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Journal of Virology, April 2003, p. 4781-4793, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4781-4793.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Kinetics of CD4+ and CD8+ Memory T-Cell Responses during Hepatitis C Virus Rechallenge of Previously Recovered Chimpanzees

Michelina Nascimbeni,1 Eishiro Mizukoshi,1,{dagger} Markus Bosmann,1 Marian E. Major,2 Kathleen Mihalik,2 Charles M. Rice,3 Stephen M. Feinstone,2 and Barbara Rehermann1*

Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,1 Laboratory of Hepatitis Research, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892,2 Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 100213

Received 2 October 2002/ Accepted 22 January 2003

The immunological correlates of hepatitis C virus (HCV)-specific immunity are not well understood. Antibodies to HCV structural proteins do not appear to play a key role in clearance of the virus and do not persist after recovery. Here, we studied the kinetics of the cellular immune responses of three HCV-recovered chimpanzees during rechallenge with increasing doses of homologous HCV. Although HCV envelope antibodies remained undetectable throughout the rechallenge, all animals mounted rapid HCV-specific T-cell responses. The pattern of the cellular immune response in blood and liver correlated with the virological outcome. The animal that most rapidly cleared circulating HCV as determined by nested reverse transcription-PCR (RT-PCR) displayed the most vigorous and sustained response of gamma interferon (IFN-{gamma})-producing and proliferating CD4+ T cells in the blood. Vigorous CD4+ T-cell proliferation during viremia was followed by an increased frequency and a phenotypic and functional change of the tetramer+ CD8+ T-cell population. The second animal cleared HCV initially with strong peripheral and intrahepatic CD4+ T-cell responses but experienced low-level HCV recrudescence 12 weeks later, when HCV-specific T cells became undetectable. The third animal maintained minute amounts of circulating HCV, detectable only by nested RT-PCR, in the face of a weak IFN-{gamma}+ T-cell response. Collectively, the results suggest protective rather than sterilizing immunity after recovery from hepatitis C. The rate of HCV clearance following reexposure depends on the cellular immune response, the quality and quantity of which may vary among chimpanzees that recovered from HCV infection.

* Corresponding author. Mailing address: Liver Diseases Section, NIDDK, National Institutes of Health, 10 Center Dr., Room 9B16, Bethesda, MD 20892. Phone: (301) 402-7144. Fax: (301) 402-0491. E-mail: Rehermann{at}nih.gov.

{dagger} Present address: First Department of Internal Medicine, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8641, Japan.

Journal of Virology, April 2003, p. 4781-4793, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4781-4793.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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