ABSTRACT – CORE B (NONHUMAN PRIMATE CORE) After over 3 decades since the discovery of Hepatitis C virus as one cause of hepatitis and cancer in patients, a preventive vaccine is still not available. More alarming is the fact that precise correlates of protection remain elusive. While passively administered neutralizing antibodies have been able to prevent initiation of infection in chimpanzees, the same treatment in the context of established infection just gave rise to mutants no longer susceptible to neutralization by this particular Mab and without apparent decrease in replication fitness. Conversely, spontaneous resolution of the infection as seen in about 25% of patient appears to primarily rely on cell mediated immune responses such as intra-hepatic CTLs. Generating such response via immunization has been a steep challenge given the multiple mechanism used by the virus to evade the effector antiviral responses. While recent development of antiviral agents have succeeded in the elimination of the majority of treated patients, this cure is expensive and patients having cleared infection therapeutically generally do not develop protective responses to a reinfection. To make matters worse, subclinical HCV infection not only does not generate protective response against superinfection but appears to paralyze many cell mediated effector immune functions, via the recruitment of regulatory T cells in the liver. Thus, generating potent and lasting protective mechanisms against HCV infection will require novel approaches, targeting both humoral and cell mediated antiviral responses, which is the goal of this collaborative program. The generation of broadly neutralizing antibodies will be attempted using HCV E1/E2 wild-type and optimized scaffolds that will minimize the presentation of non or subtype only neutralizing epitopes while presenting conserved epitopes across the 7 HCV genotypes along with potent adjuvants. A second approach will use a combination of live attenuated viral vector presenting non structural proteins Mosaic recombinant proteins in efforts to generate potent CTLs to HCV. This nonhuman primate Core will allow for testing each approach separately and in combination in a host that closely mimic the human immune system and repertoire, allowing for optimization of the responses and their analyses ex vivo for efficacy. This will be accomplished in a series of studies using the Indian origin macaque model of immunization, which will allow for repeated sampling and procurement of blood and bone marrow samples as well as biopsies of draining lymph nodes and liver of the entire monitoring period to Projects 2 and 3.