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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 ^,

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-) antiviral therapy achieves the highest rate of success when IFN- 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-- 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- 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.

Published ahead of print on 30 July 2008.

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