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Journal of Virology, June 2007, p. 5882-5892, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02202-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus (HCV)-Specific CD8+ Cells Produce Transforming Growth Factor ß That Can Suppress HCV-Specific T-Cell Responses{triangledown}

Nadia Alatrakchi,1* Camilla S. Graham,1 Hans J. J. van der Vliet,1 Kenneth E. Sherman,2 Mark A. Exley,1 and Margaret James Koziel1

Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Masachusetts,1 University of Cincinnati, Cincinnati, Ohio2

Received 6 October 2006/ Accepted 11 March 2007

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 immunospot 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 ß1 (TGF-ß1), -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-ß1, -2, and -3 neutralization. In conclusion, blockade of TGF-ß secretion could enhance peripheral HCV-specific T-cell responses even in the presence of HIV coinfection.

* Corresponding author. Mailing address: Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Rm. 219, 4 Blackfan Circle, Boston, MA 02115. Phone: (617) 667-0041. Fax: (617) 975-5235. E-mail: nalatrak{at}bidmc.harvard.edu

{triangledown} Published ahead of print on 21 March 2007.

Journal of Virology, June 2007, p. 5882-5892, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02202-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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