-regulation of CD3, CD8 and CD94, suggests that CD8+ T cells and CD94+ NK cells may play a major role in AIM. Moreover, the unique up-regulation of CD64A/B and its significant correlation with the monocyte marker CD14 was observed in CAEBV and that implies an important role of monocytes in CAEBV. In conclusion, our study reveals major cell types (particularly γδ T cells) in the host cellular immune response against AIM and CAEBV.

Comparison of the prognostic impact of serum anti-EBV antibody and plasma EBV DNA assays in nasopharyngeal carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Twu, C.-W.; Department of Otorhinolaryngology, Taichung Veterans General Hospital, Taichung; Wang, W.-Y.

Purpose: Nasopharyngeal carcinoma (NPC) has been proven as an Epstein-Barr virus (EBV)-associated cancer. Serum anti-EBV antibodies and plasma EBV DNA have been investigated as surrogate markers for NPC. A comparison of the prognostic impacts of both assays has never been reported. Methods and Materials: Paired serum and plasma samples from 114 previously untreated NPC patients were collected and subjected to an immunofluorescence assay for immunoglobulin (Ig)A and IgG antibodies against the viral capsid antigen (VCA) and a real-time quantitative polymerase chain reaction assay for EBV DNA measurement. The effects of both assays on patient prognosis were thoroughly investigated. Results: Relapsedmore » patients had significantly higher pretreatment EBV DNA concentration than patients without relapse (p 0.0006). No associations of VCA-IgA (p = 0.9669) or VCA-IgG (p = 0.6125) were observed between patients with and without relapse. The 4-year overall survival (60.3% vs. 93.1%, p < 0.0001) and relapse-free survival rates (54.4% vs. 77.9%, p = 0.0009) were significantly lower in patients with higher pretreatment EBV DNA load than in those with lower EBV DNA load. Patients with persistently detectable EBV DNA after treatment had significantly worse 4-year overall (30.8% vs. 84.6%, p < 0.0001) and relapse-free survival rates (15.4% vs. 74.0%, p < 0.0001) than those with undetectable EBV DNA. The VCA-IgA and VCA-IgG titer could not predict survivals (all p > 0.1). Cox multivariate analyses also showed the same results. Conclusion: Plasma EBV DNA is superior to serum EBV VCA antibodies in prognostic predictions for NPC.« less

Clinicopathological analysis of the age-related differences in patients with Epstein-Barr virus (EBV)-associated extranasal natural killer (NK)/T-cell lymphoma with reference to the relationship with aggressive NK cell leukaemia and chronic active EBV infection-associated lymphoproliferative disorders.

PubMed

Takahashi, Emiko; Ohshima, Koichi; Kimura, Hiroshi; Hara, Kazuo; Suzuki, Ritsuro; Kawa, Keisei; Eimoto, Tadaaki; Nakamura, Shigeo

2011-10-01

Extranodal natural killer (NK)/T-cell lymphoma (NKTL), comprising nasal NKTL and extranasal NKTL (ENKTL), is associated with Epstein-Barr virus (EBV). A bimodal age distribution was noted in NKTL patients. We examined the clinicopathological differences between two age groups of ENKTL patients (n = 23) and compared the findings with those of aggressive NK cell leukaemia (ANKL; n = 10) and monoclonal chronic active EBV infection-associated T/NK-cell lymphoproliferative disorders [chronic active EBV infection/TNK-lymphoproliferative disorders (CAEBV/TNK-LPD)] of NK-cell type (n = 45). Distinct differences existed between elderly (> 50 years; n = 13) and younger (≤ 50 years; n = 10) ENKTL patients; the latter showed a higher disease stage (P = 0.0286), worse performance status (P = 0.0244), more frequent B symptoms (P = 0.0286) and more frequent liver, spleen and bone marrow involvement (P = 0.0222, 0.0005 and 0.0259, respectively). Few clinicopathological differences existed between younger ENKTL and ANKL patients. Patients with monoclonal CAEBV/TNK-LPD of NK-cell type (n = 45) showed features similar to those in younger ENKTL/ANKL patients, except a more juvenile onset of CAEBV-related symptoms and better prognosis. However, the onset age of overt leukaemia/lymphoma in CAEBV/TNK-LPD patients and overall survival thereafter were similar to those in younger ENKTL/ANKL patients. ENKTL (≤ 50 years) is distinct from that in elderly patients and may encompass ANKL and overlap in the clinicopathological profile with NK-cell type CAEBV/TNK-LPD. 2011 Blackwell Publishing Limited.

EBNA3C Directs Recruitment of RBPJ (CBF1) to Chromatin during the Process of Gene Repression in EBV Infected B Cells.

PubMed

Kalchschmidt, Jens S; Gillman, Adam C T; Paschos, Kostas; Bazot, Quentin; Kempkes, Bettina; Allday, Martin J

2016-01-01

It is well established that Epstein-Barr virus nuclear antigen 3C (EBNA3C) can act as a potent repressor of gene expression, but little is known about the sequence of events occurring during the repression process. To explore further the role of EBNA3C in gene repression-particularly in relation to histone modifications and cell factors involved-the three host genes previously reported as most robustly repressed by EBNA3C were investigated. COBLL1, a gene of unknown function, is regulated by EBNA3C alone and the two co-regulated disintegrin/metalloproteases, ADAM28 and ADAMDEC1 have been described previously as targets of both EBNA3A and EBNA3C. For the first time, EBNA3C was here shown to be the main regulator of all three genes early after infection of primary B cells. Using various EBV-recombinants, repression over orders of magnitude was seen only when EBNA3C was expressed. Unexpectedly, full repression was not achieved until 30 days after infection. This was accurately reproduced in established LCLs carrying EBV-recombinants conditional for EBNA3C function, demonstrating the utility of the conditional system to replicate events early after infection. Using this system, detailed chromatin immunoprecipitation analysis revealed that the initial repression was associated with loss of activation-associated histone modifications (H3K9ac, H3K27ac and H3K4me3) and was independent of recruitment of polycomb proteins and deposition of the repressive H3K27me3 modification, which were only observed later in repression. Most remarkable, and in contrast to current models of RBPJ in repression, was the observation that this DNA-binding factor accumulated at the EBNA3C-binding sites only when EBNA3C was functional. Transient reporter assays indicated that repression of these genes was dependent on the interaction between EBNA3C and RBPJ. This was confirmed with a novel EBV-recombinant encoding a mutant of EBNA3C unable to bind RBPJ, by showing this virus was incapable of

Identification and characterization of EBV genomes in spontaneously immortalized human peripheral blood B lymphocytes by NGS technology.

PubMed

Lei, Haiyan; Li, Tianwei; Hung, Guo-Chiuan; Li, Bingjie; Tsai, Shien; Lo, Shyh-Ching

2013-11-19

We conducted genomic sequencing to identify Epstein Barr Virus (EBV) genomes in 2 human peripheral blood B lymphocytes that underwent spontaneous immortalization promoted by mycoplasma infections in culture, using the high-throughput sequencing (HTS) Illumina MiSeq platform. The purpose of this study was to examine if rapid detection and characterization of a viral agent could be effectively achieved by HTS using a platform that has become readily available in general biology laboratories. Raw read sequences, averaging 175 bps in length, were mapped with DNA databases of human, bacteria, fungi and virus genomes using the CLC Genomics Workbench bioinformatics tool. Overall 37,757 out of 49,520,834 total reads in one lymphocyte line (# K4413-Mi) and 28,178 out of 45,335,960 reads in the other lymphocyte line (# K4123-Mi) were identified as EBV sequences. The two EBV genomes with estimated 35.22-fold and 31.06-fold sequence coverage respectively, designated K4413-Mi EBV and K4123-Mi EBV (GenBank accession number KC440852 and KC440851 respectively), are characteristic of type-1 EBV. Sequence comparison and phylogenetic analysis among K4413-Mi EBV, K4123-Mi EBV and the EBV genomes previously reported to GenBank as well as the NA12878 EBV genome assembled from database of the 1000 Genome Project showed that these 2 EBVs are most closely related to B95-8, an EBV previously isolated from a patient with infectious mononucleosis and WT-EBV. They are less similar to EBVs associated with nasopharyngeal carcinoma (NPC) from Hong Kong and China as well as the Akata strain of a case of Burkitt's lymphoma from Japan. They are most different from type 2 EBV found in Western African Burkitt's lymphoma.

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

PubMed Central

Weiss, Eric R.; Alter, Galit; Ogembo, Javier Gordon; Henderson, Jennifer L.; Tabak, Barbara; Bakiş, Yasin; Somasundaran, Mohan; Garber, Manuel; Selin, Liisa

2016-01-01

ABSTRACT The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM. IMPORTANCE Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis.

PubMed

Weiss, Eric R; Alter, Galit; Ogembo, Javier Gordon; Henderson, Jennifer L; Tabak, Barbara; Bakiş, Yasin; Somasundaran, Mohan; Garber, Manuel; Selin, Liisa; Luzuriaga, Katherine

2017-01-01

The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM. Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a

Epstein-Barr Virus Infection of Polarized Epithelial Cells via the Basolateral Surface by Memory B Cell-Mediated Transfer Infection

PubMed Central

Shannon-Lowe, Claire; Rowe, Martin

2011-01-01

Epstein Barr virus (EBV) exhibits a distinct tropism for both B cells and epithelial cells. The virus persists as a latent infection of memory B cells in healthy individuals, but a role for infection of normal epithelial is also likely. Infection of B cells is initiated by the interaction of the major EBV glycoprotein gp350 with CD21 on the B cell surface. Fusion is triggered by the interaction of the EBV glycoprotein, gp42 with HLA class II, and is thereafter mediated by the core fusion complex, gH/gL/gp42. In contrast, direct infection of CD21-negative epithelial cells is inefficient, but efficient infection can be achieved by a process called transfer infection. In this study, we characterise the molecular interactions involved in the three stages of transfer infection of epithelial cells: (i) CD21-mediated co-capping of EBV and integrins on B cells, and activation of the adhesion molecules, (ii) conjugate formation between EBV-loaded B cells and epithelial cells via the capped adhesion molecules, and (iii) interaction of EBV glycoproteins with epithelial cells, with subsequent fusion and uptake of virions. Infection of epithelial cells required the EBV gH and gL glycoproteins, but not gp42. Using an in vitro model of normal polarized epithelia, we demonstrated that polarization of the EBV receptor(s) and adhesion molecules restricted transfer infection to the basolateral surface. Furthermore, the adhesions between EBV-loaded B cells and the basolateral surface of epithelial cells included CD11b on the B cell interacting with heparan sulphate moieties of CD44v3 and LEEP-CAM on epithelial cells. Consequently, transfer infection was efficiently mediated via CD11b-positive memory B cells but not by CD11b–negative naïve B cells. Together, these findings have important implications for understanding the mechanisms of EBV infection of normal and pre-malignant epithelial cells in vivo. PMID:21573183

Infectious Mononucleosis Hepatitis in Young Adults: Two Case Reports

PubMed Central

Kang, Min-Jung; Kim, Tae-Hun; Shim, Ki-Nam; Jung, Sung-Ae; Cho, Min-Sun; Yoo, Kwon

2009-01-01

Infectious mononucleosis due to Epstein-Barr virus (EBV) infection sometimes causes acute hepatitis, which is usually self-limiting with mildly elevated transaminases, but rarely with jaundice. Primary EBV infection in children is usually asymptomatic, but in a small number of healthy individuals, typically young adults, EBV infection results in a clinical syndrome of infectious mononucleosis with hepatitis, with typical symptoms of fever, pharyngitis, lymphadenopathy, and hepatosplenomegaly. EBV is rather uncommonly confirmed as an etiologic agent of acute hepatitis in adults. Here, we report two cases: the first case with acute hepatitis secondary to infectious mononucleosis and a second case, with acute hepatitis secondary to infectious mononucleosis concomitantly infected with hepatitis A. Both cases involved young adults presenting with fever, pharyngitis, lymphadenopathy, hepatosplenomegaly, and atypical lymphocytosis confirmed by serologic tests, liver biopsy and electron microscopic study. PMID:19949739

Evaluation of the presence of Epstein-Barr virus (EBV) in Iranian patients with thyroid papillary carcinoma.

PubMed

Homayouni, Maryam; Mohammad Arabzadeh, Seyed Ali; Nili, Fatemeh; Razi, Farideh; Amoli, Mahsa Mohammad

2017-07-01

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. EBV is one of the most important viruses related to different types of malignancies. This study investigated the relationship between EBV and papillary thyroid carcinoma. In this study the presence of Epstein-Barr Nuclear Antigen 1 (EBNA1) gene in papillary thyroid carcinoma tissues were examined by nested-PCR method. Paraffin-embedded tissues (N=41) blocks of thyroid cancer were used. DNA was extracted from all samples and then samples were evaluated for the presence of EBV gene. In 41 samples, EBNA1 was detected in 65.8% of patients with papillary thyroid carcinoma which was significantly higher in younger ages. The significant presence of EBV genome in papillary thyroid carcinoma suggests that this virus may play a role in this cancer especially in younger ages. As a result, monitoring of patients with EBV latent infection for PTC can be very important. Copyright © 2017 Elsevier GmbH. All rights reserved.

Clinicopathological characteristics of four cases of EBV positive T-cell lymphoproliferative disorders of childhood in China

PubMed Central

Huang, Wenting; Lv, Ning; Ying, Jianming; Qiu, Tian; Feng, Xiaoli

2014-01-01

A new category, “EBV positive T-cell lymphoproliferative disorders (LPD) of childhood”, was proposed in the 2008 World Health Organization’s (WHO) classifications of lymphoma. This series of lymphoproliferative disorders is rare. There are two major types of this series of disorders: systemic EBV positive T-cell LPD of childhood and hydroa vacciniforme-like lymphoma (HVLL). In this study, we describe the distinct features of four cases of EBV positive T-cell LPD of childhood in China. Two were systemic EBV positive T-cell LPD of childhood, one was HVLL and one was chronic active EBV (CAEBV). The main manifestations were lymphadenopathy, fever, hepatosplenomegaly and skin rashes. The structure of the lymph nodes in the patients ranged from preserved to partially or totally destroyed. Small- to medium-sized, atypical T cells had infiltrated the lymph nodes. In HVLL, the neoplastic cells had infiltrated the dermis and subcutaneous region surrounding sweat glands and nerves. All of the cases tested positive for CD8, other T cells, cytotoxic markers and EBV-encoded RNA (EBER) without CD56 expression. Molecular analysis was performed in three cases. All of the three analyses showed a TCRγ rearrangement and one case also had an IGH rearrangement. One of the patients with systemic EBV positive T-cell LPD of childhood experienced rapid evolved and died within five months of onset. CAEBV, systemic EBV-positive T-cell LPD of childhood and HVLL are distinct but overlapping diseases within the category of EBV-positive T-cell LPD of childhood. They constitute a continuous spectrum of EBV-infected associated disorders. PMID:25197370

Multiple Epstein-Barr virus infections in healthy individuals

NASA Technical Reports Server (NTRS)

Walling, Dennis M.; Brown, Abigail L.; Etienne, Wiguins; Keitel, Wendy A.; Ling, Paul D.; Butel, J. S. (Principal Investigator)

2003-01-01

We employed a newly developed genotyping technique with direct representational detection of LMP-1 gene sequences to study the molecular epidemiology of Epstein-Barr virus (EBV) infection in healthy individuals. Infections with up to five different EBV genotypes were found in two of nine individuals studied. These results support the hypothesis that multiple EBV infections of healthy individuals are common. The implications for the development of an EBV vaccine are discussed.

Unexplained Dyspnea in a Young Adult with Epstein–Barr Virus Infectious Mononucleosis: Pulmonary Involvement or Co-Infection with Mycoplasma pneumoniae Pneumonia?

PubMed Central

Cunha, Burke A.; Herrarte Fornos, Scarlet

2017-01-01

Clinically, in young immunocompetent adults, Epstein-Barr virus (EBV) usually manifests as infectious mononucleosis (IM). Typical clinical findings of EBV IM include fever, profound fatigue, pharyngitis, bilateral posterior cervical adenopathy, and splenomegaly. Respiratory involvement with EBV IM may occur, but is distinctly rare. We present a case of a 20 year old female who with classic EBV IM, but was inexplicably dyspneic and hypoxemic. Further diagnostic testing confirmed co-infection with Mycoplasma pneumoniae. As a non-zoonotic atypical community-acquired pneumonia (CAP), M. pneumoniae may rarely be accompanied by severe hypoxemia and even acute respiratory distress syndrome. She represented a diagnostic dilemma regarding the cause of her hypoxemia, i.e., due to EBV IM with pulmonary involvement or severe M. pneumoniae CAP. The patient slowly recovered with respiratory quinolone therapy. PMID:28869530

Unexplained Dyspnea in a Young Adult with Epstein-Barr Virus Infectious Mononucleosis: Pulmonary Involvement or Co-Infection with Mycoplasma pneumoniae Pneumonia?

PubMed

Cunha, Burke A; Herrarte Fornos, Scarlet

2017-09-04

Clinically, in young immunocompetent adults, Epstein-Barr virus (EBV) usually manifests as infectious mononucleosis (IM). Typical clinical findings of EBV IM include fever, profound fatigue, pharyngitis, bilateral posterior cervical adenopathy, and splenomegaly. Respiratory involvement with EBV IM may occur, but is distinctly rare. We present a case of a 20 year old female who with classic EBV IM, but was inexplicably dyspneic and hypoxemic. Further diagnostic testing confirmed co-infection with Mycoplasma pneumoniae . As a non-zoonotic atypical community-acquired pneumonia (CAP), M. pneumoniae may rarely be accompanied by severe hypoxemia and even acute respiratory distress syndrome. She represented a diagnostic dilemma regarding the cause of her hypoxemia, i.e., due to EBV IM with pulmonary involvement or severe M. pneumoniae CAP. The patient slowly recovered with respiratory quinolone therapy.

Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires.

PubMed

Aslan, Nuray; Watkin, Levi B; Gil, Anna; Mishra, Rabinarayan; Clark, Fransenio G; Welsh, Raymond M; Ghersi, Dario; Luzuriaga, Katherine; Selin, Liisa K

2017-12-05

Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M1 58 (IAV-M1) and EBV BMLF1 280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer + frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer + cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link heterologous immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter. IMPORTANCE The pathogenic impact of immune responses that by chance cross-react to unrelated

Coinfection with Epstein–Barr Virus (EBV), Human Papilloma Virus (HPV) and Polyoma BK Virus (BKPyV) in Laryngeal, Oropharyngeal and Oral Cavity Cancer

PubMed Central

Drop, Bartłomiej; Strycharz-Dudziak, Małgorzata; Kliszczewska, Ewa; Polz-Dacewicz, Małgorzata

2017-01-01

Most research providing evidence for the role of oncogenic viruses in head and neck squamous cell carcinoma (SCC) development is focused on one type of virus without analyzing possible interactions between two or more types of viruses. The aim of this study was to analyse the prevalence of co-infection with human papillomavirus (HPV), Epstein–Barr virus (EBV) and polyoma BK virus (BKPyV) in oral, oropharyngeal and laryngeal squamous cell carcinomas in Polish patients. The correlations between viral infection, SCC, demographic parameters, evidence of metastases and grading were also investigated. Fresh-frozen tumour tissue samples were collected from 146 patients with laryngeal, oropharyngeal and oral cancer. After DNA extraction, the DNA of the studied viruses was detected using polymerase chain rection (PCR) assay. Males (87.7%) with a history of smoking (70.6%) and alcohol abuse (59.6%) prevailed in the studied group. Histological type G2 was recognized in 64.4% cases. The patients were most frequently diagnosed with T2 stage (36.3%) and with N1 stage (45.8%). Infection with at least two viruses was detected in 56.2% of patients. In this group, co-infection with HPV/EBV was identified in 34.1% of cases, EBV/BKV in 23.2%, HPV/BKV in 22.0%, and HPV/EBV/BKV in 20.7%. No difference of multiple infection in different locations of cancer was observed. The prevalence of poorly differentiated tumours (G3) was more frequent in co-infection with all three viruses than EBV or BKV alone. A significant correlation was observed between tumour dimensions (T) and lymph-node involvement (N) in co-infected patients compared to single infection. Further studies are necessary to clarify whether co-infection plays an important role in the initiation and/or progression of oncogenic transformation of oral, oropharyngeal and laryngeal epithelial cells. PMID:29257122

Coinfection with Epstein-Barr Virus (EBV), Human Papilloma Virus (HPV) and Polyoma BK Virus (BKPyV) in Laryngeal, Oropharyngeal and Oral Cavity Cancer.

PubMed

Drop, Bartłomiej; Strycharz-Dudziak, Małgorzata; Kliszczewska, Ewa; Polz-Dacewicz, Małgorzata

2017-12-19

Most research providing evidence for the role of oncogenic viruses in head and neck squamous cell carcinoma (SCC) development is focused on one type of virus without analyzing possible interactions between two or more types of viruses. The aim of this study was to analyse the prevalence of co-infection with human papillomavirus (HPV), Epstein-Barr virus (EBV) and polyoma BK virus (BKPyV) in oral, oropharyngeal and laryngeal squamous cell carcinomas in Polish patients. The correlations between viral infection, SCC, demographic parameters, evidence of metastases and grading were also investigated. Fresh-frozen tumour tissue samples were collected from 146 patients with laryngeal, oropharyngeal and oral cancer. After DNA extraction, the DNA of the studied viruses was detected using polymerase chain rection (PCR) assay. Males (87.7%) with a history of smoking (70.6%) and alcohol abuse (59.6%) prevailed in the studied group. Histological type G2 was recognized in 64.4% cases. The patients were most frequently diagnosed with T2 stage (36.3%) and with N1 stage (45.8%). Infection with at least two viruses was detected in 56.2% of patients. In this group, co-infection with HPV/EBV was identified in 34.1% of cases, EBV/BKV in 23.2%, HPV/BKV in 22.0%, and HPV/EBV/BKV in 20.7%. No difference of multiple infection in different locations of cancer was observed. The prevalence of poorly differentiated tumours (G3) was more frequent in co-infection with all three viruses than EBV or BKV alone. A significant correlation was observed between tumour dimensions (T) and lymph-node involvement (N) in co-infected patients compared to single infection. Further studies are necessary to clarify whether co-infection plays an important role in the initiation and/or progression of oncogenic transformation of oral, oropharyngeal and laryngeal epithelial cells.

Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students.

PubMed

Balfour, Henry H; Odumade, Oludare A; Schmeling, David O; Mullan, Beth D; Ed, Julie A; Knight, Jennifer A; Vezina, Heather E; Thomas, William; Hogquist, Kristin A

2013-01-01

University students were studied prospectively to determine the incidence of and risk factors for acquisition of primary Epstein-Barr virus (EBV) infection and the virologic and immune correlates of disease severity. EBV antibody-negative freshmen participated in monthly surveillance until graduation. If antibodies developed, proximate samples were assayed for viral load by polymerase chain reaction. Lymphocyte and natural killer (NK) cell numbers and activation were measured by flow cytometry, and plasma cytokine levels were measured by a multiplex assay. Of 546 students screened, 202 (37%) were antibody negative; 143 antibody-negative students were enrolled. During a median of 3 years of observation, 66 subjects experienced primary infection. Of these, 77% had infectious mononucleosis, 12% had atypical symptoms, and 11% were asymptomatic. Subjects reporting deep kissing with or without coitus had the same higher risk of infection than those reporting no kissing (P < .01). Viremia was transient, but median oral shedding was 175 days. Increases were observed in numbers of NK cells and CD8(+) T-cells but not in numbers of CD4(+) T-cells during acute infection. Severity of illness correlated positively with both blood EBV load (P = .015) and CD8(+) lymphocytosis (P = .0003). Kissing was a significant risk for primary EBV infection. A total of 89% of infections were symptomatic, and blood viral load and CD8(+) lymphocytosis correlated with disease severity.

Comparison of EBV DNA viral load in whole blood, plasma, B-cells and B-cell culture supernatant.

PubMed

Ouedraogo, David Eric; Bollore, Karine; Viljoen, Johannes; Foulongne, Vincent; Reynes, Jacques; Cartron, Guillaume; Vendrell, Jean-Pierre; Van de Perre, Philippe; Tuaillon, Edouard

2014-05-01

Epstein-Barr virus (EBV) genome quantitation in whole blood is used widely for therapeutic monitoring of EBV-associated disorders in immunosuppressed individuals and in patients with EBV-associated lymphoma. However, the most appropriate biological material to be used for EBV DNA quantitation remains a subject of debate. This study compare the detection rate and levels of EBV DNA from whole blood, plasma, enriched B-cells, and B-cell short-term culture supernatant using quantitative real-time PCR. Samples were collected from 33 subjects with either HIV infection or B-cell lymphoma. Overall, EBV DNA was detected in 100% of enriched B-cell samples, in 82% of B-cell culture supernatants, in 57% of plasma, and 42% of whole blood samples. A significant correlation for EBV viral load was found between enriched B-cell and B-cell culture supernatant material (ρ = 0.92; P < 0.0001), but no significant correlation existed between EBV DNA levels in whole blood and enriched B-cells (ρ = -0.02; P = 0.89), whole blood and plasma (ρ = 0.24; P = 0.24), or enriched B-cells and plasma (ρ = 0.08; P = 0.77). Testing of enriched B-cells appeared to be the most sensitive method for detection of EBV DNA as well as for exploration of the cellular reservoir. Quantitation of EBV DNA in plasma and B-cell culture supernatant may be of interest to assess EBV reactivation dynamics and response to treatment as well as to decipher EBV host-pathogen interactions in various clinical scenarios. © 2013 Wiley Periodicals, Inc.

Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires

PubMed Central

Aslan, Nuray; Watkin, Levi B.; Gil, Anna; Mishra, Rabinarayan; Clark, Fransenio G.; Welsh, Raymond M.; Ghersi, Dario; Luzuriaga, Katherine

2017-01-01

ABSTRACT Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M158 (IAV-M1) and EBV BMLF1280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer+ frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer+ cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link heterologous immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter. PMID:29208744

Healthy rabbits are susceptible to Epstein-Barr virus infection and infected cells proliferate in immunosuppressed animals.

PubMed

Khan, Gulfaraz; Ahmed, Waqar; Philip, Pretty S; Ali, Mahmoud H; Adem, Abdu

2015-02-18

Epstein-Barr virus (EBV) is an oncogenic virus implicated in the pathogenesis of several human malignancies. However, due to the lack of a suitable animal model, a number of fundamental questions pertaining to the biology of EBV remain poorly understood. Here, we explore the potential of rabbits as a model for EBV infection and investigate the impact of immunosuppression on viral proliferation and gene expression. Six healthy New Zealand white rabbits were inoculated intravenously with EBV and blood samples collected prior to infection and for 7 weeks post-infection. Three weeks after the last blood collection, animals were immunosuppressed with daily intramuscular injections of cyclosporin A at doses of 20 mg/kg for 15 days and blood collected twice a week from each rabbit. The animals were subsequently sacrificed and tissues from all major organs were collected for subsequent analysis. Following intravenous inoculation, all 6 rabbits seroconverted with raised IgG and IgM titres to EBV, but viral DNA in peripheral blood mononuclear cells (PBMCs) could only be detected intermittently. Following immunosuppression however, EBV DNA could be readily detected in PBMCs from all 4 rabbits that survived the treatment. Quantitative PCR indicated an increase in EBV viral load in PBMCs as the duration of immunosuppression increased. At autopsy, splenomegaly was seen in 3/4 rabbits, but spleens from all 4 rabbit were EBV PCR positive. EBER-in situ hybridization and immunoshistochemistry revealed the presence of a large number of EBER-positive and LMP-1 positive lymphoblasts in the spleens of 3/4 rabbits. To a lesser extent, EBER-positive cells were also seen in the portal tract regions of the liver of these rabbits. Western blotting indicated that EBNA-1 and EBNA-2 were also expressed in the liver and spleen of infected animals. EBV can infect healthy rabbits and the infected cells proliferate when the animals are immunocompromised. The infected cells expressed several EBV

Frequency of EBV associated classical Hodgkin lymphoma decreases over a 54-year period in a Brazilian population.

PubMed

Campos, Antonio Hugo Jose Froes Marques; Moreira, Adriana; Ribeiro, Karina Braga; Paes, Roberto Pinto; Zerbini, Maria Claudia; Aldred, Vera; de Souza, Carmino Antonio; Neto, Cristovam Scapulatempo; Soares, Fernando Augusto; Vassallo, Jose

2018-01-30

The epidemiology of classical Hodgkin lymphoma varies significantly in populations with different socioeconomic conditions. Among other changes, improvement in such conditions leads to a reduction in the association with EBV infection and predominance of the nodular sclerosis subtype. This study provides an overview of the epidemiology of 817 cases of classical Hodgkin lymphoma diagnosed in five reference hospitals of the State of Sao Paulo, Brazil, over 54 years (1954-2008). The cases were distributed in 3 periods (1954-1979; 1980-1999; and 2000-2008). EBV-positive cases decreased from 87% to 46%. In children and adolescents (<15 years) and in young adults (15-45 years), EBV-positive cases decreased respectively from 96% to 64%, and from 85% to 32%. The percentage of male patients declined from 80% to 58%. In older patients (>45 years), the decrease in EBV infection was not significant. Nodular Sclerosis was the most common subtype in all periods. These results support the hypothesis that, in the Brazilian State of Sao Paulo, classical Hodgkin lymphoma has changed and now shows characteristics consistent with Pattern III observed in populations that experienced a similar socioeconomic transition.

Severe Epstein-Barr virus infection in primary immunodeficiency and the normal host.

PubMed

Worth, Austen J J; Houldcroft, Charlotte J; Booth, Claire

2016-11-01

Epstein-Barr virus (EBV) infection is ubiquitous in humans, but the majority of infections have an asymptomatic or self-limiting clinical course. Rarely, individuals may develop a pathological EBV infection with a variety of life threatening complications (including haemophagocytosis and malignancy) and others develop asymptomatic chronic EBV viraemia. Although an impaired ability to control EBV infection has long been recognised as a hallmark of severe T-cell immunodeficiency, the advent of next generation sequencing has identified a series of Primary Immunodeficiencies in which EBV-related pathology is the dominant feature. Chronic active EBV infection is defined as chronic EBV viraemia associated with systemic lymphoproliferative disease, in the absence of immunodeficiency. Descriptions of larger cohorts of patients with chronic active EBV in recent years have significantly advanced our understanding of this clinical syndrome. In this review we summarise the current understanding of the pathophysiology and natural history of these diseases and clinical syndromes, and discuss approaches to the investigation and treatment of severe or atypical EBV infection. © 2016 John Wiley & Sons Ltd.

The Definition of Epstein Barr Virus (EBV)’s Role in HTLV-III Infected USAF Personnel as Related to Disease Progression

DTIC Science & Technology

1989-04-15

pathologic tissues: prevalence and titer of infectious EBV according to a transformation assay (8, 9), prevalence and quantity of EBV - DNA by spot...containing EBV - DNA were also reported in increased frequency in homosexuals and AIDS patients (3). This latter finding is being noted moreso, possibly as a...digestions (11). In addition, the concomitant presence of inLitr. HIV-l antigen and infectious virus was searched for in established EBV cell cultures

EGCG debilitates the persistence of EBV latency by reducing the DNA binding potency of nuclear antigen 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Ya-Lin; Tsai, Hsing-Lyn; Peng, Chih-Wen, E-mail: pengcw@mail.tcu.edu.tw

Highlights: Black-Right-Pointing-Pointer Two cell-based reporter platforms were established for screening of EBNA1 inhibitors. Black-Right-Pointing-Pointer EGCG acts as an inhibitor to block EBNA1 binding with the cognate oriP sequence. Black-Right-Pointing-Pointer EGCG debilitates EBNA1-dependent transcription enhancement and episome maintenance. Black-Right-Pointing-Pointer EGCG impairs persistence of EBV latency. Black-Right-Pointing-Pointer EGCG is a potent anti-EBV agent for targeting the latent cascade of EBV. -- Abstract: Because the expression of EBNA1 is prevalent in all EBV-associated tumors, it has become one of the most attractive drug targets for the discovery of anti-EBV compounds. In a cell-based reporter system, EBNA1 consistently upregulated the transcription of an oriP-Lucmore » mini-EBV episome by 6- to 8-fold. The treatment of cells with 50 {mu}M EGCG effectively blocked the binding of EBNA1 to oriP-DNA both in vivo and in vitro, which led to the abrogation of EBNA1-dependent episome maintenance and transcriptional enhancement. Importantly, the anti-EBNA1 effects caused by EGCG ultimately impaired the persistence of EBV latent infection. Our data suggest that the inhibition of EBNA1 activity by EGCG could be a promising starting point for the development of new protocols for anti-EBV therapy.« less

[Molecular tests in diagnosis of Cytomegalovirus (CMV), human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) using real-time PCR in HIV positive and HIV-negative pregnant women in Ouagadougou, Burkina Faso].

PubMed

Ouedraogo, Alice Rogomenoma; Kabre, Madeleine; Bisseye, Cyrille; Zohoncon, Théodora Mahoukèdè; Asshi, Maleki; Soubeiga, Serge Théophile; Diarra, Birama; Traore, Lassina; Djigma, Florencia Wendkuuni; Ouermi, Djénéba; Pietra, Virginio; Barro, Nicolas; Simpore, Jacques

2016-01-01

Herpesvirus EBV, CMV and HHV-6 are viruses that evolve based on pandemic modeling and are responsible for congenital infections causing severe sequelae in infants. This study aims to determine the prevalence of CMV, EBV and HHV-6 among HIV (+) and HIV (-) pregnant women in Ouagadougou. In this study 200 blood plasma samples taken from pregnant women, of whom 100 with HIV(+) and 100 with HIV(-), were analyzed using multiplex real-time PCR which detected three infections (EBV, CMV and HHV-6). Out of the 200 samples tested, 18(9.0%) were positive for at least one of the three viruses, 12(6.0%) were positive for EBV, 13(6.5%) were positive for CMV and 12(6.0%) were positive for HHV-6. Among the 18 cases with infections, 10 cases (55.6%) had co-infections of whom 90.0% (9/10) with multiple EBV/CMV/HHV6 infection and 10.0% with EBV/HHV6 co-infection. HHVs infection rate was higher among HIV (-) pregnant women than among HIV (+) pregnant women (12.0% versus 6.0%). Among HIV (+) pregnant women, PCR showed 7.1% (6/85) of HHVs infection in patients who were not treated with ARV against 0% in those treated with ARVs. Herpes virus infections are a common condition in pregnant women in Burkina Faso. They may represent a real threat to pregnant women because of complications and risks of infection in infants.

Humanized Mouse Models of Epstein-Barr Virus Infection and Associated Diseases

PubMed Central

Fujiwara, Shigeyoshi; Matsuda, Go; Imadome, Ken-Ichi

2013-01-01

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus infecting more than 90% of the adult population of the world. EBV is associated with a variety of diseases including infectious mononucleosis, lymphoproliferative diseases, malignancies such as Burkitt lymphoma and nasopharyngeal carcinoma, and autoimmune diseases including rheumatoid arthritis (RA). EBV in nature infects only humans, but in an experimental setting, a limited species of new-world monkeys can be infected with the virus. Small animal models, suitable for evaluation of novel therapeutics and vaccines, have not been available. Humanized mice, defined here as mice harboring functioning human immune system components, are easily infected with EBV that targets cells of the hematoimmune system. Furthermore, humanized mice can mount both cellular and humoral immune responses to EBV. Thus, many aspects of human EBV infection, including associated diseases (e.g., lymphoproliferative disease, hemophagocytic lymphohistiocytosis and erosive arthritis resembling RA), latent infection, and T-cell-mediated and humoral immune responses have been successfully reproduced in humanized mice. Here we summarize recent achievements in the field of humanized mouse models of EBV infection and show how they have been utilized to analyze EBV pathogenesis and normal and aberrant human immune responses to the virus. PMID:25436886

Diagnostic dilemma: Epstein-Barr virus (EBV) infectious mononucleosis with lung involvement or co-infection with Legionnaire's disease?

PubMed

Cunha, Burke A; Gian, John

Hospitalized adults with fever and "pneumonia" can be a difficult diagnostic challenge particularly when the clinical findings may be due to different infectious diseases. We recently had an elderly female who presented with fever, fatigue and dry cough with elevated serum transaminases and lung infiltrates. The diagnosis of Epstein-Barr virus (EBV) infectious mononucleosis (IM) was made based on a positive Monospot test, elevated EBV VCA IgM titer, and highly elevated EBV viral load. Her chest infiltrates were not accompanied by hilar adenopathy which may occur with EBV IM. Her dry cough persisted and she developed abdominal pain. Legionnaire's disease was considered because she had extra-pulmonary findings characteristic of Legionnaire's disease, e.g., relative bradycardia, abdominal pain, hyponatremia, hypophosphatemia, elevated ferritin levels, microscopic hematuria. Legionella titers were negative, but Legionella (serogroup 1) urinary antigen was positive. We present a diagnostic dilemma in an elderly female with both Legionnaire's disease and Epstein-Barr virus infectious mononucleosis with pulmonary involvement. Copyright © 2016 Elsevier Inc. All rights reserved.

Mice with Reconstituted Human Immune System Components as a Tool to Study Immune Cell Interactions in EBV Infection.

PubMed

Heuts, Frank; Nagy, Noemi

2017-01-01

Recent developments in mouse models that harbor part of a human immune system have proved extremely valuable to study the in vivo immune response to human specific pathogens such as Epstein-Barr virus. Over the last decades, advances in immunodeficient mouse strains that can be used as recipients for human immune cells have greatly enhanced the use of these models. Here, we describe the generation of mice with reconstituted human immune system (HIS mice) using immunocompromised mice transplanted with human CD34 + hematopoietic stem cells. We will also describe how such mice, in which human immune cells are generated de novo, can be used to study EBV infection.

Epstein–Barr Virus: Diseases Linked to Infection and Transformation

PubMed Central

Jha, Hem C.; Pei, Yonggang; Robertson, Erle S.

2016-01-01

Epstein–Barr virus (EBV) was first discovered in 1964, and was the first known human tumor virus now shown to be associated with a vast number of human diseases. Numerous studies have been conducted to understand infection, propagation, and transformation in various cell types linked to human diseases. However, a comprehensive lens through which virus infection, reactivation and transformation of infected host cells can be visualized is yet to be formally established and will need much further investigation. Several human cell types infected by EBV have been linked to associated diseases. However, whether these are a direct result of EBV infection or indirectly due to contributions by additional infectious agents will need to be fully investigated. Therefore, a thorough examination of infection, reactivation, and cell transformation induced by EBV will provide a more detailed view of its contributions that drive pathogenesis. This undoubtedly expand our knowledge of the biology of EBV infection and the signaling activities of targeted cellular factors dysregulated on infection. Furthermore, these insights may lead to identification of therapeutic targets and agents for clinical interventions. Here, we review the spectrum of EBV-associated diseases, the role of the encoded latent antigens, and the switch to latency or lytic replication which occurs in EBV infected cells. Furthermore, we describe the cellular processes and critical factors which contribute to cell transformation. We also describe the fate of B-cells and epithelial cells after EBV infection and the expected consequences which contribute to establishment of viral-associated pathologies. PMID:27826287

Epstein-Barr virus (EBV) load in cerebrospinal fluid and peripheral blood of patients with EBV-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

PubMed

Liu, Q-F; Ling, Y-W; Fan, Z-P; Jiang, Q-L; Sun, J; Wu, X-L; Zhao, J; Wei, Q; Zhang, Y; Yu, G-P; Wu, M-Q; Feng, R

2013-08-01

To evaluate the diagnostic and prognostic utility of monitoring the Epstein-Barr virus (EBV) load in the cerebrospinal fluid (CSF) and peripheral blood for the patients with EBV-associated central nervous system (CNS) diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT), 172 patients undergoing allo-HSCT were enrolled in the study. The EBV DNA levels of blood were monitored regularly in recipients of transplants for 3 years post transplantation. The EBV DNA levels of CSF were monitored in patients with EBV-associated CNS diseases before the treatment and at different points following the treatment. Post-transplant EBV-associated diseases developed in 27 patients, including 12 patients with EBV-associated CNS diseases. The 3-year cumulative incidences of EBV-associated diseases and EBV-associated CNS diseases were 19.5 ± 3.5% and 8.6 ± 2.4%, respectively. Patients with EBV-associated diseases showed higher loads of EBV DNA in their blood compared with patients with EBV DNA-emia. No difference was seen between the EBV DNA levels of blood in patients with CNS involvement and patients without CNS involvement. The EBV DNA loads of blood increased 3-14 days before the clinical manifestations of EBV-associated diseases emerged. The EBV DNA loads of CSF were higher than that of blood in patients with EBV-associated CNS diseases. In 12 patients with EBV-associated CNS diseases, EBV DNA levels were declining in both blood and CSF with the control of diseases, and the EBV DNA loads of CSF decreased faster than that of blood in 5 patients who responded to treatment, and the EBV DNA levels of CSF increased in 5 patients who were unresponsive to treatment. On multivariate analysis, the use of anti-thymocyte globulin and intensified conditioning regimens were independent risk factors for EBV-associated diseases and EBV-associated CNS diseases. EBV-associated CNS diseases are not rare after allo-HSCT. The EBV DNA loads of CSF could act as an important

Chronic active Epstein-Barr virus infection mimicking Henoch-Schönlein purpura.

PubMed

Guissa, Vanessa R; Aragão, Paula A; Marques, Heloisa H; Jacob, Cristina M; Silva, Clovis A

2010-01-01

Chronic active Epstein-Barr virus (CAEBV) infection is characterized by chronic or recurrent symptoms for at least 3 months, such as fever, hepatosplenomegaly and lymphadenopathy. The diagnosis is established due to the presence of anti-EBV antibodies or isolation of this infectious agent in affected tissues. Three cases of CAEBV infection mimicking Henoch-Schönlein purpura (HSP) were described. CASE 1: Female 3-year old patient with cervical adenomegaly, anemia and fever developed palpable purpura, haematuria and arthritis. CAEBV infection was established by serology test. She received methylprednisolone and acyclovir. She had generalized lymphadenopathy, hepatomegaly, splenomegaly, disseminated intravascular coagulation and deceased. CASE 2: Male 12-year old patient with persistent anemia, lymphadenopathy, hepatomegaly and splenomegaly had CAEBV infection diagnosis by serology test. He developed purpura and arthritis and received methylprednisolone. CASE 3: Male 13-year old patient had purpura, abdominal pain, haematuria, hepatomegaly, splenomegaly, lymphadenopathy, anemia and elevated liver enzymes. The cervical lymph node biopsy was positive to EBV infection. He received methylprednisolone and acyclovir, developing acute fulminant hepatitis and death. CAEBV infection mimicking HSP was rarely observed in our population.

Telomerase Activity Impacts on Epstein-Barr Virus Infection of AGS Cells

PubMed Central

Rac, Jürgen; Haas, Florian; Schumacher, Andrina; Middeldorp, Jaap M.; Delecluse, Henri-Jacques; Speck, Roberto F.

2015-01-01

The Epstein-Barr virus (EBV) is transmitted from host-to-host via saliva and is associated with epithelial malignancies including nasopharyngeal carcinoma (NPC) and some forms of gastric carcinoma (GC). Nevertheless, EBV does not transform epithelial cells in vitro where it is rapidly lost from infected primary epithelial cells or epithelial tumor cells. Long-term infection by EBV, however, can be established in hTERT-immortalized nasopharyngeal epithelial cells. Here, we hypothesized that increased telomerase activity in epithelial cells enhances their susceptibility to infection by EBV. Using HONE-1, AGS and HEK293 cells we generated epithelial model cell lines with increased or suppressed telomerase activity by stable ectopic expression of hTERT or of a catalytically inactive, dominant negative hTERT mutant. Infection experiments with recombinant prototypic EBV (rB95.8), recombinant NPC EBV (rM81) with increased epithelial cell tropism compared to B95.8, or recombinant B95.8 EBV with BZLF1-knockout that is not able to undergo lytic replication, revealed that infection frequencies positively correlate with telomerase activity in AGS cells but also partly depend on the cellular background. AGS cells with increased telomerase activity showed increased expression mainly of latent EBV genes, suggesting that increased telomerase activity directly acts on the EBV infection of epithelial cells by facilitating latent EBV gene expression early upon virus inoculation. Thus, our results indicate that infection of epithelial cells by EBV is a very selective process involving, among others, telomerase activity and cellular background to allow for optimized host-to-host transmission via saliva. PMID:25856387

L-Asparaginase monotherapy for EBV-positive T/NK lymphoproliferative diseases: A pilot Study.

PubMed

Jinta, Minako; Imadome, Ken-Ichi; Komatsu, Honami; Yoshimori, Mayumi; Kurata, Morito; Fujiwara, Shigeyoshi; Miura, Osamu; Arai, Ayako

2015-03-30

We investigated the effects of L-asparaginase (L-asp) on Epstein-Barr virus (EBV)-positive T/NK lymphoproliferative diseases (EBV-T/ NK-LPDs). Seven doses of L-asp (6,000 U/m2) were administered intravenously, with one dose administered on every alternate day. Five consecutive patients were enrolled. Three patients completed the treatment. The clinical symptoms resolved in 1 patient who started the administration 8 months after the onset, being the earliest among the 5 patients. Her EBV-DNA level in whole blood markedly decreased to 0.08 times of that before treatment, and the level in plasma became undetectable. In the other 2 patients whose administration was started 3 and 3.5 years after the onset, however, a remarkable improvement was not detected. Treatment was discontinued in 2 patients because of disease progression or idiopathic dystonia. The mRNA levels of asparagine synthetase in EBV-infected cells were examined. The level from the patient who responded to L-asp treatment was low, but it did not correlate with the effects in the other patients. Liver dysfunction (grades 2 and 3) was observed in 2 patients and neutropenia (grade 3) was noted in 1 patient. In conclusion, the effect of L-asp as monotherapy in EBV-T/NK-LPDs is limited, and early treatment initiation might be effective.

[Immunodeficiency and carcinogenesis in patients with chronic active Epstein-Barr virus infection].

PubMed

Nagafuchi, S; Fujisaki, T; Ohshima, K; Anzai, K; Otsuka, T; Kikuchi, H; Nasu, M; Kikuchi, M; Sawae, Y; Niho, Y

1997-01-01

Three adult patients with chronic active Epstein-Barr virus infection (CAEBV) had high anti-EBV-VCA antibody, positive anti-EA, low anti-EBNA and were associated with systemic lymphadenopathies and immunosuppression. The case 1 and 2 had elevated serum immunoglobulin levels, and recurrent infections, and case 3 showed pancytopenia. These 3 cases developed both EBV and latent membrane protein (LMP) positive malignant histiocytosis, EBV positive but LMP negative plasmacytoma, and EBV negative acute myelogeneous leukemia, respectively. It was suggested that CAEBV belonged to high risk groups for the development of malignant neoplasms. Since HLA of the case 1 and his father was identical, we conducted a in vitro cytotoxicity test using EBV transformed autologous B lymphocytes, K562 cells, and Raji cells to clarify the association of immunosuppression and HLA. The case 1 showed a low level of specific cytotoxicity to autologous EBV transformed B cells, while his parents were negative for the specific cytotoxicity. The patient and his parents developed inducible cytotoxicity to all targets after in vitro incubation of peripheral mononuclear cells with recombinant interleukin 2 (rIL-2) for 7 days. The patient and his mother showed lower enhancement of cytotoxicity, while HLA identical father could induce good cytotoxic activity to all targets as well as normal controls, indicating that a low IL-2 induced cytotoxic activity observed in CAEBV was independent of HLA associated immunoregulation at least in the case 1. Further studies are required to clarify the exact mechanisms responsible for the development of CAEBV.

Early Epstein-Barr Virus Genomic Diversity and Convergence toward the B95.8 Genome in Primary Infection.

PubMed

Weiss, Eric R; Lamers, Susanna L; Henderson, Jennifer L; Melnikov, Alexandre; Somasundaran, Mohan; Garber, Manuel; Selin, Liisa; Nusbaum, Chad; Luzuriaga, Katherine

2018-01-15

Over 90% of the world's population is persistently infected with Epstein-Barr virus. While EBV does not cause disease in most individuals, it is the common cause of acute infectious mononucleosis (AIM) and has been associated with several cancers and autoimmune diseases, highlighting a need for a preventive vaccine. At present, very few primary, circulating EBV genomes have been sequenced directly from infected individuals. While low levels of diversity and low viral evolution rates have been predicted for double-stranded DNA (dsDNA) viruses, recent studies have demonstrated appreciable diversity in common dsDNA pathogens (e.g., cytomegalovirus). Here, we report 40 full-length EBV genome sequences obtained from matched oral wash and B cell fractions from a cohort of 10 AIM patients. Both intra- and interpatient diversity were observed across the length of the entire viral genome. Diversity was most pronounced in viral genes required for establishing latent infection and persistence, with appreciable levels of diversity also detected in structural genes, including envelope glycoproteins. Interestingly, intrapatient diversity declined significantly over time ( P < 0.01), and this was particularly evident on comparison of viral genomes sequenced from B cell fractions in early primary infection and convalescence ( P < 0.001). B cell-associated viral genomes were observed to converge, becoming nearly identical to the B95.8 reference genome over time (Spearman rank-order correlation test; r = -0.5589, P = 0.0264). The reduction in diversity was most marked in the EBV latency genes. In summary, our data suggest independent convergence of diverse viral genome sequences toward a reference-like strain within a relatively short period following primary EBV infection. IMPORTANCE Identification of viral proteins with low variability and high immunogenicity is important for the development of a protective vaccine. Knowledge of genome diversity within circulating viral

Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection.

PubMed

Descamps, V; Mahe, E; Houhou, N; Abramowitz, L; Rozenberg, F; Ranger-Rogez, S; Crickx, B

2003-05-01

Association of drug-induced hypersensitivity syndrome with viral infection is debated. Human herpesvirus 6 (HHV-6) reactivation has been the most frequently reported infection associated with this syndrome. However, a case of cytomegalovirus (CMV) infection was recently described associated with anticonvulsant-induced hypersensitivity syndrome. We report a case of severe allopurinol-induced hypersensitivity syndrome with pancreatitis associated with Epstein-Barr virus (EBV) infection. Active EBV infection was demonstrated in two consecutive serum samples by the presence of anti-EBV early antigen (EA) IgM antibodies and an increase in anti-EBV EA IgG antibodies, whereas no anti-EBV nuclear antigen IgG antibodies were detected. EBV DNA was detected by polymerase chain reaction (PCR) in peripheral blood mononuclear cells. Reactivation of HHV-6 was suggested only by the presence of anti-HHV-6 IgM antibodies, but HHV-6 DNA was not detected by PCR in the serum. Other viral investigations showed previous infection (CMV, rubella, measles, parvovirus B19), immunization after vaccination (hepatitis B virus), or absence of previous infection (hepatitis C virus, human immunodeficiency virus). We suggest that EBV infection may participate in some cases, as do the other herpesviruses HHV-6 or CMV, in the development of drug-induced hypersensitivity syndrome.

Determining EBV load: current best practice and future requirements.

PubMed

Ruf, Stephanie; Wagner, Hans-Joachim

2013-02-01

EBV, a gammaherpesvirus and the pathogenic agent for infectious mononucleosis, is also associated with a broad spectrum of lymphoid and epithelial malignancies in immunocompetent and immunosuppressed individuals. EBV-DNA-load measurement by PCR has been shown to be a potential tool for the diagnosis of these diseases, a prognostic factor of their outcome and a successful method to monitor immunosuppressed patients. Since the end of 2011, there is an international WHO standard reference for EBV quantification available; however, many questions still remain; for instance about the optimal amplified region of the EBV genome, or the best-used specimen for EBV detection. Additionally, the optimal specimen and amplified region may vary in different malignancies. In this article, the authors review the different methods to measure EBV load, focus on the best-used specimen for the different EBV-associated malignancies and discuss future requirements and opportunities for EBV-load measurement.

Current research on chronic active Epstein-Barr virus infection in Japan.

PubMed

Fujiwara, Shigeyoshi; Kimura, Hiroshi; Imadome, Ken-ichi; Arai, Ayako; Kodama, Eiichi; Morio, Tomohiro; Shimizu, Norio; Wakiguchi, Hiroshi

2014-04-01

Epstein-Barr virus (EBV) infection is usually asymptomatic and persists lifelong. Although EBV-infected B cells have the potential for unlimited proliferation, they are effectively removed by the virus-specific cytotoxic T cells, and EBV-associated lymphoproliferative disease develops only in immunocompromised hosts. Rarely, however, individuals without apparent immunodeficiency develop chronic EBV infection with persistent infectious mononucleosis-like symptoms. These patients have high EBV-DNA load in the peripheral blood and systemic clonal expansion of EBV-infected T cells or natural killer (NK) cells. Their prognosis is poor with life-threatening complications including hemophagocytic lymphohistiocytosis, organ failure, and malignant lymphomas. The term "chronic active EBV infection" (CAEBV) is now generally used for this disease. The geographical distribution of CAEBV is markedly uneven and most cases have been reported from Japan and other East Asian countries. Here we summarize the current understanding of CAEBV and describe the recent progress of CAEBV research in Japan. © 2014 Japan Pediatric Society.

Measurement of Epstein-Barr virus DNA load using a novel quantification standard containing two EBV DNA targets and SYBR Green I dye.

PubMed

Lay, Meav-Lang J; Lucas, Robyn M; Ratnamohan, Mala; Taylor, Janette; Ponsonby, Anne-Louise; Dwyer, Dominic E

2010-09-22

Reactivation of Epstein-Barr virus (EBV) infection may cause serious, life-threatening complications in immunocompromised individuals. EBV DNA is often detected in EBV-associated disease states, with viral load believed to be a reflection of virus activity. Two separate real-time quantitative polymerase chain reaction (QPCR) assays using SYBR Green I dye and a single quantification standard containing two EBV genes, Epstein-Barr nuclear antigen-1 (EBNA-1) and BamHI fragment H rightward open reading frame-1 (BHRF-1), were developed to detect and measure absolute EBV DNA load in patients with various EBV-associated diseases. EBV DNA loads and viral capsid antigen (VCA) IgG antibody titres were also quantified on a population sample. EBV DNA was measurable in ethylenediaminetetraacetic acid (EDTA) whole blood, peripheral blood mononuclear cells (PBMCs), plasma and cerebrospinal fluid (CSF) samples. EBV DNA loads were detectable from 8.0 × 10(2) to 1.3 × 10(8) copies/ml in post-transplant lymphoproliferative disease (n = 5), 1.5 × 10(3) to 2.0 × 10(5) copies/ml in infectious mononucleosis (n = 7), 7.5 × 10(4) to 1.1 × 10(5) copies/ml in EBV-associated haemophagocytic syndrome (n = 1), 2.0 × 10(2) to 5.6 × 10(3) copies/ml in HIV-infected patients (n = 12), and 2.0 × 10(2) to 9.1 × 10(4) copies/ml in the population sample (n = 218). EBNA-1 and BHRF-1 DNA were detected in 11.0% and 21.6% of the population sample respectively. There was a modest correlation between VCA IgG antibody titre and BHRF-1 DNA load (rho = 0.13, p = 0.05) but not EBNA-1 DNA load (rho = 0.11, p = 0.11). Two sensitive and specific real-time PCR assays using SYBR Green I dye and a single quantification standard containing two EBV DNA targets, were developed for the detection and measurement of EBV DNA load in a variety of clinical samples. These assays have application in the investigation of EBV-related illnesses in immunocompromised individuals.

Gammaherpesvirus Infection of Human Neuronal Cells

PubMed Central

Jha, Hem Chandra; Mehta, Devan; Lu, Jie; El-Naccache, Darine; Shukla, Sanket K.; Kovacsics, Colleen; Kolson, Dennis

2015-01-01

ABSTRACT Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers. HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically associated with various neurological diseases such as primary central nervous system lymphoma, multiple sclerosis, Alzheimer’s disease, cerebellar ataxia, and encephalitis. However, the possibility that EBV and Kaposi’s sarcoma-associated herpesvirus (KSHV) can directly infect neurons has been largely overlooked. This study has, for the first time, characterized EBV infection in neural cell backgrounds by using the Sh-Sy5y neuroblastoma cell line, teratocarcinoma Ntera2 neurons, and primary human fetal neurons. Furthermore, we also demonstrated KSHV infection of neural Sh-Sy5y cells. These neuronal cells were infected with green fluorescent protein-expressing recombinant EBV or KSHV. Microscopy, genetic analysis, immunofluorescence, and Western blot analyses for specific viral antigens supported and validated the infection of these cells by EBV and KSHV and showed that the infection was efficient and productive. Progeny virus produced from infected neuronal cells efficiently infected fresh neuronal cells, as well as peripheral blood mononuclear cells. Furthermore, acyclovir was effective at inhibiting the production of virus from neuronal cells similar to lymphoblastoid cell lines; this suggests active lytic replication in infected neurons in vitro. These studies represent a potentially new in vitro model of EBV- and KSHV-associated neuronal disease development and pathogenesis. PMID:26628726

Self-Reported Mental Health Predicts Acute Respiratory Infection.

PubMed

Maxwell, Lizzie; Barrett, Bruce; Chase, Joseph; Brown, Roger; Ewers, Tola

2015-06-01

Poor mental health conditions, including stress and depression, have been recognized as a risk factor for the development of acute respiratory infection. Very few studies have considered the role of general mental health in acute respiratory infection occurrence. The aim of this analysis is to determine if overall mental health, as assessed by the mental component of the Short Form 12 Health Survey, predicts incidence, duration, or severity of acute respiratory infection. Data utilized for this analysis came from the National Institute of Health-funded Meditation or Exercise for Preventing Acute Respiratory Infection (MEPARI) and MEPARI-2 randomized controlled trials examining the effects of meditation or exercise on acute respiratory infection among adults aged > 30 years in Madison, Wisconsin. A Kendall tau rank correlation compared the Short Form 12 mental component, completed by participants at baseline, with acute respiratory infection incidence, duration, and area-under-the-curve (global) severity, as assessed by the Wisconsin Upper Respiratory Symptom Survey. Participants were recruited from Madison, Wis, using advertisements in local media. Short Form 12 mental health scores significantly predicted incidence (P = 0.037) of acute respiratory infection, but not duration (P = 0.077) or severity (P = 0.073). The Positive and Negative Affect Schedule (PANAS) negative emotion measure significantly predicted global severity (P = 0.036), but not incidence (P = 0.081) or duration (P = 0.125). Mindful Attention Awareness Scale scores significantly predicted incidence of acute respiratory infection (P = 0.040), but not duration (P = 0.053) or severity (P = 0.70). The PHQ-9, PSS-10, and PANAS positive measures did not show significant predictive associations with any of the acute respiratory infection outcomes. Self-reported overall mental health, as measured by the mental component of Short Form 12, predicts acute respiratory infection incidence.

Novel Epstein-Barr virus-like particles incorporating gH/gL-EBNA1 or gB-LMP2 induce high neutralizing antibody titers and EBV-specific T-cell responses in immunized mice

PubMed Central

Perez, Elizabeth M.; Foley, Joslyn; Tison, Timelia; Silva, Rute; Ogembo, Javier Gordon

2017-01-01

Previous Epstein-Barr virus (EBV) prophylactic vaccines based on the major surface glycoprotein gp350/220 as an immunogen have failed to block viral infection in humans, suggesting a need to target other viral envelope glycoproteins. In this study, we reasoned that incorporating gH/gL or gB, critical glycoproteins for viral fusion and entry, on the surface of a virus-like particle (VLP) would be more immunogenic than gp350/220 for generating effective neutralizing antibodies to prevent viral infection of both epithelial and B cell lines. To boost the humoral response and trigger cell-mediated immunity, EBV nuclear antigen 1 (EBNA1) and latent membrane protein 2 (LMP2), intracellular latency proteins expressed in all EBV-infected cells, were also included as critical components of the polyvalent EBV VLP. gH/gL-EBNA1 and gB-LMP2 VLPs were efficiently produced in Chinese hamster ovary cells, an FDA-approved vehicle for mass-production of biologics. Immunization with gH/gL-EBNA1 and gB-LMP2 VLPs without adjuvant generated both high neutralizing antibody titers in vitro and EBV-specific T-cell responses in BALB/c mice. These data demonstrate that EBV glycoprotein(s)-based VLPs have excellent immunogenicity, and represent a potentially safe vaccine that will be invaluable not only in preventing EBV infection, but importantly, in preventing and treating the 200,000 cases of EBV-associated cancers that occur globally every year. PMID:27926486

EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma.

PubMed

Lung, Raymond W-M; Hau, Pok-Man; Yu, Ken H-O; Yip, Kevin Y; Tong, Joanna H-M; Chak, Wing-Po; Chan, Anthony W-H; Lam, Ka-Hei; Lo, Angela Kwok-Fung; Tin, Edith K-Y; Chau, Shuk-Ling; Pang, Jesse C-S; Kwan, Johnny S-H; Busson, Pierre; Young, Lawrence S; Yap, Lee-Fah; Tsao, Sai-Wah; To, Ka-Fai; Lo, Kwok-Wai

2018-04-01

Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors

Prospective Characterization of the Risk Factors for Transmission and Symptoms of Primary Human Herpesvirus Infections Among Ugandan Infants

PubMed Central

Gantt, Soren; Orem, Jackson; Krantz, Elizabeth M.; Morrow, Rhoda Ashley; Selke, Stacy; Huang, Meei-Li; Schiffer, Joshua T.; Jerome, Keith R.; Nakaganda, Annet; Wald, Anna; Casper, Corey; Corey, Lawrence

2016-01-01

Background. Human herpesvirus (HHV) infections are common during infancy. Primary infections are frequently asymptomatic and best studied prospectively by using direct viral detection. Methods. Oropharyngeal swab specimens were collected weekly from Ugandan newborn infants, their mothers, and other children in the household. Blood specimens were collected every 4 months. Samples were tested for herpes simplex virus (HSV) types 1 and 2, Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6A, HHV-6B, and HHV-8, using quantitative polymerase chain reaction. Results. Thirty-two infants, 32 mothers, and 49 other household children were followed for a median of 57 weeks. Seventeen mothers had human immunodeficiency virus type 1 (HIV) infection; no infants acquired HIV-1. The 12-month incidence of postnatal infection was 76% for HHV-6B, 59% for CMV, 47% for EBV, 8% for HSV-1, and 0% for HHV-8. The quantity of oropharyngeal shedding by contacts was associated with HHV-6A or HHV-6B transmission. Maternal HIV-1 infection was associated with EBV transmission, while breastfeeding and younger child contacts were associated with CMV transmission. Except for HSV-1, primary HHV infections were subclinical. Conclusions. By capturing exposures and acquisition events, we found that the incidence and risk factors of infection vary by HHV type. HSV-1 infection, unlike other HHV infections, caused acute clinical illness in these infants. PMID:26917575

Systemic lupus erythematosus due to Epstein-Barr virus or Epstein-Barr virus infection provocating acute exacerbation of systemic lupus erythematosus?

PubMed

Kasapcopur, Ozgur; Ergul, Yakup; Kutlug, Seyhan; Candan, Cengiz; Camcioglu, Yildiz; Arisoy, Nil

2006-06-01

Systemic lupus erythematosus (SLE) is a rheumatologic disease characterized by an inflammatory destruction of the target organ systems of the body in an unknown way by autoantibodies formed against self-antigens. Infectious agents like Epstein-Barr virus (EBV), cytomegalovirus and parvovirus B19 may have a role in the occurrence or the exacerbation of the SLE. In this report, the clinical follow-up of a 14-year-old girl diagnosed with SLE following an EBV infection with bicytopenia, lymphadenomegaly and hepatomegaly is discussed. This case could support the role of viral infections in the etiology of SLE.

[A case of chronic active Epstein-Barr virus infection associated with recurrent cerebellar ataxia and skin eruptions].

PubMed

Araki, Katsuya; Okuno, Tatsusada; Honorat, Josephe Archie; Kinoshita, Makoto; Takahashi, Masanori P; Mizuki, Masao; Kitagawa, Kazuo; Mochizuki, Hideki

2013-01-01

A 62-year-old woman presented with subacute cerebellar ataxia, lymph node swelling and skin eruption. Laboratory tests revealed elevated titers of anti-VCA-IgG antibody and anti-EADR-IgG antibody, with Epstein-Barr virus (EBV) DNA detected from the blood and CSF by PCR. Since these data were highlighted with the diagnosis of chronic active EBV infection (CAEBV) and her ataxia improved concomitantly with the remission of other infectious mononucleosis-like symptoms, we supposed her ataxia is associated with CAEBV. Five years later, at the age of 67, her ataxia relapsed concurrently with skin eruptions, whereas MRI demonstrated progression of cerebellar atrophy. After high-dose intravenous methylprednisolone treatment, the clinical symptoms resolved. Initial infection of EBV in childhood often causes autoimmune acute cerebellitis but cerebellar ataxia has rarely been described in CAEBV. Furthermore, immunohistochemical analysis revealed a reactivity of the patient's serum and CSF on rat cerebellum, suggesting an autoimmune pathomechanism for the ataxia.

[Two young adult cases of Epstein-Barr virus associated-hemophagocytic lymphohistiocytosis with monoclonal proliferation of virus-infected cells within a short period after primary infection].

PubMed

Idutsu, Kensaku; Abe, Yasunobu; Matsushima, Takamitsu; Sada, Eriko; Ohtsuka, Rie; Kiyasu, Junichi; Shiratsuchi, Motoaki; Kotoh, Kazuhiro; Nishimura, Junji; Ohga, Shouichi; Takayanagi, Ryoichi

2008-11-01

Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe complication of Epstein-Barr virus (EBV) infection. Interactions between EBV-infected T cells and activated macrophages cause several conditions such as pancytopenia, liver dysfunction and coagulopathy. We describe here two young adults with EBV-associated HLH with monoclonal proliferation of EBV-infected T cells within a short period after infectious mononucleosis as a primary infection. One patient was a 16-year-old man who developed severe pancytopenia and liver dysfunction two months after infectious mononucleosis. Bone marrow examination showed hemophagocytosis, and laboratory data demonstrated monoclonal proliferation of EBV-infected T cells. Several treatments such as immunosuppressive therapy, chemotherapy and hematopoietic stem cell transplantation were not effective, and the patient died of progressive disease. The other patient was a 19-year-old woman who developed thrombocytopenia and liver dysfunction two months after infectious mononucleosis. Findings of hemophagocytosis and monoclonal proliferation of EBV-infected T cells were similar to those in the first case. Clinical signs and symptoms were resolved completely by immunosuppressive therapy containing methyl-prednisolone and cyclosporine. Since these two cases each demonstrated a distinct clinical course, an investigation of the prognostic factors and treatment strategies for EBV-HLH is warranted.

[Clinical and laboratory characteristics of chronic active Epstein-Barr virus infection in children].

PubMed

Mao, Jun-Qing; Yang, Shi-Long; Song, Hua; Zhao, Fen-Ying; Xu, Xiao-Jun; Gu, Min-Er; Tang, Yong-Min

2014-11-01

To study the clinical and laboratory characteristics of chronic active Epstein-Barr virus (EBV) infection (CAEBV) in children and to provide a basis for the diagnosis and treatment of CAEBV. The clinical data of 13 children with CAEBV, as well as 15 cases of acute EBV infection (AEBV) as controls, were analyzed, including clinical manifestations, EBV antibodies, EBV DNA, and peripheral blood lymphocyte subsets. Both groups of patients had infectious mononucleosis-like symptoms such as fever, hepatomegaly, splenomegaly, and lymphadenectasis, but CAEBV patients had a longer course of disease and continuous and recurrent symptoms. Compared with the AEBV group, the CAEBV group had a significantly higher EBV DNA load in peripheral blood (P<0.05), a significantly higher VCA-IgG titer (P<0.05), and significantly lower numbers of white blood cells, lymphocytes, B cells, total T cells, CD4+ T cells, and CD8+ T cells in peripheral blood (P<0.05). Among 13 CAEBV patients followed up, 8 cases died, 2 cases showed an improvement, 2 cases had a recurrence, and 1 case was lost to follow-up after being transferred to another hospital. All the AEBV patients were cured and had no recurrence during the one-year follow-up. The clinical manifestations of CAEBV vary in children. It is difficult to distinguish CAEBV from AEBV early. More attention should be paid to CAEBV because of its severe complications, poor prognosis, and high mortality. Measurement of EBV DNA load, VCA-IgG titer, and lymphocyte subsets in peripheral blood may be helpful in the diagnosis and differential diagnosis of CAEBV.

Novel Epstein-Barr virus-like particles incorporating gH/gL-EBNA1 or gB-LMP2 induce high neutralizing antibody titers and EBV-specific T-cell responses in immunized mice.

PubMed

Perez, Elizabeth M; Foley, Joslyn; Tison, Timelia; Silva, Rute; Ogembo, Javier Gordon

2017-03-21

Previous Epstein-Barr virus (EBV) prophylactic vaccines based on the major surface glycoprotein gp350/220 as an immunogen have failed to block viral infection in humans, suggesting a need to target other viral envelope glycoproteins. In this study, we reasoned that incorporating gH/gL or gB, critical glycoproteins for viral fusion and entry, on the surface of a virus-like particle (VLP) would be more immunogenic than gp350/220 for generating effective neutralizing antibodies to prevent viral infection of both epithelial and B cell lines. To boost the humoral response and trigger cell-mediated immunity, EBV nuclear antigen 1 (EBNA1) and latent membrane protein 2 (LMP2), intracellular latency proteins expressed in all EBV-infected cells, were also included as critical components of the polyvalent EBV VLP. gH/gL-EBNA1 and gB-LMP2 VLPs were efficiently produced in Chinese hamster ovary cells, an FDA-approved vehicle for mass-production of biologics. Immunization with gH/gL-EBNA1 and gB-LMP2 VLPs without adjuvant generated both high neutralizing antibody titers in vitro and EBV-specific T-cell responses in BALB/c mice. These data demonstrate that will be invaluable not only in preventing EBV infection, but importantly, in preventing and treating the 200,000 cases of EBV-associated cancers that occur globally every year.

Strict lymphotropism of Epstein-Barr virus during acute infectious mononucleosis in nonimmunocompromised individuals.

PubMed

Karajannis, M A; Hummel, M; Anagnostopoulos, I; Stein, H

1997-04-15

Previous investigations of exfoliated oropharyngeal cells from individuals suffering from infectious mononucleosis (IM) suggested that the oropharyngeal epithelia are the primary target and also the site of life-long persistence of the Epstein-Barr virus (EBV). This concept was widely accepted. However, the investigation of histological sections with more sensitive EBV detection techniques has drawn this concept into doubt since EBV proved to be constantly absent in normal epithelial cells. To elucidate the discrepancy, throat washings and peripheral mononuclear blood cells from 16 patients suffering from IM were investigated for EBV-DNA and EBV gene products employing highly sensitive in situ hybridization, immunocytochemistry, and polymerase chain reaction. Although all patients exhibited latently infected B lymphocytes in peripheral blood, samples of exfoliated oropharyngeal cells were constantly EBV-negative with the exception of three cases. In these cases, the patients additionally suffered from purulent ulcerating tonsillitis, EBV-infected B cells, but no EBV-infected epithelial cells were detectable. These findings support the view that recirculating lymphocytes of B-cell origin, but not epithelial cells are the initial target of EBV during primary infection and that B cells also represent the site of life-long viral persistence.

Reproduction of Epstein-Barr Virus Infection and Pathogenesis in Humanized Mice

PubMed Central

2014-01-01

Epstein-Barr virus (EBV) is etiologically associated with a variety of diseases including lymphoproliferative diseases, lymphomas, carcinomas, and autoimmune diseases. Humans are the only natural host of EBV and limited species of new-world monkeys can be infected with the virus in experimental conditions. Small animal models of EBV infection, required for evaluation of novel therapies and vaccines for EBV-associated diseases, have not been available. Recently the development of severely immunodeficient mouse strains enabled production of humanized mice in which human immune system components are reconstituted and express their normal functions. Humanized mice can serve as infection models for human-specific viruses such as EBV that target cells of the immune system. This review summarizes recent studies by the author's group addressing reproduction of EBV infection and pathogenesis in humanized mice. PMID:24605074

Why Human Papillomavirus Acute Infections Matter

PubMed Central

2017-01-01

Most infections by human papillomaviruses (HPVs) are ‘acute’, that is non-persistent. Yet, for HPVs, as for many other oncoviruses, there is a striking gap between our detailed understanding of chronic infections and our limited data on the early stages of infection. Here we argue that studying HPV acute infections is necessary and timely. Focusing on early interactions will help explain why certain infections are cleared while others become chronic or latent. From a molecular perspective, descriptions of immune effectors and pro-inflammatory pathways during the initial stages of infections have the potential to lead to novel treatments or to improved handling algorithms. From a dynamical perspective, adopting concepts from spatial ecology, such as meta-populations or meta-communities, can help explain why HPV acute infections sometimes last for years. Furthermore, cervical cancer screening and vaccines impose novel iatrogenic pressures on HPVs, implying that anticipating any viral evolutionary response remains essential. Finally, hints at the associations between HPV acute infections and fertility deserve further investigation given their high, worldwide prevalence. Overall, understanding asymptomatic and benign infections may be instrumental in reducing HPV virulence. PMID:28994707

Increased EBV Shedding in Astronaut Saliva During Spaceflight

NASA Technical Reports Server (NTRS)

Pierson, D. L.; Stowe, R. P.; Phillips, T.; Lugg, D. J.; Mehta, S. K.

2003-01-01

Shedding of Epstein-Barr virus (EBV) by astronauts before, during, and after space shuttle missions was quantified. Of 1398 saliva specimens from 32 astronauts, 314 (23%) were positive for EBV DNA by PCR analysis. Of the saliva specimens collected before flight, 29% were positive for EBV DNA and of those collected during or after flight, 16% were EBV-positive. The number of EBV DNA copies from samples taken during the flight was 417+/-31, significantly higher (P < 0.05) than the number of copies from the preflight (40+/-1.7) and postflight (44+/-5) phases. Eighteen control subjects shed EBV DNA with a frequency of 3.7% and a copy number of 40+/-2 per ml saliva. Ten days before flight and on landing day, antibody titers to EBV viral capsid antigen (VCA) were significantly (P < 0.05) higher than baseline levels. On landing day, urinary level of cortiso1 and catecholamines, and plasma levels of substance P and other neuropeptides, were increased over their preflight value. Results suggested that stress associated with spaceflight decreases cellular immunity and thereby leads to increased viral reactivation.

EBV-driven B-cell lymphoproliferative disorders: from biology, classification and differential diagnosis to clinical management

PubMed Central

Ok, Chi Young; Li, Ling; Young, Ken H

2015-01-01

Epstein–Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. EBV targets B-lymphocytes and achieves latent infection in a circular episomal form. Different latency patterns are recognized based on latent gene expression pattern. Latent membrane protein-1 (LMP-1) mimics CD40 and, when self-aggregated, provides a proliferation signal via activating the nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase pathways to promote cellular proliferation. LMP-1 also induces BCL-2 to escape from apoptosis and gives a signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of retinoblastoma (Rb) protein and by inhibiting p16 and p27. LMP-2A blocks the surface immunoglobulin-mediated lytic cycle reactivation. It also activates the Ras/PI3K/Akt pathway and induces Bcl-xL expression to promote B-cell survival. Recent studies have shown that ebv-microRNAs can provide extra signals for cellular proliferation, cell cycle progression and anti-apoptosis. EBV is well known for association with various types of B-lymphocyte, T-lymphocyte, epithelial cell and mesenchymal cell neoplasms. B-cell lymphoproliferative disorders encompass a broad spectrum of diseases, from benign to malignant. Here we review our current understanding of EBV-induced lymphomagenesis and focus on biology, diagnosis and management of EBV-associated B-cell lymphoproliferative disorders. PMID:25613729

Chronic active Epstein-Barr virus infection in an adult with no detectable immune deficiency.

PubMed

de Boer, M; Mol, M J T M; Bogman, M J J T; Galama, J M D; Raymakers, R A P

2003-11-01

Epstein-Barr virus (EBV) establishes lifelong latent infection. In some patients the host-virus balance is disturbed, resulting in a chronic active EBV infection. The following case illustrates the difficulty in diagnosing and treating chronic EBV infection. A 30-year-old woman was referred because of recurrent swellings of lymphatic tissue of both eyelids, orbit and lymph nodes and general malaise since the age of 19. In the past, repeated biopsies showed MALT lymphoma and nonspecific lymphoid infiltrations. Now, a biopsy of an axillary lymph node showed paracortical hyperplasia with a polymorphous polyclonal lymphoid proliferation, and large numbers of EBV-encoded small RNA (EBER) positive cells, consistent with EBV infection. Laboratory investigation showed a high EBV viral load. No evidence of immunodeficiency was found. Chronic active EBV infection (CAEBV) was diagnosed. Treatment with high-dose acyclovir did not significantly reduce the viral load. Rituximab was given in an attempt to reduce the amount of EBV-infected B lymphocytes. However, soon after the second dose the patient died of a sub-arachnoidal haemorrhage. This case report illustrates CAEBV as a rare manifestation of EBV-induced disease, which will be detected more frequently with the use of EBV-EBER hybridisation of lymph nodes and polymerase chain reaction (PCR) for EBV DNA. The prognosis is poor with no established therapeutic strategies.

Decreasing the configurational entropy and the hydrophobicity of EBV-derived peptide 11389 increased its antigenicity, immunogenicity and its ability of inducing IL-6.

PubMed

Urquiza, Mauricio; Guevara, Tatiana; Rodriguez, Cristina; Melo-Cardenas, Johanna; Vanegas, Magnolia; Patarroyo, Manuel E

2012-06-01

Peptide 11389 from CD21-binding region of EBV-gp350/220 protein binds to PBMCs inducing IL-6 expression and inhibiting EBV-binding to PBMCs. In addition, anti-peptide 11389 antibodies recognize EBV-infected cells and inhibit both EBV infection and IL-6 production in PBMCs. We have postulated that native structure stabilization of peptide 11389 sequence can increase its biological activity. The strategy was to modify its sequence to restrict the number of structures that peptide 11389 could acquire in solution (decreasing peptide's configurational entropy) and to weaken the non-relevant intermolecular interactions (decreasing its hydrophobicity), preserving CD21-interacting residues and structure as displayed in the native protein. Thirteen analog peptides were designed and synthesized; most of them were monomers containing an intra-chain disulfide bridge. Analog peptides 34058, 34060, 34061, 34296, 34298, 34299 and 34300 inhibited EBV invasion of PBMCs. Peptides 34059, 34060, 34295 and 34297 induced IL-6 levels in PBMCs (EC50=3.4, 3.3, 0.5, 0.5 μM, respectively) at higher potency than peptide 11389 (EC50=5.8 μM). Peptides 34057, 34059, 34060, 34301 and 34302 interacted with anti-EBV antibodies with affinities from 3 to 50 times higher than peptide 11389. Most of analog peptides were highly immunogenic and elicited antibodies that cross-react with EBV. In conclusion, we have designed peptides displaying higher biological activity than peptide 11389.

Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Manbok, E-mail: manbok66@dankook.ac.kr; Rahman, Masmudur M.; Cogle, Christopher R.

Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignanciesmore » in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.« less

Clinical presentation and course of acute hepatitis C infection in HIV-infected patients.

PubMed

Luetkemeyer, Annie; Hare, C Bradley; Stansell, John; Tien, Phyllis C; Charlesbois, Edwin; Lum, Paula; Havlir, Diane; Peters, Marion

2006-01-01

Hepatitis C virus (HCV) has become a significant source of morbidity and mortality in HIV-infected patients. However, little is known about the clinical presentation and course of acute HCV infection in this population. This study reports the outcomes of acute HCV infection in 9 HIV-infected men. Sex with men was the only reported risk factor for HCV infection in 6 of the subjects. Clinical presentation of acute HCV ranged from incidentally discovered elevated transaminases to severe liver dysfunction requiring hospitalization. At the time of HCV diagnosis, 8 of 9 patients had CD4+ counts >250 cells/mm(3), and 6 had HIV viral loads of < or =5000 copies/mL. Eight patients were receiving antiretroviral therapy. Outcome of these acute HCV infections varied. Five patients experienced virologic clearance, 2 in whom virus cleared spontaneously and 3 who were treated with pegylated interferon and ribavirin. Four patients developed chronic infection, one of whom had a relapse during HCV treatment and 3 of whom were untreated. All 4 patients to whom HCV therapy was administered experienced significant anemia or neutropenia, necessitating dose reduction or support with growth factors. Prompt recognition of acute HCV infection may minimize antiretroviral treatment interruption and will allow early treatment, which may improve virologic clearance. Unexplained transaminase elevations in HIV-infected patients, including men who have sex with men, should trigger an evaluation for acute HCV infection.

Monoclonal and anti-idiotypic anti-EBV/C3d receptor antibodies detect two binding sites, one for EBV and one for C3d on glycoprotein 140, the EBV/C3dR, expressed on human B lymphocytes.

PubMed

Barel, M; Fiandino, A; Delcayre, A X; Lyamani, F; Frade, R

1988-09-01

Glycoprotein (gp) 140, the EBV/C3dR of B lymphocytes, is a membrane site involved in human cell regulation. To analyze the specificities of the binding sites for EBV and for C3d on the gp 140 molecule, two distinct approaches were used. First, anti-EBV/C3dR mAb were prepared against highly purified EBV/C3dR. Nine anti-EBV/C3dR mAb were obtained. Four of these anti-EBV/C3dR mAb inhibited C3d binding but not EBV binding on gp 140, whereas four others exerted an inverse effect. These differences could not be due to differences in isotype, antibody concentration, affinity constant, and number of molecules bound on cell surface, as these parameters were identical for the nine used mAb. Second, polyclonal anti-idiotypic antibodies (Ab2) were prepared against F(ab)'2 fragments of polyclonal anti-EBV/C3dR (Ab1). Ab2 recognized the variable portion of Ab1 as controlled by immunoblotting experiments. Ab2, which did not react with the cell surface, inhibited Ab1 binding on Raji cells. Ab2 mimicked the EBV/C3dR by its properties to bind to particle-bound C3d and EBV, preventing their binding on Raji cell surface. C3d binding specificities contained in Ab2 were isolated by affinity chromatography on C3b/C3bi-Sepharose. These specificities, being the internal image of C3d binding site of EBV/C3dR, reacted with Ab1 and inhibited particle-bound C3d binding on Raji cells but did not react with EBV. Taken together, these data support strongly that gp 140, the EBV/C3dR, carried two distinct binding sites, one for EBV and one for C3d.

[Chronic active Epstein-Barr virus infection].

PubMed

Kimura, Hiroshi

2011-12-01

The ubiquitous Epstein-Barr virus (EBV), which establishes latency after primary infection, does not cause any symptomatic diseases as long as cellular immunity is intact. In apparently immunocompetent individuals, a chronic infection can develop, and this has been called as chronic active EBV infection (CAEBV). CAEBV is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and, hepatosplenomegaly. This disease is rare but severe with high morbidity and mortality. Recently, its pathophysiology is not an infection but a clonal expansion of EBV-infected T or natural killer NK cells. In this review, I discuss our current understanding of the pathogenesis of CAEBV and summarize its clinical features, therapies, and prognosis.

Evaluation of HPV, CMV, HSV and EBV in esophageal squamous cell carcinomas from a high-incidence area of China.

PubMed

Chang, F; Syrjänen, S; Shen, Q; Cintorino, M; Santopietro, R; Tosi, P; Syrjänen, K

2000-01-01

Certain viruses, notably human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV) and Epstein-Barr virus (EBV), are known to produce tumors in animals and cell transformation in vitro and they have been implicated in the pathogenesis of human cancers. All these viruses are also known to infect the esophagus. This study was aimed to determine whether these viruses play any causal role in the etiology of esophageal squamous cell carcinoma. A series of 103 esophageal squamous cell carcinomas derived from patients in the high-incidence area of northern China were analyzed by DNA in situ hybridization and polymerase chain reaction (PCR) for the presence of HPV DNA sequences and, using immunohistochemistry, for the demonstration of CMV, HSV and EBV infections. Six (5.8%) of the 103 tumors were found to contain HPV 16, 18 or 30 DNA sequences. HPV types 6, 11 and 53 were not detected in any of the cases. Amplified HPV DNA sequences were found in 17 out of 101 (16.8%) carcinoma specimens by PCR with L1 consensus primers. None of the 103 carcinomas tested was immunohistochemically positive for CMV, HSV or EBV. Our results confirmed the HPV involvement in esophageal carcinomas and provided further evidence to support a causal association of HPV infection with esophageal squamous cell carcinoma. However, the three herpesviruses, CMV, HSV and EBV, are highly unlikely to be involved in the pathogenesis of this malignancy in the high-incidence area of China.

Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection

PubMed Central

Chijioke, Obinna; Müller, Anne; Feederle, Regina; Barros, Mario Henrique M.; Krieg, Carsten; Emmel, Vanessa; Marcenaro, Emanuela; Leung, Carol S.; Antsiferova, Olga; Landtwing, Vanessa; Bossart, Walter; Moretta, Alessandro; Hassan, Rocio; Boyman, Onur; Niedobitek, Gerald; Delecluse, Henri-Jacques; Capaul, Riccarda; Münz, Christian

2014-01-01

SUMMARY Primary infection with the human oncogenic Epstein Barr virus (EBV) can result in infectious mononucleosis (IM), a self-limiting disease caused by massive lymphocyte expansion, which predisposes for the development of distinct EBV-associated lymphomas. It remains unclear why some individuals experience this symptomatic primary EBV infection, while the majority acquires the virus asymptomatically. Using a mouse model with reconstituted human immune system components, we show here that depletion of human natural killer (NK) cells enhances IM symptoms and promotes EBV-associated tumorigenesis, mainly due to loss of immune control over lytic EBV infection. These data suggest that failure of innate immune control by human NK cells augments symptomatic lytic EBV infection, which drives lymphocyte expansion and predisposes for EBV-associated malignancies. PMID:24360958

EBV driven natural killer cell disease of the central nervous system presenting as subacute cognitive decline.

PubMed

Brett, Francesca M; Flavin, Richard; Chen, Daphne; Loftus, Teresa; Looby, Seamus; McCarthy, Allan; de Gascun, Cillian; Jaffe, Elaine S; Nor, Nurul; Javadpour, Mohsen; McCabe, Dominick

2017-11-01

Brain biopsy in patients presenting with subacute encephalopathyis never straightforward and only undertaken when a 'treatable condition' is a realistic possibility. This 63 year old right handed, immunocompetent Caucasian woman presented with an 8 month history of rapidly progressive right-sided hearing impairment, a 4 month history of intermittent headaches, tinnitus, 'dizziness', dysphagia, nausea and vomiting, with the subsequent evolution of progressive gait ataxia and a subacute global encephalopathy. The possibility of CJD was raised. Brain biopsy was carried out. Western blot for prion protein was negative. She died 9 days later and autopsy brain examination confirmed widespread subacute infarction due to an EBV positive atypical NK/T-cell infiltrate with positivity for CD3, CD56, granzyme B, perforin and EBER with absence of CD4, CD5 and CD8 expression. Molecular studies for T-cell clonality were attempted but failed due to insufficient DNA quality. Serology was consistent with past EBV infection (EBV VCA and EBNA IgG Positive). There was no evidence of disease outside the CNS. Primary central nervous system NK/T-cell lymphoma is extremely rare. The rare reported cases all present with a discrete intracranial mass, unlike the diffuse infiltrative pattern in this case. Whilst the diffuse interstitial pattern is reminiscent of chronic active EBV infection (CAEBV) seen in other organ systems such as the liver and bone marrow, the clinical presentation and epidemiologic profile are not typical for CAEBV.

EBV driven natural killer cell disease of the central nervous system presenting as subacute cognitive decline

PubMed Central

Brett, Francesca M.; Flavin, Richard; Chen, Daphne; Loftus, Teresa; Looby, Seamus; McCarthy, Allan; de Gascun, Cillian; Jaffe, Elaine S.; Nor, Nurul; Javadpour, Mohsen; McCabe, Dominick

2017-01-01

Brain biopsy in patients presenting with subacute encephalopathyis never straightforward and only undertaken when a ‘treatable condition’ is a realistic possibility. This 63 year old right handed, immunocompetent Caucasian woman presented with an 8 month history of rapidly progressive right-sided hearing impairment, a 4 month history of intermittent headaches, tinnitus, ‘dizziness’, dysphagia, nausea and vomiting, with the subsequent evolution of progressive gait ataxia and a subacute global encephalopathy. The possibility of CJD was raised. Brain biopsy was carried out. Western blot for prion protein was negative. She died 9 days later and autopsy brain examination confirmed widespread subacute infarction due to an EBV positive atypical NK/T-cell infiltrate with positivity for CD3, CD56, granzyme B, perforin and EBER with absence of CD4, CD5 and CD8 expression. Molecular studies for T-cell clonality were attempted but failed due to insufficient DNA quality. Serology was consistent with past EBV infection (EBV VCA and EBNA IgG Positive). There was no evidence of disease outside the CNS. Primary central nervous system NK/T-cell lymphoma is extremely rare. The rare reported cases all present with a discrete intracranial mass, unlike the diffuse infiltrative pattern in this case. Whilst the diffuse interstitial pattern is reminiscent of chronic active EBV infection (CAEBV) seen in other organ systems such as the liver and bone marrow, the clinical presentation and epidemiologic profile are not typical for CAEBV. PMID:28845389

Partial Least Squares Based Gene Expression Analysis in EBV- Positive and EBV-Negative Posttransplant Lymphoproliferative Disorders.

PubMed

Wu, Sa; Zhang, Xin; Li, Zhi-Ming; Shi, Yan-Xia; Huang, Jia-Jia; Xia, Yi; Yang, Hang; Jiang, Wen-Qi

2013-01-01

Post-transplant lymphoproliferative disorder (PTLD) is a common complication of therapeutic immunosuppression after organ transplantation. Gene expression profile facilitates the identification of biological difference between Epstein-Barr virus (EBV) positive and negative PTLDs. Previous studies mainly implemented variance/regression analysis without considering unaccounted array specific factors. The aim of this study is to investigate the gene expression difference between EBV positive and negative PTLDs through partial least squares (PLS) based analysis. With a microarray data set from the Gene Expression Omnibus database, we performed PLS based analysis. We acquired 1188 differentially expressed genes. Pathway and Gene Ontology enrichment analysis identified significantly over-representation of dysregulated genes in immune response and cancer related biological processes. Network analysis identified three hub genes with degrees higher than 15, including CREBBP, ATXN1, and PML. Proteins encoded by CREBBP and PML have been reported to be interact with EBV before. Our findings shed light on expression distinction of EBV positive and negative PTLDs with the hope to offer theoretical support for future therapeutic study.

Hemophagocytic syndromes and infection.

PubMed Central

Fisman, D. N.

2000-01-01

Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, splenomegaly, jaundice, and the pathologic finding of hemophagocytosis (phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors) in bone marrow and other tissues. HLH may be diagnosed in association with malignant, genetic, or autoimmune diseases but is also prominently linked with Epstein-Barr (EBV) virus infection. Hyperproduction of cytokines, including interferon-gamma and tumor necrosis factor-alpha, by EBV- infected T lymphocytes may play a role in the pathogenesis of HLH. EBV-associated HLH may mimic T-cell lymphoma and is treated with cytotoxic chemotherapy, while hemophagocytic syndromes associated with nonviral pathogens often respond to treatment of the underlying infection. PMID:11076718

The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events.

PubMed

Dunmire, Samantha K; Grimm, Jennifer M; Schmeling, David O; Balfour, Henry H; Hogquist, Kristin A

2015-12-01

Epstein-Barr virus (EBV) is a human herpesvirus that causes acute infectious mononucleosis and is associated with cancer and autoimmune disease. While many studies have been performed examining acute disease in adults following primary infection, little is known about the virological and immunological events during EBV's lengthy 6 week incubation period owing to the challenge of collecting samples from this stage of infection. We conducted a prospective study in college students with special emphasis on frequent screening to capture blood and oral wash samples during the incubation period. Here we describe the viral dissemination and immune response in the 6 weeks prior to onset of acute infectious mononucleosis symptoms. While virus is presumed to be present in the oral cavity from time of transmission, we did not detect viral genomes in the oral wash until one week before symptom onset, at which time viral genomes were present in high copy numbers, suggesting loss of initial viral replication control. In contrast, using a sensitive nested PCR method, we detected viral genomes at low levels in blood about 3 weeks before symptoms. However, high levels of EBV in the blood were only observed close to symptom onset-coincident with or just after increased viral detection in the oral cavity. These data imply that B cells are the major reservoir of virus in the oral cavity prior to infectious mononucleosis. The early presence of viral genomes in the blood, even at low levels, correlated with a striking decrease in the number of circulating plasmacytoid dendritic cells well before symptom onset, which remained depressed throughout convalescence. On the other hand, natural killer cells expanded only after symptom onset. Likewise, CD4+ Foxp3+ regulatory T cells decreased two fold, but only after symptom onset. We observed no substantial virus specific CD8 T cell expansion during the incubation period, although polyclonal CD8 activation was detected in concert with viral

HLA class I associations with EBV+ post-transplant lymphoproliferative disorder.

PubMed

Jones, Kimberley; Wockner, Leesa; Thornton, Alycia; Gottlieb, David; Ritchie, David S; Seymour, John F; Kumarasinghe, Gayathri; Gandhi, Maher K

2015-03-01

Epstein-Barr virus (EBV) is frequently associated with post-transplant lymphoproliferative disorders (EBV(+) PTLD). In these cases, impaired Epstein-Barr virus (EBV)-specific CD8(+) T-cell immunity is strongly implicated and antigen presentation within the malignant B-cell is intact. Interestingly, several studies have reported HLA class I alleles with protective or susceptibility associations. However, results are conflicting, likely influenced by methodology including inconsistent use of multiple hypothesis testing. By contrast, HLA class I associations have been repeatedly reported for classical Hodgkin Lymphoma (cHL), in which EBV is also implicated in a proportion of cases. In contrast to EBV(+) PTLD which expresses the immunodominant EBV latency III EBNA3A/B/C proteins, EBV(+) cHL is restricted to the subdominant EBNA1/LMP1/LMP2 proteins. Herein, we report a study of HLA class I associations in EBV(+) PTLD, with 263 patients with lymphoma (cHL or PTLD) evaluated. Two Australian population cohorts, n = 23,736 and n = 891 were used for comparison. Contrary to previous reports, no HLA class I associations with EBV(+) PTLD were found, whereas for cHL known HLA class I associations were confirmed, with HLA-A*02 homozygous individuals having the lowest odds of developing EBV(+) cHL. Our results suggest that HLA class I does not influence susceptibility to the viral latency III expressing lymphoma, EBV(+) PTLD. Further studies are required for definitive confirmation. Copyright © 2015. Published by Elsevier B.V.

Screening for acute HIV infection in South Africa: finding acute and chronic disease

PubMed Central

Bassett, Ingrid V.; Chetty, Senica; Giddy, Janet; Reddy, Shabashini; Bishop, Karen; Lu, Zhigang; Losina, Elena; Freedberg, Kenneth A.; Walensky, Rochelle P.

2010-01-01

Background The yield of screening for acute HIV infection among general medical patients in resource-scarce settings remains unclear. Our objective was to evaluate a strategy of pooled HIV plasma RNA to diagnose acute HIV infection in patients with negative or discordant rapid HIV antibody tests in Durban, South Africa. Methods We prospectively enrolled patients with negative or discordant rapid HIV antibody tests from a routine HIV screening program in an outpatient department in Durban with an HIV prevalence of 48%. Study participants underwent venipuncture for pooled qualitative HIV RNA, and if positive, quantitative RNA, enzyme immunoassay and Western Blot (WB). Patients with negative or indeterminate WB and positive quantitative HIV RNA were considered acutely infected. Those with chronic infection (positive RNA and WB) despite negative or discordant rapid HIV tests were considered false negative rapid antibody tests. Results Nine hundred ninety-four participants were enrolled with either negative (N=976) or discordant (N=18) rapid test results. Eleven (1.1%, 95% CI: 0.6–2.0%) had acute HIV infection. Of the 994 patients, an additional 20 (2.0%, 95% CI: 1.3–.3.1%) had chronic HIV infection (false negative rapid test). Conclusions One percent of outpatients with negative or discordant rapid HIV tests in Durban, South Africa had acute HIV infection readily detectable through pooled serum HIV RNA screening. Pooled RNA testing also identified an additional 2% of patients with chronic HIV infection. HIV RNA screening has the potential to identify both acute and chronic HIV infections that are otherwise missed by standard HIV testing algorithms. PMID:20553336

Seroprevalence of human herpes simplex, hepatitis B and epstein-barr viruses in children with acute lymphoblastic leukemia in southern iran.

PubMed

Mahjour, Seyed Babak; Ghaffarpasand, Fariborz; Fattahi, Mohammad Javad; Ghaderi, Abbas; Fotouhi Ghiam, Alireza; Karimi, Mehran

2010-12-01

To investigate the seroprevalence of Herpes Simplex Viruses (HSV1 and HSV2), Ebstein-Barr Virus (EBV) and Hepatitis B Virus (HBV) in children with acute lymphoblastic leukemia (ALL) in southern Iran. 90 patients with ALL and 90 age-sex matched healthy participants were enrolled in this study. Antibodies (IgG) against HBsAg, HSV1, HSV2, EBV different antigens including Epstein-Barr nuclear antigen-1 (EBNA-1), viral capsid antigen (VCA) and early antigen (EA) were measured by enzyme-linked immunosorbent assay (ELISA). There were 54 (60%) male and 36 (40%) female in both study groups with mean age of 8.47 ± 3.61 and 8.61 ± 2.84 years in case and control group respectively (P = 0.812). The prevalence of antibodies against HBsAg (P = 0.002), HSV1 (P < 0.0001), VCA (P = 0.021) and EA (P < 0.0001) antigens of EBV were significantly higher in ALL patients. With the results of this study, we could not exclude a connection between these viral infections and later leukemogenesis in childhood ALL, although nor latent infection nor congenital infection cannot be excluded by this method.

Host genetics of Epstein-Barr virus infection, latency and disease.

PubMed

Houldcroft, Charlotte J; Kellam, Paul

2015-03-01

Epstein-Barr virus (EBV) infects 95% of the adult population and is the cause of infectious mononucleosis. It is also associated with 1% of cancers worldwide, such as nasopharyngeal carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma. Human and cancer genetic studies are now major forces determining gene variants associated with many cancers, including nasopharyngeal carcinoma and Hodgkin's lymphoma. Host genetics is also important in infectious disease; however, there have been no large-scale efforts towards understanding the contribution that human genetic variation plays in primary EBV infection and latency. This review covers 25 years of studies into host genetic susceptibility to EBV infection and disease, from candidate gene studies, to the first genome-wide association study of EBV antibody response, and an EBV-status stratified genome-wide association study of Hodgkin's lymphoma. Although many genes are implicated in EBV-related disease, studies are often small, not replicated or followed up in a different disease. Larger, appropriately powered genomic studies to understand the host response to EBV will be needed to move our understanding of the biology of EBV infection beyond the handful of genes currently identified. Fifty years since the discovery of EBV and its identification as a human oncogenic virus, a glimpse of the future is shown by the first whole-genome and whole-exome studies, revealing new human genes at the heart of the host-EBV interaction. © 2014 The Authors Reviews in Medical Virology published by John Wiley & Sons Ltd.

Host genetics of Epstein–Barr virus infection, latency and disease

PubMed Central

Houldcroft, Charlotte J; Kellam, Paul

2015-01-01

Epstein–Barr virus (EBV) infects 95% of the adult population and is the cause of infectious mononucleosis. It is also associated with 1% of cancers worldwide, such as nasopharyngeal carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma. Human and cancer genetic studies are now major forces determining gene variants associated with many cancers, including nasopharyngeal carcinoma and Hodgkin's lymphoma. Host genetics is also important in infectious disease; however, there have been no large-scale efforts towards understanding the contribution that human genetic variation plays in primary EBV infection and latency. This review covers 25 years of studies into host genetic susceptibility to EBV infection and disease, from candidate gene studies, to the first genome-wide association study of EBV antibody response, and an EBV-status stratified genome-wide association study of Hodgkin's lymphoma. Although many genes are implicated in EBV-related disease, studies are often small, not replicated or followed up in a different disease. Larger, appropriately powered genomic studies to understand the host response to EBV will be needed to move our understanding of the biology of EBV infection beyond the handful of genes currently identified. Fifty years since the discovery of EBV and its identification as a human oncogenic virus, a glimpse of the future is shown by the first whole-genome and whole-exome studies, revealing new human genes at the heart of the host–EBV interaction. © 2014 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd. PMID:25430668

Two cases of chronic active Epstein-Barr virus infection in which EBV-specific cytotoxic T lymphocyte was induced after allogeneic bone marrow transplantation.

PubMed

Miyamura, Takako; Chayama, Kousuke; Wada, Tomoaki; Yamaguchi, Kazunari; Yamashita, Nobuko; Ishida, Toshiaki; Washio, Kana; Morishita, Naoto; Manki, Akira; Oda, Megumi; Morishima, Tsuneo

2008-08-01

CAEBV is a high mortality and morbidity disease with life-threatening complications. Nevertheless, the treatment regimens for CAEBV have not yet been established. Although some reports have described CAEBV therapy involving treatments such as antiviral drugs, immunomodulatory agents, and immunochemotherapy, none of these treatments have been demonstrated to be effective. The only treatment reported to be effective is allogeneic SCT. However, the complications of SCT are severe, so treatment results have been poor. Recently, immunotherapy has been devised, but this is still in the developmental stage. In this report, two cases of CAEBV in which allogeneic SCT was performed soon after diagnosis are reported. In both cases, a high EBV genome titer in the peripheral blood was detected at onset. After SCT, the EBV genome titer decreased as CTL activity gradually increased. This fact suggested that not only high-dose chemotherapy as a preconditioning treatment of SCT but also increased CTL activity which could eliminate virus-infected cells might be effective, although additional cases should be studied in order to establish effective treatments.

Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection.

PubMed

Chijioke, Obinna; Müller, Anne; Feederle, Regina; Barros, Mario Henrique M; Krieg, Carsten; Emmel, Vanessa; Marcenaro, Emanuela; Leung, Carol S; Antsiferova, Olga; Landtwing, Vanessa; Bossart, Walter; Moretta, Alessandro; Hassan, Rocio; Boyman, Onur; Niedobitek, Gerald; Delecluse, Henri-Jacques; Capaul, Riccarda; Münz, Christian

2013-12-26

Primary infection with the human oncogenic Epstein-Barr virus (EBV) can result in infectious mononucleosis (IM), a self-limiting disease caused by massive lymphocyte expansion that predisposes for the development of distinct EBV-associated lymphomas. Why some individuals experience this symptomatic primary EBV infection, whereas the majority acquires the virus asymptomatically, remains unclear. Using a mouse model with reconstituted human immune system components, we show that depletion of human natural killer (NK) cells enhances IM symptoms and promotes EBV-associated tumorigenesis mainly because of a loss of immune control over lytic EBV infection. These data suggest that failure of innate immune control by human NK cells augments symptomatic lytic EBV infection, which drives lymphocyte expansion and predisposes for EBV-associated malignancies. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Sexual history and Epstein-Barr virus infection.

PubMed

Crawford, Dorothy H; Swerdlow, Anthony J; Higgins, Craig; McAulay, Karen; Harrison, Nadine; Williams, Hilary; Britton, Kathryn; Macsween, Karen F

2002-09-15

To determine the role of sexual contact in transmission of Epstein-Barr virus (EBV) and occurrence of infectious mononucleosis (IM), a cross-sectional study was undertaken of EBV serologic testing and histories of IM and sexual behavior among 1006 new students at Edinburgh University. Prevalence of EBV seropositivity was significantly greater among women (79.2%) than among men (67.4%; P<.001) and among those who had ever been sexually active (82.7%) than among those who had not (63.7%; P<.001). Having a greater number of sex partners was a highly significant risk factor for EBV seropositivity. Two thirds of IM cases, but only a tenth of asymptomatic primary EBV infections, were statistically attributable to sexual intercourse. The findings suggest that EBV transmission occurs during sexual intercourse or closely associated behaviors. Transmission in this way appears to account for most cases of IM but for only a minority of cases of asymptomatic EBV infection, which mainly occur at younger ages.

Early age at time of primary Epstein-Barr virus infection results in poorly controlled viral infection in infants from Western Kenya: clues to the etiology of endemic Burkitt lymphoma.

PubMed

Piriou, Erwan; Asito, Amolo S; Sumba, Peter O; Fiore, Nancy; Middeldorp, Jaap M; Moormann, Ann M; Ploutz-Snyder, Robert; Rochford, Rosemary

2012-03-15

Infection with Epstein-Barr virus (EBV) early in life and repeated malaria exposure have been proposed as risk factors for endemic Burkitt lymphoma (eBL). Infants were enrolled from 2 rural sites in Kenya: the Kisumu District, where malaria transmission is holoendemic and risk for eBL is high, and the Nandi District, where malaria transmission is limited and the risk for eBL is low. Blood samples were taken from infants through 2 years of age to measure EBV viral load, EBV antibodies, and malaria parasitemia. We observed a significantly younger age at time of primary EBV infection in children from Kisumu compared with children from Nandi (mean age, 7.28 months [±0.33 SEM] in Kisumu vs 8.39 months [±0.26 SEM] in Nandi), with 35.3% of children in Kisumu infected before 6 months of age. To analyze how different predictors affected EBV viral load over time, we performed multilevel mixed modeling. This modeling revealed that residence in Kisumu and younger age at first EBV infection were significant predictors for having a higher EBV viral load throughout the period of observation. Children from a region at high risk for eBL were infected very early in life with EBV, resulting in higher viral loads throughout infancy.

[Characterization of BZLF1 gene and its promoter Zp of EBV strains in children with EBV-associated diseases in recent 5 years in Beijing area].

PubMed

Liu, Ya-Li; Ai, Uun-Hong; Yan, Jing; Guan, Xiao-Lei; Liu, Chun-Yan; Xie, Zheng-De

2014-01-01

This study aims to investigate the genetic characteristics of BZLF1 gene and its promoter Zp of the epidemic strains in children with primary Epstein-Barr virus (EBV)-associated diseases. Total DNA was extracted from the peripheral blood of 134 children with EBV-associated infectious mononucleosis (EBV-IM) and 32 children with EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) who were admitted to Beijing Children's Hospital from 2006 to 2011. The EBNA3C, BZLF1, and Zp genes were amplified by PCR assay. Typing of EBV was performed according to the size of the amplification product of EBNA3C gene; the amplification products of BZLF1 and Zp genes were subjected to direct sequencing, and sequence analysis was performed using BioEdit 7. 0. 9. The results were as follows: (1) EBV-1 was present in 140 samples (97.2%, 140/144) and EBV-II in 4 samples (2.8%, 4/144). (2) Three BZLF1 genotypes and their 12 subtypes (including 6 newly found subtypes) were detected in this study; there were no significant differences in the frequencies of BZLF1-A and BZLF1-B between the children with EBV-IM and EBV-HLH (P = 0.083); BZLF1-A1 was the dominant genotype in children with EBV-associated diseases; t BZLF1-A mostly had three 29-bp repeats in the first intron of BZLF1 gene, and BZLF1-B mostly had 30-bp repeats (P = 0.000), with the number of repeats varying from 1 to 13. (3) Four Zp genotypes were detected in this study, including Zp-P, Zp-V3, Zp-V4, and Zp-V1; there were no significant differences in the frequencies of these Zp genotypes between children with EBV-IM and EBV-HLH (P = 0.272, 0.252, 1.0, and 1.0, respectively). (4) The linkage analysis of BZLF1 gene and its promoter Zp showed that BZLF1-A1 was highly associated with Zp-V3 (P = 0.000), while BZLF1-B4 with Zp-P (P = 0.000); EBV-I + BZLF1 A1 was highly associated with Zp-V3 (P = 0.000), while EBV-I+BZLF1-B4 with Zp-P (P = 0.000). The conclusions are as follows: (1) BZLF1-A1 is the dominant genotype in children with

Inflammatory cytokine production in chronic active Epstein-Barr virus infection.

PubMed

Onozawa, Erika; Shibayama, Haruna; Imadome, Ken-Ichi; Tsuzura, Akiho; Koyama, Takatoshi; Miura, Osamu; Arai, Ayako

2017-01-01

In order to clarify the mechanisms underlying the development of inflammation in chronic active Epstein-Barr virus infection (CABEV), we examined cytokine production using patient samples. Eleven patients were analyzed. The serum concentrations of IFN-γ, TNF-α, and IL-6 were significantly higher in patients than in healthy donors. The mRNAs of these cytokines in peripheral blood mononuclear cells were elevated in patients as compared with healthy donors. The mRNA of IFN-γ was significantly higher in patients than in healthy donors. We examined which fraction produced the cytokines in the CD4-, CD8-, and CD56-positive fractions of PBMCs. The mRNAs of IFN-γ, TNF-α, and IL-6 were highly expressed in EBV-infected cells, whereas expression was also observed in non-infected cells. We performed in vitro infection of EBV on a T-cell line, MOLT4. EBV infection enhanced the mRNA expressions of IFN-γ and TNF-α. These results suggest that the inflammatory cytokines in CAEBV are produced not only by EBV-infected but also non-infected cells. EBV itself may have roles in the cytokine production observed in infected cells.

Acute infection contributes to racial disparities in stroke mortality.

PubMed

Levine, Deborah A; Langa, Kenneth M; Rogers, Mary A M

2014-03-18

It is unknown whether racial differences in exposure to acute precipitants of stroke, specifically infection, contribute to racial disparities in stroke mortality. Among participants in the nationally representative Health and Retirement Study with linked Medicare data (1991-2007), we conducted a case-crossover study employing within-person comparisons to study racial/ethnic differences in the risks of death and hospitalization from ischemic stroke following acute infection. There were 964 adults hospitalized for ischemic stroke. Acute infection increased the 30-day risks of ischemic stroke death (5.82-fold) and ischemic stroke hospitalization (1.87-fold). Acute infection was a more potent trigger of acute ischemic stroke death in non-Hispanic blacks (odds ratio [OR] 39.21; 95% confidence interval [CI] 9.26-166.00) than in non-Hispanic whites (OR 4.50; 95% CI 3.14-6.44) or Hispanics (OR 5.18; 95% CI 1.34-19.95) (race-by-stroke interaction, p = 0.005). When adjusted for atrial fibrillation, infection remained more strongly associated with stroke mortality in blacks (OR 34.85) than in whites (OR 3.58) and Hispanics (OR 3.53). Acute infection increased the short-term risk of incident stroke similarly across racial/ethnic groups. Infection occurred often before stroke death in non-Hispanic blacks, with 70% experiencing an infection in the 30 days before stroke death compared to a background frequency of 15%. Acute infection disproportionately increases the risk of stroke death for non-Hispanic blacks, independently of atrial fibrillation. Stroke incidence did not explain this finding. Acute infection appears to be one factor that contributes to the black-white disparity in stroke mortality.

TET2 functions as a resistance factor against DNA methylation acquisition during Epstein-Barr virus infection.

PubMed

Namba-Fukuyo, Hiroe; Funata, Sayaka; Matsusaka, Keisuke; Fukuyo, Masaki; Rahmutulla, Bahityar; Mano, Yasunobu; Fukayama, Masashi; Aburatani, Hiroyuki; Kaneda, Atsushi

2016-12-06

Extensive DNA methylation is observed in gastric cancer with Epstein-Barr virus (EBV) infection, and EBV infection is the cause to induce this extensive hypermethylaton phenotype in gastric epithelial cells. However, some 5' regions of genes do not undergo de novo methylation, despite the induction of methylation in surrounding regions, suggesting the existence of a resistance factor against DNA methylation acquisition. We conducted an RNA-seq analysis of gastric epithelial cells with and without EBV infection and found that TET family genes, especially TET2, were repressed by EBV infection at both mRNA and protein levels. TET2 was found to be downregulated by EBV transcripts, e.g. BARF0 and LMP2A, and also by seven human miRNAs targeting TET2, e.g., miR-93 and miR-29a, which were upregulated by EBV infection, and transfection of which into gastric cells repressed TET2. Hydroxymethylation target genes by TET2 were detected by hydroxymethylated DNA immunoprecipitation sequencing (hMeDIP-seq) with and without TET2 overexpression, and overlapped significantly with methylation target genes in EBV-infected cells. When TET2 was knocked down by shRNA, EBV infection induced de novo methylation more severely, including even higher methylation in methylation-acquired promoters or de novo methylation acquisition in methylation-protected promoters, leading to gene repression. TET2 knockdown alone without EBV infection did not induce de novo DNA methylation. These data suggested that TET2 functions as a resistance factor against DNA methylation in gastric epithelial cells and repression of TET2 contributes to DNA methylation acquisition during EBV infection.

Severe systemic autoimmune disease associated with Epstein-Barr virus infection.

PubMed

Sevilla, Julián; del Carmen Escudero, Maria; Jiménez, Raquel; González-Vicent, Marta; Manzanares, Javier; García-Novo, Dolores; Madero, Luis

2004-12-01

Infection with Epstein-Barr virus (EBV) has been associated with different autoimmune manifestations. The authors describe a girl who developed a severe systemic autoimmune disease with severe autoimmune hemolytic anemia, mild autoimmune thrombopenia, antineutrophil antibodies, and fatal autoimmune hepatitis after EBV infection. Despite immunosuppressive treatment and ultimately liver transplantation, this patient could not overcome her clinical condition and died. The etiopathogenesis of this complex disease and the association with EBV infection is discussed.

Acute infection contributes to racial disparities in stroke mortality

PubMed Central

Langa, Kenneth M.; Rogers, Mary A.M.

2014-01-01

Objective: It is unknown whether racial differences in exposure to acute precipitants of stroke, specifically infection, contribute to racial disparities in stroke mortality. Methods: Among participants in the nationally representative Health and Retirement Study with linked Medicare data (1991–2007), we conducted a case-crossover study employing within-person comparisons to study racial/ethnic differences in the risks of death and hospitalization from ischemic stroke following acute infection. Results: There were 964 adults hospitalized for ischemic stroke. Acute infection increased the 30-day risks of ischemic stroke death (5.82-fold) and ischemic stroke hospitalization (1.87-fold). Acute infection was a more potent trigger of acute ischemic stroke death in non-Hispanic blacks (odds ratio [OR] 39.21; 95% confidence interval [CI] 9.26–166.00) than in non-Hispanic whites (OR 4.50; 95% CI 3.14–6.44) or Hispanics (OR 5.18; 95% CI 1.34–19.95) (race-by-stroke interaction, p = 0.005). When adjusted for atrial fibrillation, infection remained more strongly associated with stroke mortality in blacks (OR 34.85) than in whites (OR 3.58) and Hispanics (OR 3.53). Acute infection increased the short-term risk of incident stroke similarly across racial/ethnic groups. Infection occurred often before stroke death in non-Hispanic blacks, with 70% experiencing an infection in the 30 days before stroke death compared to a background frequency of 15%. Conclusions: Acute infection disproportionately increases the risk of stroke death for non-Hispanic blacks, independently of atrial fibrillation. Stroke incidence did not explain this finding. Acute infection appears to be one factor that contributes to the black–white disparity in stroke mortality. PMID:24510494

Comparing the Clinical Features and Outcomes of Acute Hepatitis E Viral Infections with Those of Acute Hepatitis A, B, and C Infections in Korea.

PubMed

Oh, Hye Won; Cha, Ra Ri; Lee, Sang Soo; Lee, Chang Min; Kim, Wan Soo; Jo, Yun Won; Kim, Jin Joo; Lee, Jae Min; Kim, Hong Jun; Ha, Chang Yoon; Kim, Hyun Jin; Kim, Tae Hyo; Jung, Woon Tae; Lee, Ok Jae

2017-01-01

This study investigated the etiology of acute viral hepatitis and compared the clinical features of hepatitis E virus (HEV) infections with those of other acute viral hepatitis infections in Korea. This study included 2,357 consecutive patients who were diagnosed with acute hepatitis, based on acute illness with jaundice or elevated alanine aminotransferase levels (>100 IU/L), between January 2007 and January 2016. Acute viral infections were observed in 23 (19.8%) patients with HEV, 49 (42.2%) patients with hepatitis A virus, 28 (24.1%) patients with hepatitis B virus, and 16 (13.8%) patients with hepatitis C virus. The incidence of acute HEV infection was higher among older patients (median age: 49 years) and male patients (69.6%), and was associated with the consumption of undercooked or uncooked meat (43.5%). Half of the acute HEV infections involved underlying liver disease, such as alcoholic liver disease, chronic hepatitis B, common bile duct stones, and autoimmune hepatitis. Two HEV-infected patients were diagnosed with Guillain-Barré syndrome, although no patients developed fulminant hepatitis. Our findings indicate that HEV infection in Korea is frequently transmitted through the consumption of raw meat and may cause acute or chronic liver disease. © 2017 S. Karger AG, Basel.

Evaluation of Lipid Profile Changes in Pediatric Patients with Acute Mononucleosis

PubMed Central

2017-01-01

Background Acute Epstein-Barr virus (EBV) infection could lead to atherogenic lipid profile changes in adults; while there is no evidence about the children with Infectious mononucleosis (IM). The aim of this study was to evaluate the lipid profile of the children in acute phase of mononucleosis and two months after the recovery. Materials and Methods From 2010 through 2012, 36 children with IM aged 1-10 years were enrolled in a prospective cross-sectional study. Fasting serum total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglyceride level were measured during acute phase of the disease and after 2 months of the recovery. Results From 36 patients enrolled, 25 (69.4%) cases were male and the mean age of the patients was 4.1 ± 2.0 years. The mean of the total cholesterol level in the acute phase and 2 months after the recovery were149.5 ± 35.3 mg/dL and 145.7±30.6, respectively (P = 0.38). However, the serum level of HDL cholesterol in patients after 2 months of recovery was significantly increased (37.9 ± 9.3 mg/dL vs. 28.5 ± 10.6 mg/dL, P <0.001). The mean value of serum LDL cholesterol was significantly reduced, two months after recovery (81.4 ± 19.5 mg/dL, vs. 92.6 ± 28.8 mg/dL, P = 0.009). Furthermore, the serum triglyceride level was significantly reduced after the recovery (108.7 ± 36.9 mg/dL) compared with the acute phase (163.8 ± 114.3 mg/dL) (P = 0.004). Conclusion EBV infection in children could change lipid profile which is partially restored 2 months after the recovery. PMID:28332346

Acute Toxoplasma infection among family members of patients with acute lymphadenopathic toxoplasmosis.

PubMed

Luft, B J; Remington, J S

1984-01-01

Studies were performed to determine how frequently acute infections with Toxoplasma gondii occur among family members of patients with acute acquired lymphadenopathic toxoplasmosis. In five of the nine families studied, more than one family member had serologic evidence of recent acute infection with T gondii. In three of the families, the immunoglobulin M and immunoglobulin G antibody titers to T gondii among infected family members were similar irrespective of whether lymphadenopathy was present. Lymphadenopathy developed in one family member in each of two families (families VIII and IX) three and eight months after lymphadenopathy had developed in the index case (proband). These results suggest that common-source outbreaks occur with surprising frequency among family members of patients with lymphadenopathic toxoplasmosis and that the humoral response is similar with different manifestations of the infection.

The Role of Infected Cell Proliferation in the Clearance of Acute HBV Infection in Humans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goyal, Ashish; Ribeiro, Ruy Miguel; Perelson, Alan S.

Around 90–95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans. We employed fitting of mathematical models to human acute infection datamore » together with physiological constraints to investigate the role of these hypothesized mechanisms in the clearance of infection. Results suggest that cellular proliferation of infected cells resulting in two uninfected cells is required to minimize the destruction of the liver during the clearance of acute HBV infection. In contrast, we find that a cytokine-mediated cure of infected cells alone is insufficient to clear acute HBV infection. Lastly, our modeling indicates that HBV clearance without lethal loss of liver mass is associated with the production of two uninfected cells upon proliferation of an infected cell.« less

The Role of Infected Cell Proliferation in the Clearance of Acute HBV Infection in Humans

DOE PAGES

Goyal, Ashish; Ribeiro, Ruy Miguel; Perelson, Alan S.

2017-11-18

Around 90–95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans. We employed fitting of mathematical models to human acute infection datamore » together with physiological constraints to investigate the role of these hypothesized mechanisms in the clearance of infection. Results suggest that cellular proliferation of infected cells resulting in two uninfected cells is required to minimize the destruction of the liver during the clearance of acute HBV infection. In contrast, we find that a cytokine-mediated cure of infected cells alone is insufficient to clear acute HBV infection. Lastly, our modeling indicates that HBV clearance without lethal loss of liver mass is associated with the production of two uninfected cells upon proliferation of an infected cell.« less

Epstein-Barr virus-infected B cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction.

PubMed

Kurth, Julia; Hansmann, Martin-Leo; Rajewsky, Klaus; Küppers, Ralf

2003-04-15

To assess the impact of the germinal center (GC) reaction on viral spread in Epstein-Barr virus (EBV) infection, we isolated EBV(+) GC B cells from the tonsils of two infectious mononucleosis patients, sequenced their rearranged V genes, and determined expression of the EBV latency genes EBV nuclear antigen 2 and latent membrane protein 1. Most EBV(+) GC B cells belonged to clones of cells harboring somatically mutated V gene rearrangements. Ongoing somatic hypermutation, the hallmark of the GC reaction, was seen only in uninfected GC B cell clones, not in EBV(+) B cell clones. Thus, in infectious mononucleosis, GC and/or memory B cells are directly infected by EBV and expand without somatic hypermutation, whereas the GC passage of EBV-infected naive B cells does not contribute detectably to the generation of infected memory B cells, the main reservoir of EBV during persistence. Most, if not all, EBV-infected cells in GCs exhibited an unusual EBV gene expression pattern in that they were positive for EBV nuclear antigen 2 but negative for latent membrane protein 1. Although the three main types of EBV-associated B cell lymphomas (Burkitt's, Hodgkin's, and posttransplant lymphomas) presumably are derived from GC B cells, EBV(+) GC B cells resembling these EBV(+) GC B cell lymphomas in terms of EBV gene expression and somatic hypermutation pattern could not be identified.

Prospective Characterization of the Risk Factors for Transmission and Symptoms of Primary Human Herpesvirus Infections Among Ugandan Infants.

PubMed

Gantt, Soren; Orem, Jackson; Krantz, Elizabeth M; Morrow, Rhoda Ashley; Selke, Stacy; Huang, Meei-Li; Schiffer, Joshua T; Jerome, Keith R; Nakaganda, Annet; Wald, Anna; Casper, Corey; Corey, Lawrence

2016-07-01

Human herpesvirus (HHV) infections are common during infancy. Primary infections are frequently asymptomatic and best studied prospectively by using direct viral detection. Oropharyngeal swab specimens were collected weekly from Ugandan newborn infants, their mothers, and other children in the household. Blood specimens were collected every 4 months. Samples were tested for herpes simplex virus (HSV) types 1 and 2, Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6A, HHV-6B, and HHV-8, using quantitative polymerase chain reaction. Thirty-two infants, 32 mothers, and 49 other household children were followed for a median of 57 weeks. Seventeen mothers had human immunodeficiency virus type 1 (HIV) infection; no infants acquired HIV-1. The 12-month incidence of postnatal infection was 76% for HHV-6B, 59% for CMV, 47% for EBV, 8% for HSV-1, and 0% for HHV-8. The quantity of oropharyngeal shedding by contacts was associated with HHV-6A or HHV-6B transmission. Maternal HIV-1 infection was associated with EBV transmission, while breastfeeding and younger child contacts were associated with CMV transmission. Except for HSV-1, primary HHV infections were subclinical. By capturing exposures and acquisition events, we found that the incidence and risk factors of infection vary by HHV type. HSV-1 infection, unlike other HHV infections, caused acute clinical illness in these infants. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

In situ hybridisation of EBV DNA-DNA hybrids using wet heat in polypropylene containers.

PubMed Central

Labrecque, L G

1992-01-01

AIMS: To explore procedures designed to optimise DNA-DNA in situ hybridisation, using cells infected with Epstein-Barr virus (EBV) and tissues and subfragments of the EBV DNA as probes. METHODS: The denaturation step occurred in a polypropylene container, using wet heat generated by a hot water container, the pressure cooker, or the microwave oven, without coverslips, reaching a temperature of 121 degrees C or more in these two last systems. Two different visualisation systems were used. RESULTS: Fixed cells and tumours harbouring a high and medium to low copy number (a few hundreds to 33 copies per cell), were clearly labelled, using a simple reiterated subfragment (BamW) of the EBV DNA, and fresh frozen cells, harbouring a very low copy number (one to two on average) labelled using BamW as well as BamH (single non-reiterated 6 kilobase subfragment). CONCLUSION: This is a valuable alternative technique for DNA-DNA ISH that can be used in fresh frozen samples as well as fixed samples. Images PMID:1336018

Virus-specific cytotoxic T cells in chronic active Epstein-Barr virus infection.

PubMed

Shibayama, Haruna; Imadome, Ken-Ichi; Onozawa, Erika; Tsuzura, Akiho; Miura, Osamu; Koyama, Takatoshi; Arai, Ayako

2017-01-01

Chronic active Epstein-Barr virus infection (CAEBV) is a disease characterized by clonally proliferating and activated EBV-infected T or NK cells accompanied by chronic inflammation and T- or NK-cell neoplasms. However, the mechanism for developing CAEBV has not been clarified to date. Because the decreased number or inactivation of EBV-specific cytotoxic T lymphocytes (CTLs) resulted in the development of EBV-positive B-cell neoplasms, we investigated the number of CTLs in CAEBV patients using the tetrameric complexes of HLA-restricted EBV-specific peptides. Among the seven patients examined, EBV-specific CTLs were detected in the peripheral blood mononuclear cells (PBMCs) of four cases but were not detected in three cases. The ratio of EBV-specific CTLs in PBMCs tended to be higher in the patients with active disease than in those with inactive disease. In two patients in whom EBV-specific CTLs had not been detected, CTLs appeared after the eradication of EBV-infected T cells by allogeneic bone marrow transplantation. These results suggested that the failure of CTLs had a role in developing CAEBV, although the induction number and function of EBV-specific CTLs might vary in each patient.

Infectious mononucleosis

PubMed Central

Balfour, Henry H; Dunmire, Samantha K; Hogquist, Kristin A

2015-01-01

Infectious mononucleosis is a clinical entity characterized by pharyngitis, cervical lymph node enlargement, fatigue and fever, which results most often from a primary Epstein–Barr virus (EBV) infection. EBV, a lymphocrytovirus and a member of the γ-herpesvirus family, infects at least 90% of the population worldwide, the majority of whom have no recognizable illness. The virus is spread by intimate oral contact among adolescents, but how preadolescents acquire the virus is not known. During the incubation period of approximately 6 weeks, viral replication first occurs in the oropharynx followed by viremia as early as 2 weeks before onset of illness. The acute illness is marked by high viral loads in both the oral cavity and blood accompanied by the production of immunoglobulin M antibodies against EBV viral capsid antigen and an extraordinary expansion of CD8+ T lymphocytes directed against EBV-infected B cells. During convalescence, CD8+ T cells return to normal levels and antibodies develop against EBV nuclear antigen-1. A typical clinical picture in an adolescent or young adult with a positive heterophile test is usually sufficient to make the diagnosis of infectious mononucleosis, but heterophile antibodies are not specific and do not develop in some patients especially young children. EBV-specific antibody profiles are the best choice for staging EBV infection. In addition to causing acute illness, long-term consequences are linked to infectious mononucleosis, especially Hodgkin lymphoma and multiple sclerosis. There is no licensed vaccine for prevention and no specific approved treatment. Future research goals are development of an EBV vaccine, understanding the risk factors for severity of the acute illness and likelihood of developing cancer or autoimmune diseases, and discovering anti-EBV drugs to treat infectious mononucleosis and other EBV-spurred diseases. PMID:25774295

Infectious mononucleosis.

PubMed

Balfour, Henry H; Dunmire, Samantha K; Hogquist, Kristin A

2015-02-01

Infectious mononucleosis is a clinical entity characterized by pharyngitis, cervical lymph node enlargement, fatigue and fever, which results most often from a primary Epstein-Barr virus (EBV) infection. EBV, a lymphocrytovirus and a member of the γ-herpesvirus family, infects at least 90% of the population worldwide, the majority of whom have no recognizable illness. The virus is spread by intimate oral contact among adolescents, but how preadolescents acquire the virus is not known. During the incubation period of approximately 6 weeks, viral replication first occurs in the oropharynx followed by viremia as early as 2 weeks before onset of illness. The acute illness is marked by high viral loads in both the oral cavity and blood accompanied by the production of immunoglobulin M antibodies against EBV viral capsid antigen and an extraordinary expansion of CD8(+) T lymphocytes directed against EBV-infected B cells. During convalescence, CD8(+) T cells return to normal levels and antibodies develop against EBV nuclear antigen-1. A typical clinical picture in an adolescent or young adult with a positive heterophile test is usually sufficient to make the diagnosis of infectious mononucleosis, but heterophile antibodies are not specific and do not develop in some patients especially young children. EBV-specific antibody profiles are the best choice for staging EBV infection. In addition to causing acute illness, long-term consequences are linked to infectious mononucleosis, especially Hodgkin lymphoma and multiple sclerosis. There is no licensed vaccine for prevention and no specific approved treatment. Future research goals are development of an EBV vaccine, understanding the risk factors for severity of the acute illness and likelihood of developing cancer or autoimmune diseases, and discovering anti-EBV drugs to treat infectious mononucleosis and other EBV-spurred diseases.

Infection frequency of Epstein-Barr virus in subgingival samples from patients with different periodontal status and its correlation with clinical parameters*

PubMed Central

Wu, Yan-min; Yan, Jie; Chen, Li-li; Sun, Wei-lian; Gu, Zhi-yuan

2006-01-01

Objective: To detect the infection frequencies of different genotypes of Epstein-Barr virus (EBV) in subgingival samples from chronic periodontitis (CP) patients, and to discuss the correlation between infection with EBV and clinical parameters. Methods: Nested-PCR assay was used to detect EBV-1 and EBV-2 in subgingival samples from 65 CP patients, 65 gingivitis patients and 24 periodontally healthy individuals. The amplicons were further identified by restriction fragment length polymorphism analysis (RFLP) with endonucleases Afa I and Stu I. Clinical parameters mainly included bleeding on probing (BOP), probing depth (PD), attachment loss (AL) in six sites of the dentition. Results: In CP patients, gingivitis and periodontally healthy individuals, the infection frequencies were 47.7%, 24.6% and 16.7% for EBV-1, and 15.4%, 7.7% and 0% for EBV-2, respectively. In 2 out of the 65 CP patients co-infection of EBV-1 and EBV-2 was found. The positive rate of EBV-1 in chronic periodontitis patients was higher than that in gingivitis patients (P=0.01) and periodontally healthy individuals (P=0.01). But no significant difference was shown in EBV-1 frequency between gingivitis patients and healthy individuals (P>0.05) or in EBV-2 frequency among the three groups (P>0.05). In CP patients, higher mean BOP value was found in EBV-1 or EBV-2 positive patients than that in EBV negative ones (P<0.01), but with no statistical difference in the mean PD or AL value between EBV positive and negative patients (P>0.05). After initial periodontal treatment, 12 out of the 21 EBV-1 positive CP patients did not show detectable EBV-1 in subgingival samples. Conclusion: nPCR plus RFLP analysis is a sensitive, specific and stable method to detect EBV-1 and EBV-2 in subgingival samples. Subgingival infection with EBV-1 is closely associated with chronic periodontitis. Infection of EBV in subgingival samples was correlated with BOP. PMID:17048301

Mononucleosis syndrome and coincidental human herpesvirus-7 and Epstein-Barr virus infection

PubMed Central

Chiu, H; Lee, C; Lee, P; Lin, K; Huang, L

1998-01-01

Two girls (a 5 year old and a 21 month old) experiencing mononucleosis syndrome with coincidental human herpesvirus (HHV)-7 and Epstein-Barr virus (EBV) infections are described. One patient had primary HHV-7 infection and reactivated EBV infection. The other had primary HHV-7 and EBV infections. These cases indicated that HHV-7 is capable of inducing infectious mononucleosis-like illness. Multiple herpesvirus infection in one of the patients also suggests that interaction among herpesviruses can occur in vivo. The consequence of this interaction may have clinical implications.

 PMID:9659100

[Agranulocytosis as a complication of acute infectious mononucleosis].

PubMed

Brkić, S; Aleksić-Dordević, M; Belić, A; Jovanović, J; Bogdanović, M

1998-01-01

Acute infections mononucleosis is the most common clinical manifestation of primary Epstein-Barr virus (EBV) infection occurring during adolescence. It is a benign lymphoproliferative, usually self-limiting disease. Complications are relatively rare, but they may occur, especially hematological. Most common are autoimmune hematolytic anemia and thrombocytopenia, and they respond to corticoid therapy. Deuteration of white blood cells is rather rare, whereas mild neutropenia is a normal finding during the course of acute disease. On the other hand, agranulocytosis is extremely rate, and almost every case has been reported in the literature. Filgrastim--the recombinant human granulocyte colony-stimulating factor (G-CSF) stimulates the activation, proliferation and maturation of progenitor granulocyte cells. This drug is usually applied in treatment of iatrogenic neutropenia, during chemotherapy of malignancies and in some idiopathic and cyclic neutopenias. A female patient, 18 years of age, has been hospitalized at the Clinic of Infectious Diseases in Novi Sad on two occasions. First because of severe acute infectious mononucleosis with acute hepatitis and jaundice 10 days after onset of symptoms. Physical examination revealed severe intoxication, dehydration, icteric skin, mucosis and massive hepatosplenomegaly. The diagnosis was confirmed by ELISA IgM, EBV VCA positive and ELISA IgG EBV VCA and IgG EBVNA negative results. The patient was discharged from hospital after 24 days without complaints and with normal physical and laboratory findings. For several days she felt well, but gradually severe fatigue and malaise occurred and she became febrile again. That was the reason why she was hospitalized again, two weeks later. This time she was febrile, extremely intoxicated with general lymphadenopathy, catarrhal gingivostomatitis and massive splenomegaly. The first laboratory findings showed severe neutropenia (absolute count of granulocytes was 0.156 x 10/l, with only

Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient.

PubMed

Ates, İhsan; Kaplan, Mustafa; Yilmaz, Nisbet; Çiftçi, Filiz

2015-01-01

Acute hepatitis is a disorder that goes with liver cell necrosis and liver inflammation. Among the causes of acute hepatitis, the most common reasons are viral hepatitis. About 95% of the acute hepatitis generate because of hepatotropic viruses. Epstein-barr virus (EBV) and cytomegalovirus (CMV) are from the family of herpes viruses and rare causes of acute hepatitis. In this case report, acute hepatitis due to EBV and CMV coinfection will be described. Ates İ, Kaplan M, Yilmaz N, Çiftçi F. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient. Euroasian J Hepato-Gastroenterol 2015;5(1):60-61.

Epstein-Barr virus DNA loads in adult human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy

NASA Technical Reports Server (NTRS)

Ling, Paul D.; Vilchez, Regis A.; Keitel, Wendy A.; Poston, David G.; Peng, Rong Sheng; White, Zoe S.; Visnegarwala, Fehmida; Lewis, Dorothy E.; Butel, Janet S.

2003-01-01

Patients with human immunodeficiency virus type 1 (HIV-1) infection are at high risk of developing Epstein-Barr virus (EBV)-associated lymphoma. However, little is known of the EBV DNA loads in patients receiving highly active antiretroviral therapy (HAART). Using a real-time quantitative polymerase chain reaction assay, we demonstrated that significantly more HIV-1-infected patients receiving HAART than HIV-1-uninfected volunteers had detectable EBV DNA in blood (57 [81%] of 70 vs. 11 [16%] of 68 patients; P=.001) and saliva (55 [79%] of 68 vs. 37 [54%] of 68 patients; P=.002). The mean EBV loads in blood and saliva samples were also higher in HIV-1-infected patients than in HIV-1-uninfected volunteers (P=.001). The frequency of EBV detection in blood was associated with lower CD4+ cell counts (P=.03) among HIV-1-infected individuals, although no differences were observed in the EBV DNA loads in blood or saliva samples in the HIV-1-infected group. Additional studies are needed to determine whether EBV-specific CD4+ and CD8+ cells play a role in the pathogenesis of EBV in HIV-1-infected patients receiving HAART.

[Correlation between results of PCR and specific serological tests in diagnosis of Epstein-Barr virus in patients with mononucleosis syndrome].

PubMed

Banko, A V; Lazarević, I B; Cupić, M D; Knezević, A M; Stevanović, G D; Krejović-Trivić, S B; Jovanović, T P

2009-01-01

Routine laboratory diagnosis of infectious mononucleosis is based on EBV serological testing, but due to problems in interpretation of results, molecular methods, especially PCR, are often necessary. The aim of the present study was to investigate correlation between results of PCR and specific serological tests in diagnosis of Epstein-Barr virus in patients with mononucleosis syndrome. The study comprised 68 patients with mononucleosis syndrome. Their blood samples were tested using ELISA for detection of 4 EBV specific antibodies (anti-VCA IgM and IgG, anti-EA-D IgG and anti-EBNA-1 IgG) and PCR for detection of EBV DNA. According to results of serology 42 patients had acute primary infection, 2 reactivation, 1 chronic active infection, 19 past infection, and 4 have been EBV seronegative. EBV DNA was detected in 17 patients (25%) and all of them were serologically defined as acutely infected. PCR was useful for resolving unclear serology results. Specific serology is the first step in diagnosis of IM, but PCR may serve as a useful additional diagnostic tool for clarifying serological dilemmas, reaching final diagnosis and defining status of the infection.

Epstein-Barr virus lytic infection promotes activation of Toll-like receptor 8 innate immune response in systemic sclerosis monocytes.

PubMed

Farina, Antonella; Peruzzi, Giovanna; Lacconi, Valentina; Lenna, Stefania; Quarta, Silvia; Rosato, Edoardo; Vestri, Anna Rita; York, Michael; Dreyfus, David H; Faggioni, Alberto; Morrone, Stefania; Trojanowska, Maria; Farina, G Alessandra

2017-02-28

Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma; SSc), with increased expression of interferon (IFN)-regulatory genes and inflammatory cytokines, suggesting dysregulation of the innate immune response in autoimmunity. In this study, we investigated whether the lytic form of Epstein-Barr virus (EBV) infection (infectious EBV) is present in scleroderma monocytes and contributes to their activation in SSc. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) depleted of the CD19+ cell fraction, using CD14/CD16 negative-depletion. Circulating monocytes from SSc and healthy donors (HDs) were infected with EBV. Gene expression of innate immune mediators were evaluated in EBV-infected monocytes from SSc and HDs. Involvement of Toll-like receptor (TLR)8 in viral-mediated TLR8 response was investigated by comparing the TLR8 expression induced by infectious EBV to the expression stimulated by CL075/TLR8/agonist-ligand in the presence of TLR8 inhibitor in THP-1 cells. Infectious EBV strongly induced TLR8 expression in infected SSc and HD monocytes in vitro. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were upregulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally induced TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral mRNA and proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes. This study provides the first evidence of infectious EBV in monocytes from patients with SSc and links EBV to the activation of TLR8 and IFN innate immune response in freshly isolated SSc monocytes. This study provides the first evidence of EBV replication activating the TLR8 molecular pathway

Acute renal failure: unusual complication of Epstein-Barr virus-induced infectious mononucleosis.

PubMed

Lei, P S; Lowichik, A; Allen, W; Mauch, T J

2000-12-01

A 17-year-old boy with juvenile rheumatoid arthritis presented with jaundice, confusion, hemolytic anemia, thrombocytopenia, and acute renal failure secondary to titer-confirmed acute Epstein-Barr virus (EBV). Renal biopsy specimen revealed interstitial nephritis with an inflammatory infiltrate composed of cytotoxic/suppressor T cells, and interstitial mononuclear cell nuclei expressed EBV encoded RNA-1 (EBER-1) mRNA. Methylprednisolone treatment resulted in rapid improvement.

Dynamics of Viral and Host Immune Cell MicroRNA Expression during Acute Infectious Mononucleosis

PubMed Central

Kaul, Vandana; Weinberg, Kenneth I.; Boyd, Scott D.; Bernstein, Daniel; Esquivel, Carlos O.; Martinez, Olivia M.; Krams, Sheri M.

2018-01-01

Epstein–Barr virus (EBV) is the etiological agent of acute infectious mononucleosis (IM). Since acute IM is a self-resolving disease with most patients regaining health in 1–3 weeks there have been few studies examining molecular signatures in early acute stages of the disease. MicroRNAs (miRNAs) have been shown, however, to influence immune cell function and consequently the generation of antibody responses in IM. In this study, we performed a comprehensive analysis of differentially expressed miRNAs in early stage uncomplicated acute IM. miRNAs were profiled from patient peripheral blood obtained at the time of IM diagnosis and at subsequent time points, and pathway analysis performed to identify important immune and cell signaling pathways. We identified 215 differentially regulated miRNAs at the most acute stage of infection when the patients initially sought medical help. The number of differentially expressed miRNAs decreased to 148 and 68 at 1 and 2 months post-primary infection, with no significantly changed miRNAs identified at 7 months post-infection. Interferon signaling, T and B cell signaling and antigen presentation were the top pathways influenced by the miRNAs associated with IM. Thus, a dynamic and regulated expression profile of miRNA accompanies the early acute immune response, and resolution of infection, in IM. PMID:29379474

Infectious mononucleosis at the United States Military Academy. A prospective study of a single class over four years.

PubMed

Hallee, T J; Evans, A S; Niederman, J C; Brooks, C M; Voegtly, j H

1974-09-01

A prospective study of EB virus infections was initiated in July, 1969 in the entering class of 1401 cadets, at the U.S. Military Academy at West Point, N.Y. and continued over 4 yr. On entry 63.5% possessed EBV antibody and 36.5 lacked EBV antibody. The rate of antibody prevalence varied with the geographic area from which the cadet originated.Except in two cadets already ill on first bleeding no evidence of clinical infectious mononucleosis (I.M.) occurred over the 4 yr period in the 890 cadets entering the Academy with EBV antibody. Among 437 cadets without antibody on entry, 54 or 12.4% were infected (seroconverted) in the freshman year; 15 of these had clinical I.M., 12 had suggestive I.M., and 39 had no known mono-like illness. The annual infection rates in susceptible cadets in the second, third, and fourth years were 24.4, 15.1, and 30.8 per 100, respectively. Of 201 cadets infected with EBV over 4 yr only 26.4% were manifested by heterophile positive clinical infectious mononucleosis. Overall, 46% of the 437 cadets entering without EBV antibody became infected over 40 mo of serologic observation; definite clinical infectious mononucleosis developed in 53 cadets, a clinical attack rate of 12.1 per 100 for 4 yr. The EBV infection rate among exposed and susceptible roommates of known cases was no higher than in roommates not so exposed.Elevations of EBV-specific and total IgM occurred during acute illness and disappeared in late convalescence. Total IgG and IgA levels were less commonly elevated. EBV-specific-IgM antibody was demonstrable during the acute illness but was absent 12 mo later. Analysis of EBV infection rates revealed no difference among persons of different ABO blood groups.

Infectious Mononucleosis at the United States Military Academy. A Prospective Study of a Single Class Over Four Years 1

PubMed Central

Hallee, T. James; Evans, Alfred S.; Niederman, James C.; Brooks, Charles M.; Voegtly, John H.

1974-01-01

A prospective study of EB virus infections was initiated in July, 1969 in the entering class of 1401 cadets, at the U.S. Military Academy at West Point, N.Y. and continued over 4 yr. On entry 63.5% possessed EBV antibody and 36.5 lacked EBV antibody. The rate of antibody prevalence varied with the geographic area from which the cadet originated. Except in two cadets already ill on first bleeding no evidence of clinical infectious mononucleosis (I.M.) occurred over the 4 yr period in the 890 cadets entering the Academy with EBV antibody. Among 437 cadets without antibody on entry, 54 or 12.4% were infected (seroconverted) in the freshman year; 15 of these had clinical I.M., 12 had suggestive I.M., and 39 had no known mono-like illness. The annual infection rates in susceptible cadets in the second, third, and fourth years were 24.4, 15.1, and 30.8 per 100, respectively. Of 201 cadets infected with EBV over 4 yr only 26.4% were manifested by heterophile positive clinical infectious mononucleosis. Overall, 46% of the 437 cadets entering without EBV antibody became infected over 40 mo of serologic observation; definite clinical infectious mononucleosis developed in 53 cadets, a clinical attack rate of 12.1 per 100 for 4 yr. The EBV infection rate among exposed and susceptible roommates of known cases was no higher than in roommates not so exposed. Elevations of EBV-specific and total IgM occurred during acute illness and disappeared in late convalescence. Total IgG and IgA levels were less commonly elevated. EBV-specific-IgM antibody was demonstrable during the acute illness but was absent 12 mo later. Analysis of EBV infection rates revealed no difference among persons of different ABO blood groups. PMID:4374836

Clinicopathological analysis of 12 patients with Epstein-Barr virus-positive primary intestinal T/natural killer-cell lymphoma (EBV+ ITNKL).

PubMed

Hu, Lei-Ming; Takata, Katsuyoshi; Miyata-Takata, Tomoko; Asano, Naoko; Takahashi, Emiko; Furukawa, Katsuya; Miyoshi, Hiroaki; Satou, Akira; Kohno, Kei; Kosugi, Hiroshi; Kinoshita, Tomohiro; Hirooka, Yoshiki; Goto, Hidemi; Nakamura, Shigeo; Kato, Seiichi

2017-06-01

Epstein-Barr virus-positive (EBV + ) intestinal T/natural killer (NK) cell lymphoma (ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor (TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV + ITNKL. We enrolled 12 patients with EBV + ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL (PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection (CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression (P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR-γ rearrangement was found in six patients (50%). Interestingly, EBV + intra-epithelial lymphocytosis was observed in one case with a background of CAEBV. This study is the first to shed light on the significant heterogeneity of EBV + ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice. © 2017 John Wiley & Sons Ltd.

Infections and systemic lupus erythematosus.

PubMed

Esposito, S; Bosis, S; Semino, M; Rigante, D

2014-09-01

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that presents a protean spectrum of clinical manifestations, and may affect any organ. The typical course of SLE is insidious, slow, and progressive, with potential exacerbations and remissions, and even dramatically acute and rapidly fatal outcomes. Recently, infections have been shown to be highly associated with the onset and/or exacerbations of SLE, and their possible causative and/or protective role has been largely emphasized in the medical literature. However, the etiopathogenesis of SLE is still obscure and far from being completely elucidated. Among infections, particularly Epstein-Barr virus (EBV), parvovirus B19, retrovirus, and cytomegalovirus (CMV) infections might play a pivotal pathogenetic role. The multifaceted interactions between infections and autoimmunity reveal many possibilities for either causative or protective associations. Indeed, some infections, primarily protozoan infections, might confer protection from autoimmune processes, depending on the unique interaction between the microorganism and host. Further studies are needed in order to demonstrate that infectious agents might, indeed, be causative of SLE, and to address the potential clinical sequelae of infections in the field of autoimmunity.

Nonsteroidal Anti-Inflammatory Drugs Quickly Resolve Symptoms Associated with EBV-Induced Infectious Mononucleosis in Patients with Atopic Predispositions.

PubMed

Kazama, Itsuro; Miura, Chieko; Nakajima, Toshiyuki

2016-02-14

Infectious mononucleosis is a clinical syndrome most commonly associated with primary Epstein-Barr virus (EBV) infection. In adults, the symptoms can often be severe and prolonged, sometimes causing serious complications. Analgesic or antipyretic drugs are normally used to relieve the symptoms. However, there is no causal treatment for the disease. Two cases of adult patients with atopic predispositions developed nocturnal fever, general fatigue, pharyngitis and lymphadenopathy after an exacerbation of atopic symptoms or those of allergic rhinitis. Due to the positive results for EBV viral-capsid antigen (VCA) IgM and negative results for EBV nuclear antigen (EBNA) IgG, diagnoses of infectious mononucleosis induced by EBV were made in both cases. Although oral antibiotics or acetaminophen alone did not improve the deteriorating symptoms, including fever, headache and general fatigue, nonsteroidal anti-inflammatory drugs (NSAIDs), such as tiaramide or loxoprofen, completely improved the symptoms quickly after the initiation. In these cases, given the atopic predispositions of the patients, an enhanced immunological response was likely to be mainly responsible for the pathogenesis of the symptoms. In such cases, NSAIDs, that are known to reduce the activity of EBV, may dramatically improve the deteriorating symptoms quickly after the initiation. In the present cases, the immunosuppressive property of these drugs was considered to suppress the activity of lymphocytes and thus provide the rapid and persistent remission of the disease.

Epstein-Barr Virus-positive T-cell Lymphoproliferative Disease Following Umbilical Cord Blood Transplantation for Acute Myeloid Leukemia.

PubMed

Yui, Shunsuke; Yamaguchi, Hiroki; Imadome, Ken-ichi; Arai, Ayako; Takahashi, Mikiko; Ohashi, Ryuji; Tamai, Hayato; Moriya, Keiichi; Nakayama, Kazutaka; Shimizu, Akira; Inokuchi, Koiti

2016-01-01

We report a case of the extremely rare condition Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (LPD) which occurred after umbilical cord blood transplantation. A 25-year-old Japanese man underwent cord blood transplantation from a male human leukocyte antigen 4/6-matched donor due to acute myeloid leukemia with trisomy 8. Bone marrow examination on day 30 showed chimerism with at least 90% donor cells and complete hematological response. Chronic symptoms of graft-versus-host disease appeared only on the skin and were successfully treated with cyclosporine alone. Three years later, however, the patient experienced repeated cold-like symptoms and was hospitalized with liver dysfunction. A high fever developed and was followed by significant edema of the right side of the face. The EBV DNA copy number in whole peripheral blood was 2×10(4)/mL. Liver biopsy showed invasion of EBV-infected CD8-positive T cells. Southern blotting analysis of the whole peripheral blood showed that the T-cell receptor Cβ1 rearrangement was positive. On the basis of these results, EBV-positive T-cell LPD was diagnosed and treated with prednisolone, cyclosporine, and etoposide, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient died of cardiac function failure, pneumonia, and pulmonary hemorrhage, all of unidentified cause. Most cases of EBV-related LPD after hematopoietic stem cell transplantation consist of EBV-positive B-cell LPD, and, to our knowledge, de novo EBV-positive T-cell LPD subsequent to transplantation has not been previously reported.

A possible link between the Epstein-Barr virus infection and autoimmune thyroid disorders.

PubMed

Dittfeld, Anna; Gwizdek, Katarzyna; Michalski, Marek; Wojnicz, Romuald

2016-01-01

The Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a member of the Herpesviridae virus family. EBV infection can cause infectious mononucleosis (IM) in the lytic phase of EBV's life cycle. Past EBV infection is associated with lymphomas, and may also result in certain allergic and autoimmune diseases. Although potential mechanisms of autoimmune diseases have not been clearly elucidated, both genetic and environmental factors, such as infectious agents, are considered to be responsible for their development. In addition, EBV modifies the host immune response. The worldwide prevalence of autoimmune diseases shows how common this pathogen is. Normally, the virus stays in the body and remains dormant throughout life. However, this is not always the case, and a serious EBV-related illness may develop later in life. This explains the chronic course of autoimmune diseases that is often accompanied by exacerbations of symptoms. Based on the present studies, EBV infection can cause autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren's syndrome, and autoimmune hepatitis. The EBV has also been reported in patients with autoimmune thyroid disorders. Although EBV is not the only agent responsible for the development of autoimmune thyroid diseases, it can be considered a contributory factor.

Regulation of tumour related genes by dynamic epigenetic alteration at enhancer regions in gastric epithelial cells infected by Epstein-Barr virus.

PubMed

Okabe, Atsushi; Funata, Sayaka; Matsusaka, Keisuke; Namba, Hiroe; Fukuyo, Masaki; Rahmutulla, Bahityar; Oshima, Motohiko; Iwama, Atsushi; Fukayama, Masashi; Kaneda, Atsushi

2017-08-11

Epstein-Barr virus (EBV) infection is associated with tumours such as Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancer. We previously showed that EBV(+) gastric cancer presents an extremely high-methylation epigenotype and this aberrant DNA methylation causes silencing of multiple tumour suppressor genes. However, the mechanisms that drive EBV infection-mediated tumorigenesis, including other epigenomic alteration, remain unclear. We analysed epigenetic alterations induced by EBV infection especially at enhancer regions, to elucidate their contribution to tumorigenesis. We performed ChIP sequencing on H3K4me3, H3K4me1, H3K27ac, H3K27me3, and H3K9me3 in gastric epithelial cells infected or not with EBV. We showed that repressive marks were redistributed after EBV infection, resulting in aberrant enhancer activation and repression. Enhancer dysfunction led to the activation of pathways related to cancer hallmarks (e.g., resisting cell death, disrupting cellular energetics, inducing invasion, evading growth suppressors, sustaining proliferative signalling, angiogenesis, and tumour-promoting inflammation) and inactivation of tumour suppressive pathways. Deregulation of cancer-related genes in EBV-infected gastric epithelial cells was also observed in clinical EBV(+) gastric cancer specimens. Our analysis showed that epigenetic alteration associated with EBV-infection may contribute to tumorigenesis through enhancer activation and repression.

Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient

PubMed Central

Kaplan, Mustafa; Yilmaz, Nisbet; Çiftçi, Filiz

2015-01-01

Acute hepatitis is a disorder that goes with liver cell necrosis and liver inflammation. Among the causes of acute hepatitis, the most common reasons are viral hepatitis. About 95% of the acute hepatitis generate because of hepatotropic viruses. Epstein-barr virus (EBV) and cytomegalovirus (CMV) are from the family of herpes viruses and rare causes of acute hepatitis. In this case report, acute hepatitis due to EBV and CMV coinfection will be described. How to cite this article Ates İ, Kaplan M, Yilmaz N, Çiftçi F. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient. Euroasian J Hepato-Gastroenterol 2015;5(1):60-61. PMID:29201691

Pim kinases are upregulated during Epstein-Barr virus infection and enhance EBNA2 activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rainio, Eeva-Marja; Turku Graduate School of Biomedical Sciences, 20520 Turku; Ahlfors, Helena

Latent Epstein-Barr virus (EBV) infection is strongly associated with B-cell proliferative diseases such as Burkitt's lymphoma. Here we show that the oncogenic serine/threonine kinases Pim-1 and Pim-2 enhance the activity of the viral transcriptional activator EBNA2. During EBV infection of primary B-lymphocytes, the mRNA expression levels of pim genes, especially of pim-2, are upregulated and remain elevated in latently infected B-cell lines. Thus, EBV-induced upregulation of Pim kinases and Pim-stimulated EBNA2 transcriptional activity may contribute to the ability of EBV to immortalize B-cells and predispose them to malignant growth.

Dynamics of Epstein-Barr virus DNA levels in serum during EBV-associated disease.

PubMed

Berger, C; Day, P; Meier, G; Zingg, W; Bossart, W; Nadal, D

2001-08-01

A real-time polymerase chain reaction assay for quantitation of Epstein-Barr virus (EBV) DNA in serum was developed. This assay detected EBV DNA in 24 (89%) of 27 sera from patients with infectious mononucleosis, but only in 9 (18%) of 51 sera from EBV carriers (P < 0.001) and in none of the sera from 32 EBV-seronegative individuals. EBV DNA levels were higher in sera from infectious mononucleosis (median 8,000, range 1833-150,069 copies/ml) than from carriers (median < 2, range < 2-2980; P < 0.001). In sera of 36 children with infectious mononucleosis followed prospectively, EBV DNA levels correlated inversely with the duration of symptoms. Among 18 children with tumors including Hodgkin's disease (n = 7), non-Hodgkin's lymphoma (n = 6), Burkitt's lymphoma (n = 1), lymphoproliferative disorder (n = 4), and osteosarcoma (n = 1), EBV DNA was detected in serum from those 9 (100%) expressing EBV in the tumor (Hodgkin's disease, 3; non-Hodgkin's lymphoma, 2; lymphoproliferative disorder, 4), the levels peaking at diagnosis and correlating with disease activity. Quantitation of EBV DNA in serum may offer a simple means of monitoring patients at risk of EBV-associated lymphoproliferation. Copyright 2001 Wiley-Liss, Inc.

Progress and Problems in Understanding and Managing Primary Epstein-Barr Virus Infections

PubMed Central

Odumade, Oludare A.; Hogquist, Kristin A.; Balfour, Henry H.

2011-01-01

Summary: Epstein-Barr virus (EBV) is a gammaherpesvirus that infects a large fraction of the human population. Primary infection is often asymptomatic but results in lifelong infection, which is kept in check by the host immune system. In some cases, primary infection can result in infectious mononucleosis. Furthermore, when host-virus balance is not achieved, the virus can drive potentially lethal lymphoproliferation and lymphomagenesis. In this review, we describe the biology of EBV and the host immune response. We review the diagnosis of EBV infection and discuss the characteristics and pathogenesis of infectious mononucleosis. These topics are approached in the context of developing therapeutic and preventative strategies. PMID:21233512

Antibiotic treatment of acute respiratory infections in acute care settings.

PubMed

Gonzales, Ralph; Camargo, Carlos A; MacKenzie, Thomas; Kersey, Ayanna S; Maselli, Judith; Levin, Sara K; McCulloch, Charles E; Metlay, Joshua P

2006-03-01

To examine the patterns of antibiotic use for acute respiratory tract infections (ARIs) in acute care settings. Chart reviews were performed retrospectively on a random sample of adult ARI visits to seven Veterans Affairs (VA) and seven non-VA emergency departments (EDs) for the period of November 2003 to February 2004. Visits were limited to those discharged to home and those with primary diagnoses of antibiotic-responsive (pneumonia, acute exacerbation of chronic bronchitis, pharyngitis, sinusitis) and antibiotic-nonresponsive conditions (acute bronchitis, nonspecific upper respiratory tract infection [URI]). Results are expressed as adjusted odds ratios with 95% confidence intervals. Of 2,270 ARI visits, 62% were for antibiotic-nonresponsive diagnoses. Seventy-two percent of acute bronchitis and 38% of URI visits were treated with antibiotics (p < 0.001). Stratified analyses show that antibiotic prescription rates were similar among attending-only and housestaff-associated visits for antibiotic-responsive diagnoses (p = 0.11), and acute bronchitis (76% vs. 59%; p = 0.31). However, the antibiotic prescription rate for URIs was greater for attending-only visits compared with housestaff-associated visits (48% vs. 15%; p = 0.01). Antibiotic prescription rates for total ARIs varied between sites, ranging from 42% to 89%. Patient age, gender, race and ethnicity, smoking status, comorbidities, and clinical setting (VA vs. non-VA) were not independently associated with antibiotic prescribing. Acute care settings are important targets for reducing inappropriate antibiotic prescribing. The mechanisms accounting for lower antibiotic prescription rates observed with housestaff-associated visits merit further study.

Epstein-Barr virus-infected Akata cells are sensitive to histone deacetylase inhibitor TSA-provoked apoptosis.

PubMed

Kook, Sung-Ho; Son, Young-Ok; Han, Seong-Kyu; Lee, Hyung-Soon; Kim, Beom-Tae; Jang, Yong-Suk; Choi, Ki-Choon; Lee, Keun-Soo; Kim, So-Soon; Lim, Ji-Young; Jeon, Young-Mi; Kim, Jong-Ghee; Lee, Jeong-Chae

2005-11-30

Epstein-Barr virus (EBV) infects more than 90 % of the world's population and has a potential oncogenic nature. A histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), has shown potential ability in cancer chemoprevention and treatment, but its effect on EBV-infected Akata cells has not been examined. This study investigated the effect of TSA on the proliferation and apoptosis of the cells. TSA inhibited cell growth and induced cytotoxicity in the EBV-infected Akata cells. TSA treatment sensitively induced apoptosis in the cell, which was demonstrated by the increased number of positively stained cells in the TUNEL assay, the migration of many cells to the sub-G0/G1 phase in flow cytometric analysis, and the ladder formation of genomic DNA. Western blot analysis showed that caspase-dependent pathways are involved in the TSA-induced apoptosis of EBV-infected Akata cells. Overall, this study shows that EBV-infected B lymphomas are quite sensitive to TSA-provoked apoptosis.

Comparative method of protein expression and isolation of EBV epitope in E.coli DH5α

NASA Astrophysics Data System (ADS)

Anyndita, Nadya V. M.; Dluha, Nurul; Himmah, Karimatul; Rifa'i, Muhaimin; Widodo

2017-11-01

Epstein-Barr Virus (EBV) or human herpes virus 4 (HHV-4) is a virus that infects human B cell and leads to nasopharyngeal carcinoma (NPC). The prevention of this disease remains unsuccessful since the vaccine has not been discovered. The objective of this study is to over-produce EBV gp350/220 epitope using several methods in E.coli DH5α. EBV epitope sequences were inserted into pMAL-p5x vector, then transformed into DH5α E.coli and over-produced using 0.3, 1 and 2 mM IPTG. Plasmid transformation was validated using AflIII restriction enzyme in 0.8% agarose. Periplasmic protein was isolated using 2 comparative methods and then analyzed using SDS-PAGE. Method A produced a protein band around 50 kDa and appeared only at transformant. Method B failed to isolate the protein, indicated by no protein band appearing. In addition, any variations in IPTG concentration didn't give a different result. Thus it can be concluded that even the lowest IPTG concentration is able to induce protein expression.

Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma

PubMed Central

Chang, Ellen T.; Ambinder, Richard F.; Lennette, Evelyne T.; Rubertone, Mark V.; Mann, Risa B.; Borowitz, Michael; Weir, Edward G.; Abbondanzo, Susan L.; Mueller, Nancy E.

2012-01-01

An altered anti–Epstein-Barr virus (EBV) serologic profile preceding diagnosis is associated with an increased risk of Hodgkin lymphoma. It is unknown whether this atypical pattern predicts Hodgkin lymphoma risk further subdivided by determination of EBV in tumor cells. A nested case-control study of 128 incident Hodgkin lymphoma cases and 368 matched controls from active-duty military personnel with archived serum in the US Department of Defense Serum Repository was conducted to determine whether a panel of anti-EBV antibody titers differed in EBV+ and EBV− Hodgkin lymphoma. Among 40 EBV+ Hodgkin lymphoma cases and matched controls, statistically significant increased risks were associated with elevated anti-EBV VCA IgG antibody titers (relative risk = 3.1; 95% confidence interval [CI], 1.1-8.7), and an anti–EBNA-1/anti–EBNA-2 antibody ratio ≤ 1.0 versus > 1.0 (relative risk = 4.7; 95% CI, 1.6-13.8). In contrast, no significant associations were found among 88 EBV− Hodgkin lymphoma cases relative to their matched controls. In case-case analysis, EBV+ disease was significantly associated with a low anti–EBNA-1/anti–EBNA-2 antibody ratio. This distinc-tive serologic response to EBV latent antigens, indicative of immune dysfunction in other clinical settings, is associated with an increased risk of developing EBV+ but not EBV− Hodgkin lymphoma. PMID:22972983

Epstein-Barr virus, cytomegalovirus, and infectious mononucleosis.

PubMed

Bravender, Terrill

2010-08-01

Infectious mononucleosis (IM) is a clinical syndrome that is common in adolescents and young adults and is characterized by fever, lymphadenopathy, pharyngitis, and fatigue. IM is most commonly associated with Epstein-Barr virus (EBV) infection in which case laboratory findings include a lymphocytosis with an elevated number of atypical lymphocytes seen on peripheral smear and a heterophile or EBV-specific antibody response. Approximately 10% of those with IM will not be acutely infected with EBV. Many of these individuals will have their symptoms attributed to cytomegalovirus (CMV) infection. This chapter reviews the history, diagnosis, clinical management, and potential complications of both EBV- and CMV-associated IM in adolescents and young adults.

Niclosamide inhibits lytic replication of Epstein-Barr virus by disrupting mTOR activation.

PubMed

Huang, Lu; Yang, Mengtian; Yuan, Yan; Li, Xiaojuan; Kuang, Ersheng

2017-02-01

Infection with the oncogenic γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause several severe malignancies in humans. Inhibition of the lytic replication of EBV and KSHV eliminates the reservoir of persistent infection and transmission, consequently preventing the occurrence of diseases from the sources of infection. Antiviral drugs are limited in controlling these viral infectious diseases. Here, we demonstrate that niclosamide, an old anthelmintic drug, inhibits mTOR activation during EBV lytic replication. Consequently, niclosamide effectively suppresses EBV lytic gene expression, viral DNA lytic replication and virion production in EBV-infected lymphoma cells and epithelial cells. Niclosamide exhibits cytotoxicity toward lymphoma cells and induces irreversible cell cycle arrest in lytically EBV-infected cells. The ectopic overexpression of mTOR reverses the inhibition of niclosamide in EBV lytic replication. Similarly, niclosamide inhibits KSHV lytic replication. Thus, we conclude that niclosamide is a promising candidate for chemotherapy against the acute occurrence and transmission of infectious diseases of oncogenic γ-herpesviruses. Copyright © 2016 Elsevier B.V. All rights reserved.

Prognostic role of tumour-associated macrophages and regulatory T cells in EBV-positive and EBV-negative nasopharyngeal carcinoma.

PubMed

Ooft, Marc L; van Ipenburg, Jolique A; Sanders, Maxime E; Kranendonk, Mariette; Hofland, Ingrid; de Bree, Remco; Koljenović, Senada; Willems, Stefan M

2018-03-01

Tumour-associated macrophages (TAMs) and regulatory T cells (Tregs) form a special niche supporting tumour progression, and both correlate with worse survival in head and neck cancers. However, the prognostic role of TAM and Tregs in nasopharyngeal carcinoma (NPC) is still unknown. Therefore, we determined differences in TAMs and Tregs in different NPC subtypes, and their prognostic significance. Tissue of 91 NPCs was assessed for TAMs and Tregs by determination of CD68, CD163, CD206 and FOXP3 expression in the tumour microenvironment. Clinicopathological correlations were assessed using Pearson X 2 test, Fisher's exact test, analysis of variance and Mann-Whitney U test. Survival was analysed using Kaplan-Meier curves and Cox regression. CD68 and FOXP3 counts were higher in Epstein-Barr virus (EBV)-positive NPC, while CD68-/FOXP3-, CD163+/FOXP3- and CD206+/FOXP3- infiltrates were more common in EBV-negative NPC. In the whole NPC group, CD68-/FOXP3- correlated with worse overall survival (OS), and after multivariate analysis high FOXP3 count showed better OS (HR 0.352, 95% CI 0.128 to 0.968). No difference in M2 counts existed between EBV-positive and negative NPC. FOXP3, a Treg marker, seems to be an independent prognostic factor for better OS in the whole NPC group. Therefore, immune-based therapies targeting Tregs should be carefully evaluated. M2 spectrum macrophages are probably more prominent in EBV-negative NPC with also functional differences compared with EBV-positive NPC. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Type I Interferon Elevates Co-Regulatory Receptor Expression on CMV- and EBV-Specific CD8 T Cells in Chronic Hepatitis C

PubMed Central

Owusu Sekyere, Solomon; Suneetha, Pothakamuri Venkata; Hardtke, Svenja; Falk, Christine Susanne; Hengst, Julia; Manns, Michael Peter; Cornberg, Markus; Wedemeyer, Heiner; Schlaphoff, Verena

2015-01-01

Hepatitis C virus (HCV) readily sets up persistence in a large fraction of infected hosts. Mounting epidemiological and immunological evidence suggest that HCV’s persistence could influence immune responses toward unrelated pathogens and vaccines. Nonetheless, the fundamental contribution of the inflammatory milieu during persistent HCV infection in impacting immune cells specific for common pathogens such as CMV and EBV has not been fully studied. As the co-regulatory receptors PD-1, Tim-3, and 2B4 have all been shown to be vital in regulating CD8+ T cell function, we assessed their expression on CMV/EBV-specific CD8+ T cells from patients with chronic hepatitis C (CHC) and healthy controls ex vivo and upon stimulation with virus-specific peptides in vitro. Total and CMV/EBV-specific CD8+ T cells expressing PD-1, Tim-3, and 2B4 were highly enriched in patients with CHC compared to healthy individuals ex vivo. In vitro peptide stimulation further potentiated the differential co-regulatory receptor expression of PD-1, Tim-3, and 2B4, which then culminated in an enhanced functionality of CMV/EBV-specific CD8+ T cells in CHC patients. Comprehensively analyzing plasma cytokines between the two cohorts, we observed that not only was IFNα-2a dominant among 21 other inflammatory mediators elevated in CHC patients but it also correlated with PD-1 and Tim-3 expressions ex vivo. Importantly, IFNα-2a further caused upregulation of these markers upon in vitro peptide stimulation. Finally, we could prospectively study patients receiving novel IFN-free antiviral therapy. Here, we observed that treatment-induced clearance of HCV resulted in a partial reversion of the phenotype of CMV/EBV-specific CD8+ T cells in patients with CHC. These data reveal an alteration of the plasma concentrations of IFNα-2a together with other inflammatory mediators during CHC, which appeared to pervasively influence co-regulatory receptor expression on CMV/EBV-specific CD8+ T cells. PMID:26113847

Nonsteroidal Anti-Inflammatory Drugs Quickly Resolve Symptoms Associated with EBV-Induced Infectious Mononucleosis in Patients with Atopic Predispositions

PubMed Central

Kazama, Itsuro; Miura, Chieko; Nakajima, Toshiyuki

2016-01-01

Case series Patient: Female, 24 • Male, 35 Final Diagnosis: EBV-induced infectious mononucleosis Symptoms: Fever • general malaise • lymphadenopathy Medication: — Clinical Procedure: Physical examination and serological testing Specialty: Infectious diseases Objective: Rare co-existance of disease or pathology Background: Infectious mononucleosis is a clinical syndrome most commonly associated with primary Epstein-Barr virus (EBV) infection. In adults, the symptoms can often be severe and prolonged, sometimes causing serious complications. Analgesic or antipyretic drugs are normally used to relieve the symptoms. However, there is no causal treatment for the disease. Case Report: Two cases of adult patients with atopic predispositions developed nocturnal fever, general fatigue, pharyngitis and lymphadenopathy after an exacerbation of atopic symptoms or those of allergic rhinitis. Due to the positive results for EBV viral-capsid antigen (VCA) IgM and negative results for EBV nuclear antigen (EBNA) IgG, diagnoses of infectious mononucleosis induced by EBV were made in both cases. Although oral antibiotics or acetaminophen alone did not improve the deteriorating symptoms, including fever, headache and general fatigue, nonsteroidal anti-inflammatory drugs (NSAIDs), such as tiaramide or loxoprofen, completely improved the symptoms quickly after the initiation. Conclusions: In these cases, given the atopic predispositions of the patients, an enhanced immunological response was likely to be mainly responsible for the pathogenesis of the symptoms. In such cases, NSAIDs, that are known to reduce the activity of EBV, may dramatically improve the deteriorating symptoms quickly after the initiation. In the present cases, the immunosuppressive property of these drugs was considered to suppress the activity of lymphocytes and thus provide the rapid and persistent remission of the disease. PMID:26874639

Tonsillar CD56brightNKG2A+ NK cells restrict primary Epstein-Barr virus infection in B cells via IFN-γ.

PubMed

Jud, Aurelia; Kotur, Monika; Berger, Christoph; Gysin, Claudine; Nadal, David; Lünemann, Anna

2017-01-24

Natural killer (NK) cells constitute the first line of defense against viruses and cancers cells. Epstein-Barr virus (EBV) was the first human virus to be directly implicated in carcinogenesis, and EBV infection is associated with a broad spectrum of B cell lymphomas. How NK cells restrict EBV-associated oncogenesis is not understood. Here, we investigated the efficacies and mechanisms of distinct NK cell subsets from tonsils, the portal of entry of EBV, in limiting EBV infection in naïve, germinal center-associated and memory B cells. We found that CD56bright and NKG2A expression sufficiently characterizes the potent anti-EBV capacity of tonsillar NK cells. We observed restriction of EBV infection in B cells as early as 18 hours after infection. The restriction was most efficient in naïve B cells and germinal center-associated B cells, the B cell subsets that exhibited highest susceptibility to EBV infection in vitro. IFN-γ release by and partially NKp44 engagement of CD56bright and NKG2A positive NK cells mediated the restriction that eventually inhibited B-cell transformation. Thus, harnessing CD56brightNKG2A+ NK cell function might be promising to improve treatment strategies that target EBV-associated B cell lymphomas.

Inflammation and Epstein-Barr Virus Infection Are Common Features of Myasthenia Gravis Thymus: Possible Roles in Pathogenesis

PubMed Central

Cavalcante, Paola; Maggi, Lorenzo; Colleoni, Lara; Caldara, Rosa; Motta, Teresio; Giardina, Carmelo; Antozzi, Carlo; Berrih-Aknin, Sonia; Bernasconi, Pia; Mantegazza, Renato

2011-01-01

The thymus plays a major role in myasthenia gravis (MG). Our recent finding of a persistent Epstein-Barr (EBV) virus infection in some MG thymuses, combined with data showing that the thymus is in a proinflammatory state in most patients, supports a viral contribution to the pathogenesis of MG. Aim of this study was to gain further evidence for intrathymic chronic inflammation and EBV infection in MG patients. Transcriptional profiling by low density array and real-time PCR showed overexpression of genes involved in inflammatory and immune response in MG thymuses. Real-time PCR for EBV genome, latent (EBER1, EBNA1, LMP1) and lytic (BZLF1) transcripts, and immunohistochemistry for LMP1 and BZLF1 proteins confirmed an active intrathymic EBV infection, further supporting the hypothesis that EBV might contribute to onset or perpetuation of the autoimmune response in MG. Altogether, our results support a role of inflammation and EBV infection as pathogenic features of MG thymus. PMID:21961056

A possible link between the Epstein-Barr virus infection and autoimmune thyroid disorders

PubMed Central

Gwizdek, Katarzyna; Michalski, Marek; Wojnicz, Romuald

2016-01-01

The Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a member of the Herpesviridae virus family. EBV infection can cause infectious mononucleosis (IM) in the lytic phase of EBV’s life cycle. Past EBV infection is associated with lymphomas, and may also result in certain allergic and autoimmune diseases. Although potential mechanisms of autoimmune diseases have not been clearly elucidated, both genetic and environmental factors, such as infectious agents, are considered to be responsible for their development. In addition, EBV modifies the host immune response. The worldwide prevalence of autoimmune diseases shows how common this pathogen is. Normally, the virus stays in the body and remains dormant throughout life. However, this is not always the case, and a serious EBV-related illness may develop later in life. This explains the chronic course of autoimmune diseases that is often accompanied by exacerbations of symptoms. Based on the present studies, EBV infection can cause autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren’s syndrome, and autoimmune hepatitis. The EBV has also been reported in patients with autoimmune thyroid disorders. Although EBV is not the only agent responsible for the development of autoimmune thyroid diseases, it can be considered a contributory factor. PMID:27833448

The Biology and Clinical Utility of EBV Monitoring in Blood.

PubMed

Kanakry, Jennifer; Ambinder, Richard

2015-01-01

Epstein-Barr virus (EBV) DNA in blood can be quantified in peripheral blood mononuclear cells, in circulating cell-free (CCF) DNA specimens, or in whole blood. CCF viral DNA may be actively released or extruded from viable cells, packaged in virions or passively shed from cells during apoptosis or necrosis. In infectious mononucleosis, viral DNA is detected in each of these kinds of specimens, although it is only transiently detected in CCF specimens. In nasopharyngeal carcinoma, CCF EBV DNA is an established tumor marker. In EBV-associated Hodgkin lymphoma and in EBV-associated extranodal NK-/T-cell lymphoma, there is growing evidence for the utility of CCF DNA as a tumor marker.

Targeting the Ca(2+) Sensor STIM1 by Exosomal Transfer of Ebv-miR-BART13-3p is Associated with Sjögren's Syndrome.

PubMed

Gallo, Alessia; Jang, Shyh-Ing; Ong, Hwei Ling; Perez, Paola; Tandon, Mayank; Ambudkar, Indu; Illei, Gabor; Alevizos, Ilias

2016-08-01

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that is associated with inflammation and dysfunction of salivary and lacrimal glands. The molecular mechanism(s) underlying this exocrinopathy is not known, although the syndrome has been associated with viruses, such as the Epstein Barr Virus (EBV). We report herein that an EBV-specific microRNA (ebv-miR-BART13-3p) is significantly elevated in salivary glands (SGs) of pSS patients and we show that it targets stromal interacting molecule 1 (STIM1), a primary regulator of the store-operated Ca(2+) entry (SOCE) pathway that is essential for SG function, leading to loss of SOCE and Ca(2+)-dependent activation of NFAT. Although EBV typically infects B cells and not salivary epithelial cells, ebv-miR-BART13-3p is present in both cell types in pSS SGs. Importantly, we further demonstrate that ebv-miR-BART13-3p can be transferred from B cells to salivary epithelial cells through exosomes and it recapitulates its functional effects on calcium signaling in a model system. Published by Elsevier B.V.

Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma.

PubMed

Farina, Antonella; Cirone, Mara; York, Michael; Lenna, Stefania; Padilla, Cristina; Mclaughlin, Sarah; Faggioni, Alberto; Lafyatis, Robert; Trojanowska, Maria; Farina, Giuseppina A

2014-04-01

Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage, and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic γ-herpesvirus that has co-evolved with human species, infecting >95% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cells in the skin of SSc patients, characterized by the expression of the EBV noncoding small RNAs (EBERs) and the increased expression of immediate-early lytic and latency mRNAs and proteins. We report that EBV is able to persistently infect human SSc fibroblasts in vitro, inducing an aberrant innate immune response in infected cells. EBV-Toll-like receptor (TLR) aberrant activation induces the expression of selected IFN-regulatory factors (IRFs), IFN-stimulated genes (ISGs), transforming growth factor-β1 (TGFβ1), and several markers of fibroblast activation, such as smooth muscle actin and Endothelin-1, and all of these genes play a key role in determining the profibrotic phenotype in SSc fibroblasts. These findings imply that EBV infection occurring in mesenchymal, endothelial, and immune cells of SSc patients may underlie the main pathological features of SSc including autoimmunity, vasculopathy, and fibrosis, and provide a unified disease mechanism represented by EBV reactivation.

Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection.

PubMed

Price, Alexander M; Dai, Joanne; Bazot, Quentin; Patel, Luv; Nikitin, Pavel A; Djavadian, Reza; Winter, Peter S; Salinas, Cristina A; Barry, Ashley Perkins; Wood, Kris C; Johannsen, Eric C; Letai, Anthony; Allday, Martin J; Luftig, Micah A

2017-04-20

Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection. We used BH3 profiling to query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL-2) to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1 mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis.

The burden of acute respiratory infections in Ecuador 2011-2015.

PubMed

Chicaiza-Ayala, Wilson; Henríquez-Trujillo, Aquiles R; Ortiz-Prado, Esteban; Douce, Richard W; Coral-Almeida, Marco

2018-01-01

Burden of disease studies intend to improve public health decision-making and to measure social and economic impact in population. The objective of this study was to describe the burden of acute respiratory infections (ARI) in Ecuador between 2011 and 2015. Five-year period morbidity and mortality data available from national agencies of statistics was analyzed to estimate the burden of disease attributable to acute respiratory infections. Cases and deaths registered were grouped according to their ICD-10 code into three diagnostic groups: Acute upper respiratory infections (J00-J06), Influenza and pneumonia (J09-J18), and Bronchitis and other acute lower respiratory infections (J20-J22, J85, J86). Disability-adjusted life years stratified by diagnostic and age group were calculated using the "DALY" package for R. The productivity loss in monetary terms was estimated using the human capital method. Over the 5-year period studied there were a total of 14.84 million cases of acute respiratory infections, with 17 757 deaths reported (0.12%). The yearly burden of disease ranged between 98 944 to 118 651 disability-adjusted life years, with an estimated average loss of productivity of US$152.16 million (±19.6) per year. Approximately 99% of the burden can be attributed to years life lost due to premature mortality in population under 5 years old and over 60 years-old. The burden of acute respiratory infections remained steady during the analyzed period. Evidence-based prevention and control policies to tackle acute respiratory infections in Ecuador should focus on the population at extreme ages of life.

The burden of acute respiratory infections in Ecuador 2011-2015

PubMed Central

2018-01-01

Background Burden of disease studies intend to improve public health decision-making and to measure social and economic impact in population. The objective of this study was to describe the burden of acute respiratory infections (ARI) in Ecuador between 2011 and 2015. Methods Five-year period morbidity and mortality data available from national agencies of statistics was analyzed to estimate the burden of disease attributable to acute respiratory infections. Cases and deaths registered were grouped according to their ICD-10 code into three diagnostic groups: Acute upper respiratory infections (J00-J06), Influenza and pneumonia (J09-J18), and Bronchitis and other acute lower respiratory infections (J20-J22, J85, J86). Disability-adjusted life years stratified by diagnostic and age group were calculated using the “DALY” package for R. The productivity loss in monetary terms was estimated using the human capital method. Results Over the 5-year period studied there were a total of 14.84 million cases of acute respiratory infections, with 17 757 deaths reported (0.12%). The yearly burden of disease ranged between 98 944 to 118 651 disability-adjusted life years, with an estimated average loss of productivity of US$152.16 million (±19.6) per year. Approximately 99% of the burden can be attributed to years life lost due to premature mortality in population under 5 years old and over 60 years-old. Conclusions The burden of acute respiratory infections remained steady during the analyzed period. Evidence-based prevention and control policies to tackle acute respiratory infections in Ecuador should focus on the population at extreme ages of life. PMID:29715314

The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events

PubMed Central

Dunmire, Samantha K.; Grimm, Jennifer M.; Schmeling, David O.; Balfour, Henry H.; Hogquist, Kristin A.

2015-01-01

Epstein-Barr virus (EBV) is a human herpesvirus that causes acute infectious mononucleosis and is associated with cancer and autoimmune disease. While many studies have been performed examining acute disease in adults following primary infection, little is known about the virological and immunological events during EBV’s lengthy 6 week incubation period owing to the challenge of collecting samples from this stage of infection. We conducted a prospective study in college students with special emphasis on frequent screening to capture blood and oral wash samples during the incubation period. Here we describe the viral dissemination and immune response in the 6 weeks prior to onset of acute infectious mononucleosis symptoms. While virus is presumed to be present in the oral cavity from time of transmission, we did not detect viral genomes in the oral wash until one week before symptom onset, at which time viral genomes were present in high copy numbers, suggesting loss of initial viral replication control. In contrast, using a sensitive nested PCR method, we detected viral genomes at low levels in blood about 3 weeks before symptoms. However, high levels of EBV in the blood were only observed close to symptom onset–coincident with or just after increased viral detection in the oral cavity. These data imply that B cells are the major reservoir of virus in the oral cavity prior to infectious mononucleosis. The early presence of viral genomes in the blood, even at low levels, correlated with a striking decrease in the number of circulating plasmacytoid dendritic cells well before symptom onset, which remained depressed throughout convalescence. On the other hand, natural killer cells expanded only after symptom onset. Likewise, CD4+ Foxp3+ regulatory T cells decreased two fold, but only after symptom onset. We observed no substantial virus specific CD8 T cell expansion during the incubation period, although polyclonal CD8 activation was detected in concert with viral

Epstein-Barr virus infection and nasopharyngeal carcinoma: the other side of the coin.

PubMed

Perri, Francesco; Della Vittoria Scarpati, Giuseppina; Giuliano, Mario; D'Aniello, Carmine; Gnoni, Antonio; Cavaliere, Carla; Licchetta, Antonella; Pisconti, Salvatore

2015-11-01

Oncogenic viruses may have a significant impact on the therapeutic management of several malignancies besides their well-known role in tumor pathogenesis. Epstein-Barr virus (EBV) induces neoplastic transformation of epithelial cells of the nasopharynx by various molecular mechanisms mostly involving activation of oncogenes and inactivation of tumor-suppressor genes. EBV infection can also induce the expression of several immunogenic peptides on the plasma membrane of the infected cells. Importantly, these virus-related antigens may be used as targets for antitumor immunotherapy-based treatment strategies. Two different immunotherapy strategies, namely adoptive and active immunotherapy, have been developed and strongly improved in the recent years. Furthermore, EBV infection may influence the use of targeted therapies for nasopharyngeal carcinoma (NPC) considering that the presence of EBV can induce important modifications in cell signaling. As an example, latent membrane protein type 1 is a viral transmembrane protein mainly involved in the cancerogenesis process, which can also mediate overexpression of the epidermal growth factor receptor (EGFR) in NPC cells, rendering them more sensitive to anti-EGFR therapy. Finally, EBV may induce epigenetic changes in the infected cells, such as DNA hypermethylation and histone deacetylation, that can sustain tumor growth and can thus be considered potential targets for novel therapies. In conclusion, EBV infection can modify important biological features of NPC cells, rendering them more vulnerable to both immunotherapy and targeted therapy.

Kocuria kristinae infection associated with acute cholecystitis

PubMed Central

Ma, Edmond SK; Wong, Chris LP; Lai, Kristi TW; Chan, Edmond CH; Yam, WC; Chan, Angus CW

2005-01-01

Background Kocuria, previously classified into the genus of Micrococcus, is commonly found on human skin. Two species, K. rosea and K. kristinae, are etiologically associated with catheter-related bacteremia. Case presentation We describe the first case of K. kristinae infection associated with acute cholecystitis. The microorganism was isolated from the bile of a 56-year old Chinese man who underwent laparoscopic cholecystectomy. He developed post-operative fever that resolved readily after levofloxacin treatment. Conclusion Our report of K. kristinae infection associated with acute cholecystitis expands the clinical spectrum of infections caused by this group of bacteria. With increasing number of recent reports describing the association between Kocuria spp. and infectious diseases, the significance of their isolation from clinical specimens cannot be underestimated. A complete picture of infections related to Kocuria spp. will have to await the documentation of more clinical cases. PMID:16029488

Kocuria kristinae infection associated with acute cholecystitis.

PubMed

Ma, Edmond S K; Wong, Chris L P; Lai, Kristi T W; Chan, Edmond C H; Yam, W C; Chan, Angus C W

2005-07-19

Kocuria, previously classified into the genus of Micrococcus, is commonly found on human skin. Two species, K. rosea and K. kristinae, are etiologically associated with catheter-related bacteremia. We describe the first case of K. kristinae infection associated with acute cholecystitis. The microorganism was isolated from the bile of a 56-year old Chinese man who underwent laparoscopic cholecystectomy. He developed post-operative fever that resolved readily after levofloxacin treatment. Our report of K. kristinae infection associated with acute cholecystitis expands the clinical spectrum of infections caused by this group of bacteria. With increasing number of recent reports describing the association between Kocuria spp. and infectious diseases, the significance of their isolation from clinical specimens cannot be underestimated. A complete picture of infections related to Kocuria spp. will have to await the documentation of more clinical cases.

Estimating Acute Viral Hepatitis Infections From Nationally Reported Cases

PubMed Central

Liu, Stephen; Roberts, Henry; Jiles, Ruth B.; Holmberg, Scott D.

2014-01-01

Objectives. Because only a fraction of patients with acute viral hepatitis A, B, and C are reported through national surveillance to the Centers for Disease Control and Prevention, we estimated the true numbers. Methods. We applied a simple probabilistic model to estimate the fraction of patients with acute hepatitis A, hepatitis B, and hepatitis C who would have been symptomatic, would have sought health care tests, and would have been reported to health officials in 2011. Results. For hepatitis A, the frequencies of symptoms (85%), care seeking (88%), and reporting (69%) yielded an estimate of 2730 infections (2.0 infections per reported case). For hepatitis B, the frequencies of symptoms (39%), care seeking (88%), and reporting (45%) indicated 18 730 infections (6.5 infections per reported case). For hepatitis C, the frequency of symptoms among injection drug users (13%) and those infected otherwise (48%), proportion seeking care (88%), and percentage reported (53%) indicated 17 100 infections (12.3 infections per reported case). Conclusions. These adjustment factors will allow state and local health authorities to estimate acute hepatitis infections locally and plan prevention activities accordingly. PMID:24432918

[Aggressive primary cutaneous B-cell lymphomas and novel EBV+ entities].

PubMed

Lamos, C; Dippel, E

2017-09-01

Primary cutaneous large B‑cell lymphomas (PCBLT), EBV-positive large B‑cell lymphomas, not otherwise specified (EBV+ DLBCL, NOS), and primary cutaneous intravascular large B‑cell lymphomas (PCIVLBL) are recognized as cutaneous lymphomas with intermediate to poor prognosis. Differentiation from indolent B‑cell lymphomas or other pathologies of the skin can be complex, both clinically and histologically, but vital for the outcome of the patient. The combination of immunotherapy and polychemotherapy regimens, such as R‑CHOP, has led to significant improvements in prognosis, especially in diffuse large B‑cell lymphomas. Therapeutic decisions need to be individually made for each patient, ideally within an interdisciplinary tumor conference. Immunosenescence may be an important factor in the pathogenesis of EBV+ DLBCL, NOS in elderly individuals. Their prognosis is less favorable than that of patients with EBV-negative PCBLT, whereby this has been observed particularly in elderly patients. One third of patients with PCIVLBL progress to systemic disease. The occurrence of nodal manifestation is rarely observed. Symptoms may vary depending on the organ system involved. Currently there are no evidence-based therapy recommendations due to the rarity of the disease. EBV-positive mucocutaneous ulcer is a new provisional category in the current WHO classification for lymphoid neoplasms. It has been segregated from EBV+ DLBCL, NOS due to its self-limiting course and good response to conservative therapy.