title: Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses.
abstract: Hepatitis C virus (HCV)-specific T-cell responses are rarely detected in peripheral blood, especially in the presence of human immunodeficiency virus (HIV) coinfection. Based on recent evidence that T-regulatory cells may be increased in chronic HCV, we hypothesized that functional blockade of regulatory cells could raise HCV-specific responses and might be differentially regulated in the setting of HIV coinfection. Three groups of subjects were studied: HCV monoinfected, HCV-HIV coinfected, and healthy controls. Frequencies of peripheral T cells specific for peptides derived from HCV core, HIV type 1 p24, and recall antigens were analyzed by gamma interferon (IFN-gamma) enzyme-linked immuno-spot assay. HCV-specific T-cell responses were very weak in groups with HCV and HCV-HIV infections. Addition of blocking antibodies against transforming growth factor beta1 (TGF-beta1), -2, and -3 and interleukin-10 specifically increased the HCV-specific T-cell responses in both infected groups; however, this increase was attenuated in the group with HCV-HIV coinfection compared to HCV infection alone. No increase in recall antigen- or HIV-specific responses was observed. Flow cytometric sorter analysis demonstrated that regulatory-associated cytokines were produced by HCV-specific CD3(+)CD8(+)CD25(-) cells. Enhancement of the IFN-gamma effect was observed for both CD4 and CD8 T cells and was mediated primarily by TGF-beta1, -2, and -3 neutralization. In conclusion, blockade of TGF-beta secretion could enhance peripheral HCV-specific T-cell responses even in the presence of HIV coinfection.
authors: Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA 02115, USA. nalatrak@bidmc.harvard.edu
authors: Nadia
authors: N
authors: Alatrakchi
authors: Camilla S
authors: CS
authors: Graham
authors: Hans J J
authors: HJ
authors: van der Vliet
authors: Kenneth E
authors: KE
authors: Sherman
authors: Mark A
authors: MA
authors: Exley
authors: Margaret James
authors: MJ
authors: Koziel
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D015497:HIV-1 / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000502:physiology
chemical_list: D016212:Transforming Growth Factor beta; D007371:Interferon-gamma