Dysfunctional Epstein-Barr virus (EBV)–specific CD8+T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma

Abstract

Abstract Acquired immunodeficiency syndrome–related non-Hodgkin lymphomas (AIDS-NHL) are thought to arise because of loss of Epstein-Barr Virus (EBV)-specific cellular immunity. Here, an investigation was done to determine whether cellular immunity to EBV is lost because of physical loss or dysfunction of EBV-specific cytotoxic T cells. Data on EBV-specific cellular immunity were correlated with EBV load. For comparison, individuals who progressed to AIDS with opportunistic infections (AIDS-OI) and long-term asymptomatics (LTAs) were studied. The number of virus-specific T cells was detected using tetrameric HLA–EBV-peptide complexes; function of these EBV-specific T cells was determined using the interferon-γ (IFN-γ) Elispot assay. It was observed that EBV-specific CD8+ T cells were present in normal numbers in human immunodeficiency virus (HIV)-infected individuals. However, their functional capacity was decreased compared with HIV− individuals. In AIDS-NHL patients, EBV-specific T cells were not physically lost in the course of HIV-1 infection but showed progressive loss of their capability to produce IFN-γ in response to EBV peptides. This loss of function correlated with lower CD4+ T-cell numbers and was accompanied by increasing EBV load. In HIV-1–infected LTA individuals, in whom CD4+T-cell numbers were maintained, and progressors to AIDS-OI, IFN-γ–producing EBV-specific T cells were stable and EBV load remained stable or decreased in the course of HIV infection, suggestive of immune control. Our data indicate that functional loss of EBV-specific CD8+ T cells with a concomitant increase in EBV load may play a role in the pathogenesis of AIDS-NHL.