Project 1: Mechanisms driving breadth of HCV neutralization during repeated control of acute infection in humans PI: Stuart C. Ray, M.D. The primary objective of Project 1 is to study mechanisms driving increased breadth of neutralizing antibody responses during repeated HCV infections that are successfully cleared. We have recently demonstrated that anti-HCV humoral immune responses drive the evolution of HCV proteins E1 and E2 during acute and chronic infection, indicating that neutralizing antibodies detected in our in vitro assays reduce viral fitness in vivo. We have also demonstrated that neutralizing antibodies form clusters of similar specificities by testing them against natural HCV variants that we have cloned in a functional library. We hypothesize that repeated stimulation with varying HCV envelope sequences during reinfection drives broadening of the neutralizing antibody response. Thus, we propose the following aims to elucidate the mechanisms driving HCV neutralization breadth during acute reinfection: (I) to examine dynamic changes in anti-HCV binding and neutralizing activity during HCV re-infection, (II) to determine the mechanistic basis for changes in neutralizing activity by characterizing the circulating B cell repertoire, and (III) to identify key HCV envelope sequence changes that drive broadening of neutralization during reinfection. We anticipate that accomplishing these aims in collaboration with Dr. Cox (project 2) and Dr.Shaw (Project 3) will reveal patterns of antigenic exposure that drive shifts in the B cell response, in a manner that will help guide vaccine design and increase understanding of the host-pathogen interaction.
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