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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.

frontiers in immunology

Loss of T-Cell Multifunctionality and TCR-Vβ Repertoire Against Epstein-Barr Virus Is Associated With Worse Prognosis and Clinical Parameters in HIV+ Patients