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-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.