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Journal of Virology, October 2008, p. 10017-10031, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.01083-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Early Interferon Therapy for Hepatitis C Virus Infection Rescues Polyfunctional, Long-Lived CD8+ Memory T Cells{triangledown} ,{dagger}

Gamal Badr,1,2 Nathalie Bédard,1 Mohamed S. Abdel-Hakeem,1,3 Lydie Trautmann,1,6 Bernard Willems,1,4 Jean-Pierre Villeneuve,1,4 Elias K. Haddad,1,3,6 Rafick P. Sékaly,1,3,6 Julie Bruneau,1,5 and Naglaa H. Shoukry1,4*

Centre de Recherche du Centre Hospitalier de l'Université de Montréal, CRCHUM, Hôpital St. Luc, Montréal, QC, Canada,1 Faculty of Science, Assiut University, Assiut, Egypt,2 Département de Microbiologie et Immunologie,3 Département de Médecine,4 Département de Médecine Familiale, Université de Montréal, Montréal, QC, Canada,5 Unité INSERM (U-743), Montréal, QC, Canada6

Received 22 May 2008/ Accepted 21 July 2008

The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-{alpha}) antiviral therapy achieves the highest rate of success when IFN-{alpha} is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-{gamma}- and IL-2-producing and CD107a+) virus-specific CD8+ T cells. These polyfunctional 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 expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-{alpha} rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.

* Corresponding author. Mailing address: Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Hôpital St.-Luc, 264 Blvd. René-Lévesque Est, Local PEA-316, Montréal (Québec) H2X 1P1, Canada. Phone: (514) 890-8000. Fax: (514) 412-7377. E-mail: naglaa.shoukry{at}umontreal.ca

{triangledown} Published ahead of print on 30 July 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, October 2008, p. 10017-10031, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.01083-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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