EBV and HIV-Related Lymphoma (original) (raw)
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Frontiers in Microbiology, 2013
Epstein-Barr virus (EBV) is a ubiquitous human γ-herpes virus which establishes a life-long asymptomatic infection in immunocompetent hosts. In human immunodeficiency virus type 1 (HIV-1) infected patients, the impaired immunosurveillance against EBV may favor the development of EBV-related diseases, ranging from lymphoproliferative disorders to B cell non-Hodgkin's lymphomas (NHL). Antiretroviral therapy (ART) has significantly modified the natural course of HIV-1 infection, resulting in decreased HIV-1 plasmaviremia, increased CD4 lymphocytes, and decreased opportunistic infections, indicating a restoration of immune functions. However, the impact of ART appears to be less favorable on EBV-related malignancies than on other AIDS-defining tumors, such as Kaposi's sarcoma, and NHL remains the most common cancer during the ART era. EBV-driven tumors are associated with selective expression of latent oncogenic proteins, but uncontrolled lytic cycle with virus replication and/or reactivation may favor cell transformation, at least in the early phases. Several host's factors may promote EBV reactivation and replication; besides immunodepression, inflammation/chronic immune stimulation may play an important role. Microbial pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, through Toll-like receptors, activate the immune system and may promote EBV reactivation and/or polyclonal expansion of EBV-infected cells. A body of evidence suggests that chronic immune stimulation is a hallmark of HIV-1 pathogenesis and may persist even in ART-treated patients. This review focuses on lymphomagenesis driven by EBV both in the context of the natural history of HIV-1 infection and in ART-treated patients. Understanding the mechanisms involved in the expansion of EBV-infected cells is a premise for the identification of prognostic markers of EBV-associated malignancies.
JAIDS: Journal of Acquired Immune Deficiency Syndromes, 1999
Primary effusion lymphoma (PEL) selectively involves the serous body cavities, occurs predominantly in immunodeficient patients and is infected consistently by human herpesvirus type-8. PEL is also frequently infected by Epstein-Barr virus (EBV). The precise pathogenetic role of EBV coinfection in PEL is not fully understood. The lymphoma fails to express the EBV transforming proteins EBNA-2 and LMP-1, whereas it expresses EBNA-1 (latency I phenotype). Some studies have hypothesized that other EBV-positive lymphomas expressing the latency I phenotype may associate with specific molecular variants of EBNA-1, although this issue has not been addressed in PEL. On this basis, this study is aimed at a detailed molecular characterization of EBV in PEL. Fifteen EBV positive PEL (12 AIDS-related, one post-transplant, two arising in immunocompetent hosts) were subjected to molecular characterization of the viral genes EBNA-1 and LMP-1, as well as definition of EBV type-1/type-2. The EBNA-1 gene displayed a high degree of heterogeneity in different cases of PEL, with seven distinct recognizable variants and subvariants. A wildtype LMP-1 gene was detected in 10/15 cases, whereas in 5/15 cases the LMP-1 gene harbored a deletion spanning codons 346-355. EBV type-1 occurred in 11/15 PEL whereas EBV type-2 occurred in 4/15 cases. Despite a high degree of genetic variability of the virus in different PEL cases, each single PEL harbored only one EBV variant, consistent with monoclonality of infection and suggesting that infection preceded clonal expansion. Overall, our results indicate that: (1) individual PEL cases consistently harbor a single EBV strain; (2) EBNA-1 displays a high degree of heterogeneity in different PEL cases; (3) no specific EBV genotype preferentially associates with PEL. Leukemia (2000) 14, 271-277.
The tumor virus landscape of AIDS-related lymphomas
Blood, 2015
Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. While AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in fewer than 10% of cases. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency prot...
Open Infectious Diseases Journal, 2010
Epstein-Barr virus (EBV) infection has been implicated in the aetiopathogenic mechanisms of several neoplastic and non-neoplastic disorders. Although the precise mechanisms of the tumourigenic actions of EBV have not yet been fully elucidated, this virus has been strongly linked to subtypes of Hodgkin's and non-Hodgkin's lymphomas (especially Burkitt's lymphoma), HIV/AIDS lymphomas, nasopharyngeal carcinoma and gastric carcinoma, among several others. The fact that persistent infections occur in greater than 95% of adults with an overall relatively low incidence of EBV related tumours compared with the prevalence of infection shows that there are definitely many other factors (genetic and environmental) that contribute to tumour development in EBV positive individuals. In this article, we review some of the currently available knowledge about these relationships in the commonly encountered EBV-associated malignancies. It is hoped that with continued research in the pathogenic mechanisms of EBV, specific roles will be identified that will facilitate the development of specific targeted therapy.
HIV, EBV and KSHV: Viral cooperation in the pathogenesis of human malignancies
Cancer Letters, 2011
Malignancies associated with Epstein-Barr virus (EBV) and/or Kaposi's sarcoma human herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is frequently found in patients infected with HIV. Both these human gammaherpesviruses are known for their oncogenic properties, for the viral products that mimic or interfere with the functions of critical cellular proteins, and the ability to escape the immune responses. The introduction of the highly active anti-retroviral therapy (HAART) has significantly decreased the frequency of Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL), and primary central nervous system lymphoma (PCNSL); conversely, for some lymphomas the incidence diminished only slightly, as in Burkitt's lymphoma (BL), or had no significant variations, as Hodgkin's lymphoma (HL). These observations may indicate that HAART might have a direct impact on KSHV and EBV biology, that there is a reconstitution of the immune system in HIV-infected patients under HAART, or even that HAART perhaps has a detrimental impact in the pathogenic interactions between HIV, EBV and KSHV. The present review aim to evaluate and to discuss the data available for these hypotheses, in order to shed more light on the mechanisms for the cooperation among HIV-1, EBV and KSHV that may culminate in cell transformation and cancer development in humans.
Regression of HIV-related diffuse large B-cell lymphoma in response to antiviral therapy alone
Blood, 2008
Regression of HIV-related diffuse large B-cell lymphoma in response to antiviral therapy alone Patients with HIV on highly active antiretroviral therapy (HAART) have protection against the development of non-Hodgkin lymphoma (NHL) compared with HIV-positive patients not on HAART, and most studies have suggested that there may be improved outcomes when adding HAART to chemotherapy for the treatment of HIV-associated NHL. 1 Although HIV-related Kaposi sarcoma, extranodal mucosal-associated lymphoid tissue (MALT) lymphoma, and primary effusion lymphomas have all been reported to respond to HAART in the absence of chemotherapy, 2-4 these diseases have clear infectious etiologies. Despite the report of a mixed large and small cell lymphoma regressing to zidovudine alone, 5 the response of HIV-related NHLs to HAART alone is largely unknown. Here we report a case of diffuse large B-cell lymphoma (DLBCL) that responded solely to initiation of HAART. A 62-year-old man presented with large neck, axillary, and inguinal masses of 2 months' duration. Past medical history included thrush, anemia, and zoster. He denied fevers or night sweats, but reported an unintentional 25-pound weight loss. Exam revealed large, deforming, bilateral anterior and posterior cervical, axillary, and inguinal lymphadenopathy. Laboratory data revealed a positive HIV test with CD4 count of 185 mm 3 and viral load Ͼ 100 000 copies per milliliter, mild anemia, and normal lactate dehydrogenase (LDH). Right cervical lymph node biopsy demonstrated an Epstein-Barr (EBV)-positive CD20 ϩ , CD10 Ϫ , CD 5 Ϫ , DLBCL with monoclonality demonstrated by Ig polymerase chain reaction (PCR; Figure 1A,B). Bone marrow was negative for disease. Fluorodeoxyglucose-positron emission tomography/ compound tomography (FDG-PET/CT) scan confirmed extensive lymphadenopathy throughout the neck, chest, abdomen, and pelvis and splenomegaly with marked hypermetabolic activity. Standard uptake values (SUVs) ranged from 4 to 16. Of note, the biopsy
B cell lymphoma in hiv transgenic mice
Retrovirology, 2013
Background: Human Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas. The role of HIV in these lymphomas is unclear and currently there are no valid in vivo models for better understanding HIV-related lymphomagenesis. Transgenic (Tg) 26 mice have a 7.4-kb pNL4-3 HIV-1 provirus lacking a 3.1-kb sequence encompassing parts of the gag-pol region. Approximately 15% of these HIV Tg mice spontaneously develop lymphoma with hallmark pre-diagnostic markers including skin lesions, diffuse lymphadenopathy and an increase in pro-inflammatory serum cytokines. Here we describe the phenotypic and molecular characteristics of the B cell leukemia/lymphoma in the Tg mice.
HIV: implication in Burkitt lymphoma
Biopolymers and Cell
Europe and in the US. This effect might be due to immune suppression and low CD4-cell counts associated with the development of AIDS. However, there is also evidence of a direct effect of HIV on B cell proliferation and differentiation, which may account for the development of B cell malignancies. We shall discuss possible mechanisms of implication of HIV in BL with a focus on the role of different viral components (Tat, Nef and gp120 proteins, viral envelope) in the c-myc/IgH translocation characteristic of BL.