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HIV-1 Epitope-Specific CD8⁺ T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently¹

Emma L. Turnbull^*, A. Ross Lopes, Nicola A. Jones^*, David Cornforth, Phillipa Newton, Diana Aldam, Pierre Pellegrino, Jo Turner, Ian Williams, Craig M. Wilson, Paul A. Goepfert, Mala K. Maini and Persephone Borrow^2,*

^* The Edward Jenner Institute for Vaccine Research, Compton, Berkshire, United Kingdom; Division of Infection and Immunity and Centre for Sexual Health and HIV Research, University College London & Royal Free Medical School, London, United Kingdom; and Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35244

The ability of HIV-1-specific CD8⁺ T cell responses to recognize epitope variants resulting from viral sequence variation in vivo may affect the ease with which HIV-1 can escape T cell control and impact on the rate of disease progression in HIV-1-infected humans. Here, we studied the functional cross-reactivity of CD8 responses to HIV-1 epitopes restricted by HLA class I alleles associated with differential prognosis of infection. We show that the epitope-specific responses exhibiting the most efficient cross-recognition of amino acid-substituted variants were those strongly associated with delayed progression to disease. Not all epitopes restricted by the same HLA class I allele showed similar variant cross-recognition efficiency, consistent with the hypothesis that the reported associations between particular HLA class I alleles and rate of disease progression may be due to the quality of responses to certain "critical" epitopes. Irrespective of their efficiency of functional cross-recognition, CD8⁺ T cells of all HIV-1 epitope specificities examined showed focused TCR usage. Furthermore, interpatient variability in variant cross-reactivity correlated well with use of different dominant TCR V families, suggesting that flexibility is not conferred by the overall clonal breadth of the response but instead by properties of the dominant TCR(s) used for epitope recognition. A better understanding of the features of T cell responses associated with long-term control of viral replication should facilitate rational vaccine design.

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