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Journal of Virology, December 2002, p. 12584-12595, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12584-12595.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Broad Specificity of Virus-Specific CD4+ T-Helper-Cell Responses in Resolved Hepatitis C Virus Infection

Cheryl L. Day,1,2 Georg M. Lauer,1,2 Gregory K. Robbins,1,2 Barbara McGovern,3,4 Alysse G. Wurcel,1,2,4 Rajesh T. Gandhi,1,2 Raymond T. Chung,5 and Bruce D. Walker1,2*

Partners AIDS Research Center,1 Infectious Disease Unit,2 Gastrointestinal Unit,5 Massachusetts General Hospital and Harvard Medical School, and Division of Infectious Diseases, New England Medical Center,3 Lemuel Shattuck Hospital Boston, Massachusetts4

Received 23 May 2002/ Accepted 3 September 2002

Vigorous virus-specific CD4+ T-helper-cell responses are associated with successful control of hepatitis C virus (HCV) and other human viral infections, but the breadth and specificity of responses associated with viral containment have not been defined. To address this we evaluated the HCV-specific CD4+ T-helper-cell response in HCV antibody-positive persons who lack detectable plasma viremia, and compared this response to that in persons with chronic HCV infection. Peripheral blood mononuclear cells were stimulated with HCV proteins, followed by measurement of HCV-specific CD4+-T-cell responses to a comprehensive set of overlapping HCV peptides by intracellular gamma interferon production. In three persons with resolved HCV infection studied in detail, 13 to 14 epitopes were targeted, but none was recognized by all three. The 37 defined epitopes were predominantly distributed among the HCV proteins core, NS3, NS4, and NS5. In an expanded analysis of responses to these proteins in persons with resolved infection, an average of 10 epitopes was targeted, whereas in persons with chronic viremia never was more than one epitope targeted (P < 0.001). This comprehensive analysis of the breadth and specificity of HCV-specific T-helper-cell responses indicates that up to 14 viral epitopes can be simultaneously targeted by circulating virus-specific CD4+ T helper cells in a controlled human viral infection. Moreover, these data provide important parameters for evaluation of candidate HCV vaccines, and provide rationale for immunotherapy in chronic HCV infection.

* Corresponding author. Mailing address: Massachusetts General Hospital, Partners AIDS Research Center, 149 13th St., Rm. 5212D, Charlestown, MA 02129. Phone: (617) 724-8332. Fax (617) 726-4691. E-mail: bwalker{at}partners.org.

Journal of Virology, December 2002, p. 12584-12595, Vol. 76, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.24.12584-12595.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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