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J. Virol. doi:10.1128/JVI.02383-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Emergence of polyfunctional CD8+ T cells after prolonged suppression of HIV replication by antiretroviral therapy

Institute of Microbiology, ETH Hoenggerberg, Wolfgang-Pauli-Str. 10, 8093 Zurich, Switzerland; Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, UK; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Raemistrasse 10, 8091 Zurich, Switzerland

^* To whom correspondence should be addressed. Email: oxenius{at}micro.biol.ethz.ch.

	Abstract

Progressive 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 non progressors (LTNP). 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 (IFN, IL2, TNF) and their phenotype suggested limited potential for proliferation. During ART, cytokine secretion by HIV-specific CD8+ T cells was gradually restored, IL7R 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.

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