Immunology of EBV-Related Lymphoproliferative Disease in HIV-Positive Individuals

Abstract

Epstein-Bar virus (EBV) can directly cause lymphoproliferative disease (LPD), including AIDS-defining lymphomas such as Burkitt's lymphoma and other non-Hodgkin lymphomas (NHL), as well as human immunodeficiency virus (HIV)-related Hodgkin lymphoma (HL). The prevalence of EBV in HL and NHL is elevated in HIV-positive individuals compared with the general population. Rates of incidence of AIDS-defining cancers have been declining in HIV-infected individuals since initiation of combination anti-retroviral therapy (cART) use in 1996. However, HIV-infected persons remain at an increased risk of cancers related to infections with oncogenic viruses. Proposed pathogenic mechanisms of HIV-related cancers include decreased immune surveillance, decreased ability to suppress infection-related oncogenic processes and a state of chronic inflammation marked by alteration of the cytokine profile and expanded numbers of cytotoxic T lymphocytes with down-regulated co-stimulatory molecules and increased expression of markers of senescence in the setting of treated HIV infection. Here we discuss the cooperation of EBV-infected B cell-and environment-associated factors that may contribute to EBV-related lymphomagenesis in HIV-infected individuals. Environment-derived lymphomagenic factors include impaired host adaptive and innate immune surveillance, cytokine dysregulation and a pro-inflammatory state observed in the setting of chronic, cART-treated HIV infection. B cell factors include distinctive EBV latency patterns and host protein expression in HIV-associated LPD, as well as B cell-stimulating factors derived from HIV infection. We review the future directions for expanding therapeutic approaches in targeting the viral and immune components of EBV LPD pathogenesis.

Advances in the Pathogenesis of EBV-Associated Diffuse Large B Cell Lymphoma

“…For instance, EBV-associated posttransplant lymphoproliferative disorders (PTLDs) usually express all the latent genes, known as the latency III program, that encode six nuclear (EBNA1, -2, -3A, -3B, -3C, and -LP) and three membrane (LMP1, -2A, and -2B) antigens, along with untranslated RNAs [ 48 ]. HL express a pattern, characterized by the expression of EBNA1 and LMP1 and LMP2 antigens, identified as latency II [ 49 ], while BL displays latency I pattern, that predominantly expresses EBNA1 [ 48 ] ( Table 2 ). In all latency types, infected cells express two EBV-encoded small RNAs, known as EBER-1, and EBER-2 [ 48 ].…”

The Role of Coinfections in the EBV–Host Broken Equilibrium

“…Presently, cancer remains one of the most serious threats facing PLHW, and lymphomas are the most common cause of PLWH death in developed nations [ 75 ]. EBV is still responsible for more than half of the cases of lymphomas arising in these individuals [ 76 ]. For instance, Simard et al reported that, while the burden of AIDS-defining cancers decreased from 18% to 4.2% with ART, the risk of classical Hodgkin lymphoma (cHL) increased [ 77 ], and EBV remains responsible for close to 100% of all cHL cases [ 78 ].…”

HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients

“…EBV establishes a latent infection in over 90% of human adults, alternating between episodes of latency and reactivation inside B-lymphocytes, which may lead to the malignant transformation of B cells. Thus, EBV has been linked to a broad spectrum of human malignancies [ 55 ]. Additionally, EBV coinfection may alter HIV-infected patients' immunological response, increasing inflammation and immune activation [ 55 ].…”

“…Thus, EBV has been linked to a broad spectrum of human malignancies [ 55 ]. Additionally, EBV coinfection may alter HIV-infected patients' immunological response, increasing inflammation and immune activation [ 55 ]. However, these SDE genes deregulated in the EBV pathway are also involved in many other immune pathways that may have been affected after HCV treatment.…”