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

Front Immunol. 2018 Oct 4;9:2291. doi: 10.3389/fimmu.2018.02291. eCollection 2018.

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.

Keywords: EBV; HIV; T-cell multifunctionality; TCR-Vβ repertoire; effector T cells; memory T cells; non-Hodgkin B-cell lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Coinfection*
  • Cytokines / metabolism
  • Disease Progression
  • Epstein-Barr Virus Infections / immunology*
  • Epstein-Barr Virus Infections / mortality
  • Epstein-Barr Virus Infections / virology
  • Female
  • HIV Infections / immunology*
  • HIV Infections / virology
  • Herpesvirus 4, Human / immunology*
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Immunomodulation
  • Male
  • Middle Aged
  • Prognosis
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Young Adult

Substances

  • Cytokines
  • Receptors, Antigen, T-Cell, alpha-beta