CD8+ cytotoxic T lymphocytes in human immunodeficiency virus infection

Cytotoxic T lymphocytes (CTL) are important mediators of cellular immune responses and play a central protective role in many human viral infections. In human immunodeficiency virus (HIV) infection a vigorous antiviral CTL response is induced. However, defining the precise role of HIV-specific CTL over the clinical course of HIV infection has been the subject of much speculation. Because anti-HIV CTL kill infected CD4⁺ and antigen-presenting cells, some investigators suggest that they mediate CD4⁺ T cell depletion, contributing to the immunopathology associated with progression to AIDS. An extensive body of evidence now supports at least a partially protective role for HIV-specific CTL in controlling viral replication and delaying disease progression. However it is also clear that anti-HIV CTL fail to control HIV infection indefinitely. Multiple diverse mechanisms with the potential for contributing to the progressive deterioration of HIV -specific CTL have been shown to arise over the natural course of HIV infection, but the relative contribution of the various mechanisms to CD8⁺ T cell dysfunction has not yet been clearly defined. -- The present study examined properties of anti-HIV CTL at various stages of disease. The primary objectives of the experiments were to further elucidate the biological relevance of HIV-specific CTL, and identify reasons for their inadequate immunoprotective role. The CD8⁺ T cell population that persists through the advanced stages of infection was examined, to determine if characteristics peculiar to progressive infection were imposed on CTL over the course of disease. HIV-specific memory T cell responses of individuals at various stages of infection were examined longitudinally, to identify immunological and virological parameters affecting the maintenance of HIV-specific memory T cells, and to determine the relationship between the expanded CD8⁺CD28⁻ T cell population and disease progression. -- The studies clearly demonstrate that CD8⁺ T cells retain many functional and genetic attributes through the advanced stages of HIV infection. However, an in vivo defect in the ability to generate an effector CTL response becomes evident in the later stages of disease, despite the persistence of intact HIV-specific memory CTL precursors. This defect is overcome with effective therapy, allowing reconstitution of CD8⁺ T cell immune responses, including HIV-specific CTL activity, even following prolonged periods of advanced infection. The accumulation of CD8⁺CD8⁻ HIV-specific CTL was found to be associated with progressive disease, and these cells showed a skewed T cell receptor (TCR) beta chain variable gene (~V) usage and decreased cytokine output in comparison to their CD8⁺CD28⁺ counterparts. Most HIV-infected individuals maintained stable anti-HIV memory T cells over prolonged periods of effective viral suppression, but a minority demonstrated a specific defect in memory T cell maintenance that was associated with present or past CD4⁺ T cell depletion. -- The results of this thesis confirm the importance of HIV-specific CTL in controlling HIV disease progression and identify some of the determinants related to the CD8⁺ T cell dysfunction that is observed concurrent with progression to AIDS