Epstein-Barr virus-driven lymphomagenesis in the context of human immunodeficiency virus type 1 infection

Abstract

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.

Keywords: B cell activation; EBV; EBV lytic reactivation; EBV-related malignancies; HIV-1; antiretroviral therapy; chronic immune activation.

FIGURE 1

Mechanisms potentially contributing to polyclonal B cell activation and expansion of EBV-infected B cells in HIV-1 infected patients. HIV-1 acts as both a direct or indirect activator of B cells. Direct effects of HIV-1 include binding to B cells of HIV-1 viral proteins, such as gp120, Tat, and Nef, promoting polyclonal B cell activation. Indirect effects result from HIV-1-induced immune activation. Breakdown of gut mucosa induced by HIV-1 antigens increases intestinal permeability, resulting in translocation of microbial products. Pathogen-associated molecular patterns (PAMPs), such as LPS, 16S rDNA, and CpG DNA, and endogenous molecules created upon tissue injury (damage-associated molecular patterns, DAMPs), such as mitochondrial DNA (mtDNA), defensins and high mobility group box 1 (HMGB1) protein, by engaging Toll-like receptors (TLRs) activate signaling cascade leading to increased transcription of pro-inflammatory cytokines. In this context, both EBV-infected and uninfected B cells are activated and may undergo proliferation; EBV-infected cells may overcome uninfected ones due to higher replicative capacity and telomerase activation.