Does persistent HIV replication explain continued lymphoma incidence in the era of effective antiretroviral therapy?

Totonchy, Jennifer; Cesarman, Ethel

doi:10.1016/j.coviro.2016.09.001

Cited by 29 publications

(28 citation statements)

References 73 publications

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“…Despite years of research, we are only beginning to understand the depth of immune dysregulation associated with latent HIV infection, which persists in the lymph nodes even in the context of effective antiretroviral therapy, diminishing the canonical humoral immune response and redirecting B lymphocyte biology towards poorly understood alternative pathways. Interactions of this skewed environment, seem to influence the biology of the lymphotrophic herpesviruses in a way that contributes substantially to a pro-lymphomagenic environment in people living with HIV infection [32]. Moreover, new research in B cell immunology, a fraction of which is highlighted in this review, suggests that the generation of humoral immunity is more resilient and flexible than previously imagined.…”

Section: Discussionmentioning

confidence: 99%

Extrafollicular activities: perspectives on HIV infection, germinal center-independent maturation pathways, and KSHV-mediated lymphoproliferation

Totonchy

2017

Current Opinion in Virology

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Early events in the pathogenesis of KSHV-associated lymphoproliferations in the context of HIV disease remain poorly understood. Recent research indicates that latent HIV infection causes persistent immune dysfunction in B cell follicles. Simultaneously, lack of T cell immune surveillance in the lymph nodes disregulates the biology of EBV. In sum, these defects bias B lymphocyte maturation away from traditional T cell-dependent germinal center-mediated pathways and towards extrafollicular pathways. Recent advances in B lymphocyte immunology suggest that extrafollicular maturation pathways for antibody secreting cells are more flexible and robust than previously believed. These responses are now understood to be both durable and antigen-specific, and even canonically germinal center-restricted events such as class switch recombination and somatic hypermutation have now been demonstrated in an extrafollicular context. As a lymphotrophic pathogen which causes disease primarily in the context of HIV and EBV co-infection, future studies examining the interactions of KSHV biology with extrafollicular B cell maturation pathways will be critical to uncovering key aspects of KSHV-mediated immune pathology.

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Section: Discussionmentioning

confidence: 99%

Extrafollicular activities: perspectives on HIV infection, germinal center-independent maturation pathways, and KSHV-mediated lymphoproliferation

Totonchy

2017

Current Opinion in Virology

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“…Epithelial cancers like nasopharyngeal carcinoma and the ~10% of gastric carcinoma that are associated with EBV outnumber in incidence the EBV-associated lymphomas, which include Burkitt's, Hodgkin's, diffuse large B cell, NK/T cell and primary effusion lymphoma 6,10 . The B cell lymphomas emerge either spontaneously or during immune suppression, for example, during HIV-1 co-infection 134 .…”

Section: Box 1: Clinical Aspects Of Epstein-barr Virus Infectionmentioning

confidence: 99%

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

2019

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Epstein-Barr virus (EBV) was the first tumour virus identified in humans. The virus is primarily associated with lymphomas and epithelial cell cancers. These tumours express latent EBV antigens and the oncogenic potential of individual latent EBV proteins has been extensively explored. Nevertheless, it was presumed that the pro-proliferative and anti-apoptotic functions of these oncogenes allow the virus to persist in humans; however, recent evidence suggests that cellular transformation is not required for virus maintenance. Vice versa, lytic EBV replication was assumed to destroy latently infected cells and thereby inhibit tumorigenesis, but at least the initiation of the lytic cycle has now been shown to support EBV-driven malignancies. In addition to these changes in the roles of latent and lytic EBV proteins during tumorigenesis, the function of non-coding RNAs has become clearer, suggesting that they might mainly mediate immune escape rather than cellular transformation. In this Review, these recent findings will be discussed with respect to the role of EBV-encoded oncogenes in viral persistence and the contributions of lytic replication as well as non-coding RNAs in virus-driven tumour formation. Accordingly, early lytic EBV antigens and attenuated viruses without oncogenes and microRNAs could be harnessed for immunotherapies and vaccination. AbstractEpstein-Barr virus (EBV) was the first tumor virus identified in humans. It is primarily associated with lymphomas and epithelial cell cancers. These tumors express latent EBV antigens and the oncogenic potential of individual latent EBV proteins has been extensively explored.Nevertheless, it was presumed that the pro-proliferative and anti-apoptotic functions of these oncogenes allow the virus to persist in humans; however, recent evidence suggests that cellular transformation is not required for virus maintenance. Vice versa, lytic EBV replication was assumed to destroy latently infected cells and thereby inhibit tumorigenesis, but at least the initiation of the lytic cycle has now been shown to support EBV-driven malignancies. In addition to these changes in the roles of latent and lytic EBV proteins during tumourigenesis, the function of non-translated RNAs has become clearer, suggesting that they might mainly mediate immune escape rather than cellular transformation. In this Review, these recent findings will be discussed with respect to the role of EBV-encoded oncogenes in viral persistence and the contributions of lytic replication as well as non-translated RNAs in virus-driven tumor formation. Accordingly, early lytic EBV antigens and attenuated viruses without oncogenes and miRNAs could be harnessed for immunotherapies and vaccination. Table of contents blurb (40-50 words max.)Epstein-Barr virus (EBV) establishes latent and persistent infections in humans, and is associated with several cancers. In this Review, Münz discusses the evidence for EBV persistence without B cell transformation and the role of early abortive lytic replication, as well as non...

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“…Accordingly, PTLD development can be rapid, often occurring during the first year after organ transplantation, while Burkitt's and Hodgkin's lymphoma occur at later timepoints after transplantation [21]. In contrast, in HIV infected individuals, Burkitt's and Hodgkin's lymphoma emerge earlier than latency III immunoblastic lymphoma [22]. This is best explained by the inverse gradients of immune suppression that are observed after transplantation and HIV infection.…”

Section: Introduction Of Ebv and Its Oncogenesismentioning

confidence: 99%

Redirecting T Cells against Epstein–Barr Virus Infection and Associated Oncogenesis

Münz¹

2020

Cells

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The Epstein–Barr virus (EBV) is associated with lymphomas and carcinomas. For some of these, the adoptive transfer of EBV specific T cells has been therapeutically explored, with clinical success. In order to avoid naturally occurring EBV specific autologous T cell selection from every patient, the transgenic expression of latent and early lytic viral antigen specific T cell receptors (TCRs) to redirect T cells, to target the respective tumors, is being developed. Recent evidence suggests that not only TCRs against transforming latent EBV antigens, but also against early lytic viral gene products, might be protective for the control of EBV infection and associated oncogenesis. At the same time, these approaches might be more selective and cause less collateral damage than targeting general B cell markers with chimeric antigen receptors (CARs). Thus, EBV specific TCR transgenic T cells constitute a promising therapeutic strategy against EBV associated malignancies.

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Does persistent HIV replication explain continued lymphoma incidence in the era of effective antiretroviral therapy?

Cited by 29 publications

References 73 publications

Extrafollicular activities: perspectives on HIV infection, germinal center-independent maturation pathways, and KSHV-mediated lymphoproliferation

Extrafollicular activities: perspectives on HIV infection, germinal center-independent maturation pathways, and KSHV-mediated lymphoproliferation

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

Redirecting T Cells against Epstein–Barr Virus Infection and Associated Oncogenesis

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