Variable Fitness Impact of HIV-1 Escape Mutations to Cytotoxic T Lymphocyte (CTL) Response
Human lymphocyte antigen (HLA)-restricted CD8+ cytotoxic T lymphocytes (CTL) target and kill HIV-infected cells expressing cognate viral epitopes. This response selects for escape mutations within CTL epitopes that can diminish viral replication fitness. Here, we assess the fitness impact of escape mutations emerging in seven CTL epitopes in the gp120 Env and p24 Gag coding regions of an individual followed longitudinally from the time of acute HIV-1 infection, as well as some of these same epitopes recognized in other HIV-1-infected individuals. Nine dominant mutations appeared in five gp120 epitopes within the first year of infection, whereas all four mutations found in two p24 epitopes emerged after nearly two years of infection. These mutations were introduced individually into the autologous gene found in acute infection and then placed into a full-length, infectious viral genome. When competed against virus expressing the parental protein, fitness loss was observed with only one of the nine gp120 mutations, whereas four had no effect and three conferred a slight increase in fitness. In contrast, mutations conferring CTL escape in the p24 epitopes significantly decreased viral fitness. One particular escape mutation within a p24 epitope was associated with reduced peptide recognition and high viral fitness costs but was replaced by a fitness-neutral mutation. This mutation appeared to alter epitope processing concomitant with a reduced CTL response. In conclusion, CTL escape mutations in HIV-1 Gag p24 were associated with significant fitness costs, whereas most escape mutations in the Env gene were fitness neutral, suggesting a balance between immunologic escape and replicative fitness costs. Upon infection with a pathogen, the host mounts an immune response of specific killing by recognizing infected cells presenting the foreign entity via host cell surface proteins (aka MHC) encoded by specific HLA genes. The pathogen's proteins are chopped up into peptides (short protein sequences) by cellular enzymes. Some of these peptides are bound to MHC class I proteins and then presented on the cell surface, signifying a pathogen intrusion to the killer T cells (CTLs). In order to survive, HIV-1 evolves to mutate the specific peptides (aka epitopes) and escape recognition by MHC I and CTLs. These “forced” or selected mutations are thought to come at a cost, e.g., result in slower pathogen growth/replication. Here, we show that the escape mutations in HIV-1 genes showing slow evolution result in dramatic losses in HIV-1 replication (or fitness). In contrast, CTL escape mutations in HIV-1 genes with rapid evolution do not have a negative impact on pathogen fitness. These findings could suggest that HIV-1 (and possibly other rapidly evolving pathogens) could avoid the host's immune system with minimal detriment to its own survival and growth within the host.