5). Peak levels of the indicated T-cell marker coincided with a moderate induction of several CAL-101 solubility dmso ISGs that might be responsible for the initial control of viremia (Fig. 5). Furthermore, the DC-specific markers CD11c and CD304 were down-regulated similar to that observed in CH10273. During the follow-up, the chimpanzee developed at week 37 a pronounced increase in intrahepatic CD8 mRNA levels, which coincided with an increase in peripheral HCV-specific T-cell response (Fig. 3, weeks 37-43). This increase was accompanied by an intrahepatic induction of IFN-γ and several ISGs and then followed by disappearance of viremia after week 42 (Fig. 5). The viremia, however,

returned with a fluctuating course until the virus was ultimately Temsirolimus order cleared. The development of an HCV vaccine is challenged by the fact that HCV can infect patients that previously recovered from HCV infection,19, 20 suggesting that complete protection appears difficult to achieve. Likewise, studies in chimpanzees demonstrated that animals rechallenged with homologous or heterologous strains of HCV are not consistently protected against

reinfection following acute resolving infection.15 Aiming to better understand the immunological determinants of protective immune responses to HCV infection, we performed an extensive analysis of the innate and adaptive immune response in two chimpanzees that had previously cleared HCV and were rechallenged with homologous and/or heterologous strains of HCV. Chimpanzee 10274 was rechallenged three times with the JFH1 homologous virus derived from cell culture. The first challenge produced detectable HCV RNA lasting only 2 weeks. The chimpanzee was not infected following the subsequent challenge. The chimpanzee became virus-positive at a low level 10 weeks after the third rechallenge.

Unfortunately, the chimpanzee was rechallenged with the H77 virus on the same day per protocol and we were not able to follow this course of viremia. The homologous JFH1cc rechallenges were associated with the development of neutralizing antibodies and the induction of HCV-specific T cells, probably contributing to the rapid control of viral Arachidonate 15-lipoxygenase infection. The viral clearance was not associated with a significant increase of serum alanine aminotransferase (ALT) level, suggesting that cytolytic mechanisms were not involved in viral clearance or that the number of virus-infected cells in the liver was very low. We also did not detect any intrahepatic innate immune response in this animal. Our results are in line with several previous studies in chimpanzees demonstrating the importance of T cells in viral clearance and protection after rechallenge.11-13, 15, 21 It is interesting to note that the H77 virus overcame the protective immune responses against JFH1, dominated over the concurrent low-level JFH1 viremia, and developed into a high-viremic infection, suggesting that the protective immunity noted above was rather strain-specific.