Elucidating the consequences of HIV-1 immune escape from host CTL selection pressure

This thesis focuses on HIV-1 adaptation to CTL immune response and presents original data on the consequences of 10 published HLA-B*13-associated CTL escape mutations in Gag, Pol and Nef on HIV-1 replication capacity (RC) and Nef-mediated CD4 and HLA class I downregulation. B*13-driven immune escape at Gag-I147L and -I437L incurred replicative costs of 5% and 17% on in vitro viral RC, which was rescued to wild-type (HIV-1NL4.3) levels by Gag-A146S/K436R and Gag-K436R, respectively. One major observation was that B*13-driven double mutation, NefE24Q/Q107R impaired this protein’s HLA class I downregulation ability by 40%, with no evidence of replicative or expression defects. Moreover, cells infected with double mutant virus were “visible” to HIV-specific T cells. Our results thus suggest that B*13-mediated protective effects on HIV-1 disease progression may be attributable, in part to a novel mechanism – namely, the selection of escape mutations in Nef that dampen one of HIV-1’s key immune evasion strategies.