Molecular analysis of the T-Cell Receptor b chain repertoire during HIV infection

Abstract

Human Immunodeficiency Virus Type 1 (HIV-1) infection is characterized by relentless depletion of cells belonging to the CD4+ helper-inducer subset, leading to the appearance in the patient of a lethal state of functional immunodeficiency. Many mechanisms have been proposed to account for the virus-induced destruction of T cells, including direct cytopathic effects of the virus, induction of apoptosis, and killing of infected or bystander CD4+ T cells by the cytotoxic immune response. Also, since HIV-1 is a retrovirus, it has been proposed that, like mouse mammary tumor viruses (MMTV), it could encode a protein with superantigenic properties, which could, by itself, sequentially anergize and delete CD4+ T cells expressing specific T cell receptor (TCR) V$beta$ determinants.In order to reveal the existence of such molecules in HIV infection, different cohorts of HIV-infected subjects were studied by PCR and flow cytometry, including HIV-discordant monozygotic twins, HIV-infected and uninfected children from HIV-infected mothers, and patients undergoing primary, acute HIV infection. The presence of TCR $beta$ chain repertoire perturbations not normally observed in uninfected subjects was revealed in each of these systems. These results supported the existence of an HIV-associated superantigen (SAg).However, high-level V$beta$-specific expansions of CD8+ T cells were also observed in acutely-infected patients, and in HIV-infected children from HIV-infected mothers. These expansions were oligoclonal, and comprised cells that possessed cytotoxic activity directed against HIV-infected cells, suggesting that these cell populations were part of the primary immune response to HIV-1 infection. These expansions were also transient, encompassing defined expansion and decline phases. In some cases, disappearance of these highly expanded effectors occurred while circulating virus titers were still extremely high, and in absence of viral mutation within the cognate CTL epitopes. This suggested that disappearance of these cells resulted from a process of clonal exhaustion, a mechanism by which differentiated peripheral cytotoxic effectors are deleted in presence of overwhelming levels of antigen.Transient, high-level V$beta$-specific expansions of cytolytic T cells might represent a fundamental characteristic of primary antiviral responses not only in the context of HIV infection, but also in other acute viral diseases. As well, clonal deletion constitutes a new mechanism of viral escape that could result in the base-line CTL repertoire being progressively restricted during the course of HIV infection and HIV-associated disease. (Abstract shortened by UMI.