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Direct ex vivo analysis reveals distinct phenotypic patterns of HIV‐specific CD8+ T lymphocyte activation in response to therapeutic manipulation of virus load

Therapeutic intervention with antiretroviral therapy (ART) enables the modulation of HIV virus load and hence provides a unique opportunity to study the consequences of varying antigen load onthe phenotype of virus‐specific CD8+ T lymphocytes in a persistent human viral infection. The recent advent of tetrameric peptide / HLA class I complexes has enabled the direct phenotypic characterization of antigen‐specific T cell populations ex vivo. Here, we use this technology to examine directly ex vivo the consequences of therapeutic manipulation of HIV virus load on the phenotype of HIV‐specific CTL. Our observations show that: (1) distinct sequential activation patterns of CD8+ T cells are associated with increasing virus load; (2) T cell receptor (TCR) down‐regulation without apoptosis represents an early event during the generation of a T cell response in a natural infection and precedes the emergence of two distinct antigen‐specific CD8+ T cell populations which differ in TCR and CD8 expression levels. Clear differences in surface Annexin V staining were observed between these populations. The observation that CTL activation, demonstrated by TCR and CD8 down‐regulation, in response to rising levels of virus load, co‐segregates with apoptosis only during later stages of the response indicates that antigen‐associated cell death is restricted to distinct subpopulations of CTL.