AUTHOR=Hernández Diana M. , Valderrama Sandra , Gualtero Sandra , Hernández Catalina , López Marcos , Herrera Maria Victoria , Solano Julio , Fiorentino Susana , Quijano Sandra TITLE=Loss of T-Cell Multifunctionality and TCR-Vβ Repertoire Against Epstein-Barr Virus Is Associated With Worse Prognosis and Clinical Parameters in HIV+ Patients JOURNAL=Frontiers in Immunology VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02291 DOI=10.3389/fimmu.2018.02291 ISSN=1664-3224 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.