rechallenge of chimps

rechallenge of chimps - J OURNAL OF VIROLOGY July 2002 p...

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Unformatted text preview: J OURNAL OF VIROLOGY, July 2002, p. 6586–6595 Vol. 76, No. 13 0022-538X/02/$04.00 1 DOI: 10.1128/JVI.76.13.6586–6595.2002 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. Feinstone 1 Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, 1 and Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 2 Bethesda, Maryland, and Center for the Study of Hepatitis C, Rockefeller University, New York, New York 3 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 10 6 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, 10 3 copies/ml), and minimal ALT elevations. A comparison of intrahepatic cytokine levels in Ch1552 and Ch1605 showed greater and earlier gamma interferon (IFN- g ) 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- g 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 impli- cations for the development of a vaccine for HCV. Infection with hepatitis C virus (HCV) poses a serious public health problem. It frequently leads to chronic hepatitis and cirrhosis in humans and is associated with the development of hepatocellular carcinoma (26). Persistent infection occurs in up to 85% of patients (1) and at least 30% of chimpanzees (2)....
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This note was uploaded on 07/12/2011 for the course BIO 620 taught by Professor Hardy during the Spring '11 term at University of Florida.

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rechallenge of chimps - J OURNAL OF VIROLOGY July 2002 p...

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