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

Abstract

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-␥) 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-␥ 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.

Kinetics of the immune response during HBV and HCV infection

“…During primary HCV infection of chimpanzees, virus-specific antibody responses are detectable 8 to 12 weeks after infection and HCV-specific T-cell responses appear with identical delays. 25,[38][39][40][41] This long interval of time between infection and induction of the adaptive immunity to HBV and HCV seems to contrast with the reported kinetics of virus-specific T-cell responses to other virus infections. Although comparison of different studies must be interpreted with caution because of possible sensitivity variations in the assays, it is intriguing that although T-cell responses to simian immunodeficiency virus, human immunodeficiency virus, and cytomegalovirus already can be detectable 2 weeks after infection, 42,43 Fig.…”

“…It is interesting to note that HCVspecific cellular immune responses are detectable earlier after rechallenge (2 weeks) than after primary infection (8-10 weeks). 39,41,128,131 This acceleration of the adaptive immune response, although insufficient to prevent infection, can influence positively the course of the HCVinduced liver disease in vaccinated animals, which usually develop low viremia and mild hepatitis. These findings in HCV rechallenge experiments and in HCV-vaccinated animals reinforce the hypothesis that the long interval of time between infection and activation of the HCVspecific adaptive immune response represents a major factor that influences the rate of chronicity and the profile of the disease.…”

“…10,25,38,41,44 Signs of liver damage (alanine aminotransferase level elevation) and of adaptive immunity are detectable 6 to 8 weeks after infection. 10,25,[38][39][40][41] Viremia is substantially lower in HCV than in HBV infection. For HBV, HBV DNA is not detectable for about 4 to 7 weeks after infection.…”

Hepatitis C virus polyprotein vaccine formulations capable of inducing broad antibody and cellular immune responses

“…In addition, it has been shown that there is an inverse correlation between the frequency of HCV-specific cytotoxic T lymphocytes and virus load (Nelson et al, 1997). More recently, it was shown that the control of HCV in chimpanzees was associated with a Th1-type cellular immune response (Major et al, 2002). Therefore, accumulated evidence suggests an important role for HCV-specific T-cell responses in controlling HCV infection.…”

Experimental models to study the immunobiology of hepatitis C virus

“…Studies in reinfected chimpanzees that previously cleared the infection have revealed the existence of a protective immunity, which may, however, not be able to consistently prevent reinfection (Bukh et al, 2008;Major et al, 2002). The protection seems to be T-cell-mediated (reviewed by Bowen & Walker, 2005).…”