title: Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Gamal
authors.initials: G
authors.lastname: Badr
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bédard
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Abdel-Hakeem
authors.forename: Lydie
authors.initials: L
authors.lastname: Trautmann
authors.forename: Bernard
authors.initials: B
authors.lastname: Willems
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Villeneuve
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.forename: Rafick P
authors.initials: RP
authors.lastname: Sékaly
authors.forename: Julie
authors.initials: J
authors.lastname: Bruneau
authors.forename: Naglaa H
authors.initials: NH
authors.lastname: Shoukry
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D000939:Epitopes; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D016898:Interferon-alpha / Q000276:immunology / Q000627:therapeutic use; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*
chemical_list: D000939:Epitopes; D016898:Interferon-alpha; D053699:Interleukin-7 Receptor alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2