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HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells

Michael R. Betts, Martha C. Nason, Sadie M. West, Stephen C. De Rosa, Stephen A. Migueles, Jonathan Abraham, Michael M. Lederman, Jose M. Benito, Paul A. Goepfert, Mark Connors, Mario Roederer and Richard A. Koup

Abstract

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-γ, MIP-1β, TNF-α, 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.

  • Submitted December 13, 2005.
  • Accepted January 30, 2006.
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