Establishing a CD8 ؉ T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8 ؉ T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8 ؉ T-cell response by measuring 5 CD8 ؉ T-cell functions (degranulation, IFN-␥, MIP-1␤, TNF-␣, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors. We find that the functional profile of HIV-specific CD8 ؉ T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8 ؉ T cells. This limited functionality is independent of HLA type and T-cell memory phenotype, is HIV-specific rather than generalized, and is not effectively restored by therapeutic intervention. Whereas the total HIV-specific CD8 ؉ T-cell frequency did not correlate with viral load, the frequency and proportion of the HIV-specific T-cell response with highest functionality inversely correlated with viral load in the progressors. Thus, rather than quantity or phenotype, the quality of the CD8 ؉ T-cell functional response serves as an immune correlate of HIV disease progression and a potential qualifying factor for evaluation of HIV vaccine efficacy. (Blood. 2006;107:4781-4789)

Escape from adaptive T cell immunity through transmutation of viral antigenic structure is a cardinal feature in the pathogenesis of SIV/HIV infection and a major obstacle to antiretroviral vaccine development. However, the molecular determinants of this phenomenon at the T cell receptor (TCR)-antigen interface are unknown. Here, we show that mutational escape is intimately linked to the structural configuration of constituent TCR clonotypes within virus-specific CD8(+) T cell populations. Analysis of 3416 SIV-specific TCR sequences revealed that polyclonal T cell populations characterized by highly conserved TCRB CDR3 motifs were rendered ineffectual by single residue mutations in the cognate viral epitope. Conversely, diverse clonotypic repertoires without discernible motifs were not associated with viral escape. Thus, fundamental differences in the mode of antigen engagement direct the pattern of adaptive viral evolution. These findings have profound implications for the development of vaccines that elicit T cell immunity to combat pathogens with unstable genomes.

Worldwide HIV-1 vaccine efforts are guided by the principle that HIV-specific T cell responses may provide protection from infection or delay overt disease. However, no clear correlates of T cellmediated immune protection have been identified. Here, we examine in a HLA-B27 ؉ HIV seronegative vaccinee persistent HIVspecific vaccine-induced anti-Gag CD4 ؉ and CD8 ؉ T cell responses. Although these responses exhibited those characteristics (multifunctionality, appropriate memory phenotype, and targeting of epitopes associated with long-term nonprogression) predicted to correlate with protection from infection, the subject became HIV infected. After HIV infection, the vaccine-induced CD8 ؉ T cells expanded, but both CD4 ؉ and CD8 ؉ T cell responses acquired the functional and phenotypic patterns characteristic of chronic HIV infection. The virus quickly escaped the vaccine-induced T cell response, and the subject progressed more rapidly than expected for someone expressing the HLA-B27 allele. These data suggest that control of HIV by vaccine-elicited HIV-specific T cell responses may be difficult, even when the T cell response has those characteristics predicted to provide optimal protection. acute infection ͉ correlate of protection ͉ multiparameter flow cytometry