Abstract
Epstein-Barr virus (EBV) is an oncogenic virus associated with the development of aggressive and poor-prognosis B-cell lymphomas in patients infected with human immunodeficiency virus (HIV+ patients). The most important risk factors for these malignancies include immune dysfunction, chronic immune activation, and loss of T-cell receptor (TCR) repertoire. The combination of all these factors can favor the reactivation of EBV, malignant cell transformation, and clinical progression toward B-cell lymphomas. The overarching aim of this study was to evaluate the frequency, phenotype, functionality, and distribution of TCR clonotypes for EBV-specific T-cell subpopulations in HIV+ patients at different clinical stages and for HIV+ patients with B-cell lymphoma, as well as to establish their association with clinical variables of prognostic value. Factors were studied in 56 HIV+ patients at different clinical stages and in six HIV+ subjects with diagnosed B-cell lymphoma. We found a significant decrease in all subpopulations of EBV-specific CD4+ T cells from HIV+ patients at stage 3 and with B-cell lymphoma. EBV-specific effector CD8+ T cells, particularly effector memory cells, were also reduced in HIV+ patients with B-cell lymphoma. Interestingly, these cells were unable to produce IFN-γ and lacked multifunctionality in HIV+ patients. The TCR-Vβ repertoire, which is key for protection against EBV in healthy individuals, was less diverse in HIV+ patients due to a lower frequency of TCR-Vβ2+, Vβ4+, Vβ7.1+, Vβ9+, Vβ13.6+, Vβ14+, Vβ17+, Vβ22+ CD4+, Vβ14+, and Vβ17+ CD8+ T cells. HIV+ patients with positive plasma EBV loads (EBV+HIV+) had a noteworthy decrease in the levels of both TNF-α+ and multifunctional TNF-α+/IL-2+ and TNF-α+/IFN-γ+ CD8+ T cells. Altogether, our findings demonstrate that HIV+ patients have significant alterations in the immune response to EBV (poor-quality immunity) that can favor viral reactivation, escalating the risk for developing EBV-associated B-cell lymphomas.
Highlights
HIV infection is characterized by the progressive depletion of CD4+ T-cell subpopulations [1, 2], the establishment of chronic, persistent immune activation [3], and premature immunosenescence [4]
We found that Esptein Barr Virus (EBV)+HIV+ patients at advanced clinical stages had a qualitatively impaired response to EBV, characterized by a lack of multifunctionality and decreased or deleted T-cell antigen receptor (TCR)-Vβ families that are important for the control of EBV in healthy individuals
13/60 (21.6%) patients presented with virological failure (VF; p = 0.015), 5/61 (8.19%) had immunological failure (IF; p = 0.002), and 18/62 (29.03%) had AIDS-defining diseases (p < 0.001)
Summary
HIV infection is characterized by the progressive depletion of CD4+ T-cell subpopulations [1, 2], the establishment of chronic, persistent immune activation [3], and premature immunosenescence [4]. Alterations in the T-cell antigen receptor (TCR) repertoire have been described in HIV+ patients by spectratyping, which involves evaluating the length distribution of the third complementary-determining region (CDR3) within the variable region of the β chain of the TCR (TCR-Vβ) These studies showed deletions and expansions of some TCR-Vβ families [5, 6]. These findings have demonstrated that HIV infection differentially modulates the frequencies of some T-cell clones, giving rise to a severely restricted TCR repertoire during chronic infection [6]. These viral proteins contribute to tumor pathogenesis through the activation of different cell signaling pathways that, in turn, alter cell cycle, apoptosis and cell differentiation, influencing differential mechanisms of migration and survival in tumor cells [11, 12]
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