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Journal of Virology, April 2008, p. 3391-3404, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.02383-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Emergence of Polyfunctional CD8+ T Cells after Prolonged Suppression of Human Immunodeficiency Virus Replication by Antiretroviral Therapy{triangledown}

Manuela Rehr,1 Julia Cahenzli,1 Anna Haas,1 David A. Price,2 Emma Gostick,2 Milo Huber,3 Urs Karrer,3,{dagger} and Annette Oxenius1,{dagger}*

Institute of Microbiology, ETH Hoenggerberg, Wolfgang Pauli Strasse 10, 8093 Zurich, Switzerland,1 Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, United Kingdom,2 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland3

Received 3 November 2007/ Accepted 8 January 2008

Progressive human immunodeficiency virus type 1 (HIV-1) infection is often associated with high plasma virus load (pVL) and impaired CD8+ T-cell function; in contrast, CD8+ T cells remain polyfunctional in long-term nonprogressors. However, it is still unclear whether CD8+ T-cell dysfunction is the cause or the consequence of high pVLs. Here, we conducted a longitudinal functional and phenotypic analysis of virus-specific CD8+ T cells in a cohort of patients with chronic HIV-1 infection. During the initiation and maintenance of successful antiretroviral therapy (ART), we assessed whether the level of pVL was associated with the degree of CD8+ T-cell dysfunction. Under viremic conditions, HIV-specific CD8+ T cells were dysfunctional with respect to cytokine secretion (gamma interferon, interleukin-2 [IL-2], and tumor necrosis factor alpha), and their phenotype suggested limited potential for proliferation. During ART, cytokine secretion by HIV-specific CD8+ T cells was gradually restored, IL-7R{alpha} and CD28 expression increased dramatically, and PD-1 levels declined. Thus, prolonged ART-induced reduction of viral replication and, hence, presumably antigen exposure in vivo, allows a significant functional restoration of CD8+ T cells with the appearance of polyfunctional cells. These findings indicate that the level of pVL as a surrogate for antigen load has a dominant influence on the phenotypic and functional profile of virus-specific CD8+ T cells.

* Corresponding author. Mailing address: Institute of Microbiology, ETH Hoenggerberg, HCI G401, Wolfgang Pauli Strasse 10, 8093 Zurich, Switzerland. Phone: 41 44 632 33 17. Fax: 41 44 632 10 98. E-mail: oxenius{at}micro.biol.ethz.ch

{triangledown} Published ahead of print on 16 January 2008.

{dagger} U.K. and A.O. contributed equally to this work.

Journal of Virology, April 2008, p. 3391-3404, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.02383-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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