Clinical and Therapeutic Implications of Epstein–Barr Virus in HIV-Related Lymphomas

Abstract

The incidence of lymphomas is increased in people living with HIV (PLWH). Aggressive B-cell non-Hodgkin lymphomas (NHLs) are the most common and are considered an AIDS-defining cancer (ADC). Although Hodgkin lymphoma (HL) is not considered an ADC, its incidence is also increased in PLWH. Among all HIV-related lymphomas (HRL), the prevalence of Epstein–Barr virus (EBV) is high. It has been shown that EBV is involved in different lymphomagenic mechanisms mediated by some of its proteins, contributing to the development of different lymphoma subtypes. Additionally, cooperation between both HIV and EBV can lead to the proliferation of aberrant B-cells, thereby being an additional lymphomagenic mechanism in EBV-associated HRL. Despite the close relationship between EBV and HRL, the impact of EBV on clinical aspects has not been extensively studied. These lymphomas are treated with the same therapeutic regimens as the general population in combination with cART. Nevertheless, new therapeutic strategies targeting EBV are promising for these lymphomas. In this article, the different types of HRL are extensively reviewed, focusing on the influence of EBV on the epidemiology, pathogenesis, clinical presentation, and pathological characteristics of each lymphoma subtype. Moreover, novel therapies targeting EBV and future strategies to treat HRL harboring EBV are discussed.

Incidence and Clinical Description of Lymphomas in Children and Adolescents with Vertical Transmission of HIV in Rio de Janeiro, Brazil, in Pre- and Post-Combined Antiretroviral Therapy Eras: A Multicentric Hospital-Based Survival Analysis Study

“…Besides the 21 NHL cases, we also had 4 HL cases. NSCHL is the most frequent HL subtype in PLWH and is also often associated with EBV infection [ 12 ]. Notably, all HL cases found in our cohort were NSCHL, and this finding is consistent with the EBV epidemiology in non-Caucasian-predominant ethnic groups and people living in developing and low-income countries [ 49 ].…”

“…The incidence of cancer in children living with HIV (CLWH) is higher when compared to the general population [ 1 , 2 , 3 ], as also described for HIV-infected adults [ 4 , 5 , 6 , 7 ]. This higher occurrence is essentially due to immune system impairment resulting from the progressive depletion of CD4+ lymphocytes, loss of immune functions, persistent inflammation, chronic immune activation, and complex interactions with other oncogenic viruses (such as Epstein-Barr Virus (EBV) and Human Herpes Virus type 8 (HHV8)) and, ultimately, premature aging [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

How Does Epstein–Barr Virus Interact With Other Microbiomes in EBV-Driven Cancers?

“…The coinfection of human immunodeficiency virus (HIV) and EBV exists in a large variety of lymphoma such as Burkitt lymphoma, Hodgkin’s lymphoma, diffuse large B cell lymphoma, PEL, and primary CNS lymphoma ( Verdu-Bou et al., 2021 ) (shown as Table 1 ). The depletion of CD4+ T cells and senescence of CD8+ T cells are common in HIV carriers, which could contribute to the deficiency of EBV-specific T cell immune responses in EBV-driven lymphoma ( Piriou et al., 2005 ; Hernández et al., 2018 ).…”

“…Besides, the induction of the apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) family, which was clarified as a DNA-modifying enzyme in HIV coinfection, might be another trigger for EBV-driven lymphoma by somatic mutation accumulation ( Venkatesan et al., 2018 ). Furthermore, the cooperation between HIV and EBV in HIV-related lymphoma has been speculated, with HIV likely contributing to the generation of a permissive microenvironment for EBV infection, and the differentiation and survival of infected B-cells ( Verdu-Bou et al, 2021 ).…”

HIV-related lymphomas

“…Cooperation between both HIV and EBV as well as HIV and KSHV can lead to the proliferation of abnormal B-cells. Novel therapeutic strategies targeting EBV and KSHV have been investigated in preclinical research including oncolytic therapy [3 && , 13,14]. This treatment aims to induce oncolysis through viral replication and immune-mediated cell death of cancer cells latently infected with EBV or KSHV.…”