HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells.
Journal: 2006/August - Blood
ISSN: 0006-4971
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-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.
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Blood 107(12): 4781-4789

HIV nonprogressors preferentially maintain highly functional HIV-specific CD8<sup>+</sup> T cells

+3 authors
From the Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD; Biostatistics Research Branch, NIAID, NIH, Bethesda, MD; ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD; Center for AIDS Research, Department of Medicine, Case Western Reserve University, Cleveland, OH; Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain; and Department of Medicine, University of Alabama at Birmingham.
Reprints: Richard A. Koup, 40 Convent Dr, Rm 3502, National Institutes of Health, Bethesda, MD 20892; e-mail: vog.hin.liam@puokr; and Michael R. Betts, Department of Microbiology, 522E Johnson Pavilion, 3610 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104; e-mail: ude.nnepu.dem.liam@stteb.
Reprints: Richard A. Koup, 40 Convent Dr, Rm 3502, National Institutes of Health, Bethesda, MD 20892; e-mail: vog.hin.liam@puokr; and Michael R. Betts, Department of Microbiology, 522E Johnson Pavilion, 3610 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104; e-mail: ude.nnepu.dem.liam@stteb.
Received 2005 Dec 13; Accepted 2006 Jan 30.

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.

Abstract

ND indicates not determined.

Acknowledgments

We would like to thank David Price and Daniel Douek for review of this manuscript, and Joanne Yu and Pratip Chattophadyay for reagent manufacture and validation.

Acknowledgments

Notes

Prepublished online as Blood First Edition Paper, February 7, 2006; DOI10.1182/blood-2005-12-4818.

Supported by NIH grants AI 36219 (M.M.L.) and AI 49126 (P.A.G.).

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

Notes
Prepublished online as Blood First Edition Paper, February 7, 2006; DOI10.1182/blood-2005-12-4818.
Supported by NIH grants AI 36219 (M.M.L.) and AI 49126 (P.A.G.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

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