Changes in the Cytotoxic T-Cell Repertoire of HIV-1-Infected Individuals: Relationship to Disease Progression

The repertoire of antigen-specific receptors expressed on T lymphocytes is shaped by fixed genetic and variable environmental selective pressures. Recent technological advances have enabled the analysis of T-cell receptor (TCR) expression in the context of selective pressures arising through normal immune system development and also through pathological features of disease. The pathological features of acquired immune deficiency syndrome (AIDS) are reflected by selective depletion of particular T lymphocyte subsets and expansion of others. An important question concerning the immunopathogenesis of AIDS is whether or not the perturbation of the CD4+ and CD8+ T-cell subsets following infection with human immunodeficiency virus (HIV) is selective based on TCR variable (V) region gene expression. To address this question, we have functionally analyzed TCR V gene expression on CD8+ cytotoxic T lymphocytes from HIV-1-infected individuals. This was done using monoclonal antibodies against individual TCR V regions to trigger redirected cytolysis in 51Cr release assays. The percent specific lysis induced by each antibody functionally measures the representation of the TCR V region gene product it is specific for. Relative to non-HIV-infected controls and asymptomatic HIV-infected individuals with only moderate CD4 lymphocyte depletion, HIV-infected individuals with low CD4 lymphocyte counts exhibited skewed patterns of TCR V region representation. Therefore, the perturbation within the CD8+ cytotoxic T lymphocyte repertoire in HIV infection appears to be selective based on TCR V region usage, increasingly so as disease progresses. The TCR V genes affected varied between different HIV-infected individuals and skewing detected in functional assays was not always apparent by flow cytometric analysis. These results suggest that HIV infection causes generalized effects on the T-cell repertoire, which are reflected in the relative TCR V gene representation of the CD8+ cytotoxic T lymphocyte population in peripheral blood.