HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells.
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-gamma, MIP-1beta, TNF-alpha, 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.
Betts
Michael R
MR
Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Nason
Martha C
MC
West
Sadie M
SM
De Rosa
Stephen C
SC
Migueles
Stephen A
SA
Abraham
Jonathan
J
Lederman
Michael M
MM
Benito
Jose M
JM
Goepfert
Paul A
PA
Connors
Mark
M
Roederer
Mario
M
Koup
Richard A
RA
D016915:AIDS Vaccines / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D019562:Viral Load
D016915:AIDS Vaccines; D016207:Cytokines; D006680:HLA Antigens