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J. Virol. doi:10.1128/JVI.01083-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Early Interferon Therapy for HCV Rescues Poly-functional long-lived CD8+ Memory T Cells

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Hôpital St-Luc, Montréal, QC, Canada; Faculty of Science, Assiut University, Egypt; Département de microbiologie et immunologie, Département de médecine, Département de médecine familiale, Université de Montréal, Montréal, QC, Canada; Unité INSERM (U-743), Montréal, QC, Canada

^* To whom correspondence should be addressed. Email: naglaa.shoukry{at}umontreal.ca.

	Abstract

The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Interferon-alpha (IFN-) antiviral therapy achieves the highest rate of success when administered early during the acute phase but the underlying mechanisms are unknown. We used a panel of MHC class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV with different infection outcome and during early interferon therapy. We demonstrate that spontaneous resolution correlates with the early development of poly-functional (IFN-+, IL-2+ and CD107a+) virus-specific CD8+ T cells. These poly-functional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8+ T cells in acute infections evolving to chronicity were CD127^lo, Bcl-2^lo, exhibited diminished proliferation and cytokine production and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN- (PEG-IFN) rescued CD127^hi, Bcl-2^hi poly-functional memory T cells. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that poly-functionality of HCV-specific T cells can be predictive of the outcome of acute HCV and that early therapeutic intervention can reconstitute the pool of long-lived poly-functional memory T cells.

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