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Journal of Virology, July 2002, p. 6586-6595, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6586-6595.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Previously Infected and Recovered Chimpanzees Exhibit Rapid Responses That Control Hepatitis C Virus Replication upon Rechallenge

Marian E. Major,1* Kathleen Mihalik,1 Montserrat Puig,1 Barbara Rehermann,2 Michelina Nascimbeni,2 Charles M. Rice,3 and Stephen M. Feinstone1

Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration,1 Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland,2 Center for the Study of Hepatitis C, Rockefeller University, New York, New York3

Received 11 December 2001/ Accepted 26 March 2002

Responses in three chimpanzees were compared following challenge with a clonal hepatitis C virus (HCV) contained in plasma from an animal that had received infectious RNA transcripts. Two of the chimpanzees (Ch1552 and ChX0186) had recovered from a previous infection with HCV, while the third (Ch1605) was a naïve animal. All animals were challenged by reverse titration with decreasing dilutions of plasma and became serum RNA positive following challenge. Ch1605 displayed a typical disease profile for a chimpanzee. We observed increasing levels of serum RNA from week 1 postinoculation (p.i.), reaching a peak of 106 copies/ml at week 9 p.i., and alanine aminotransferase (ALT) elevations and seroconversion to HCV antibodies at week 10 p.i. In contrast, both Ch1552 and ChX0186 exhibited much shorter periods of viremia (4 weeks), low serum RNA levels (peak, 103 copies/ml), and minimal ALT elevations. A comparison of intrahepatic cytokine levels in Ch1552 and Ch1605 showed greater and earlier gamma interferon (IFN-{gamma}) and tumor necrosis factor alpha responses in the previously infected animal, responses that were 30-fold greater than baseline responses at week 4 p.i. for IFN-{gamma} in Ch1552 compared to 12-fold in Ch1605 at week 10 p.i. These data indicate (i) that clonal HCV generated from an infectious RNA transcript will lead to a typical HCV infection in naïve chimpanzees, (ii) that there are memory immune responses in recovered chimpanzees that control HCV infection upon rechallenge, and (iii) that these responses seem to be T-cell mediated, as none of the animals had detectable antibody against the HCV envelope glycoproteins. These observations have encouraging implications for the development of a vaccine for HCV.

* Corresponding author. Mailing address: Division of Viral Products, CBER/FDA, Bldg. 29A Rm. 1D10, HFM 448, 8800 Rockville Pike, Bethesda, MD 20892. Phone: (301) 827-1881. Fax: (301) 496-1810. E-mail: major{at}cber.fda.gov.

Journal of Virology, July 2002, p. 6586-6595, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6586-6595.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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