The goal of this research proposal is to study the mechanisms of immune escape from the cellular immune response. Previous studies have indicated that immune escape follows predictable mutational pathways based on the infected individual's genetic environment. Since immune escape is not random and determined by the individual's HLA type, it is important to study this process in order that we may elucidate novel epitopes that may be exploited for vaccine design. In addition, a complete understanding of this mutational process will allow us to further understand the dynamics of viral evolution at both a population and individual level. Previous studies addressing these questions focused on a subtype B cohort and were hindered by limitations because the sequence of the transmitted virus was unknown. We propose to characterize known CTL escape epitopes in a subtype C African cohort using epidemiologically linked transmission pairs.
Specific Aim 1 will, based on known CTL escapes epitopes and the correlating HLA alleles, determine the kinetics of escape and reversion in a subtype C African cohort.
Specific Aim 2 will determine if escape mutations in reverting epitope confer a viral fitness cost through in vitro replication assays and competition assays.
