The functional significance of AIDS virus escape from cytotoxic T-lymphocyte responses

Cytotoxic T-lymphocytes (CTL) play a crucial role in immune control of infection with human and simian immunodeficiency viruses (HIV and SIV). However, CTL can also select for viral variants that “escape” immune recognition. Escape from CTL responses has been well characterized within individual infected hosts, but the effects on viral fitness and development of CTL responses in naïve individuals infected with escape mutant viruses had not yet been thoroughly examined. We identified escape mutations that commonly occurred in three immunodominant CTL epitopes during infection of macaques with the cloned, pathogenic isolate SIVmac239, and introduced these mutations into the SIVmac239 genome, creating a cloned, “pre-escaped” virus, termed 3xSIV. We hypothesized that the mutant epitopes of 3xSIV would not be recognized by animals expressing the major histocompatibility complex (MHC) class I elements Mamu-A*01 and Mamu-B*17, which bind the wild type epitopes. Indeed, Mamu-A*01, B*17-positive macaques infected with 3xSIV had few or no CTL that could recognize the altered epitopes, and 3xSIV epitope mutations persisted throughout the course of infection. Surprisingly, however, two of three 3xSIV epitope sequences rapidly evolved towards wild type in animals that lacked Mamu-A*01 and B*17. In vitro replication studies indicated that SIV escape variants have a lower replicative capacity than wild type SIVmac239. These studies show that escape from CTL responses exacts a cost to viral fitness. It is therefore likely that some CTL epitopes will be preserved as HIV circulates in human populations. Furthermore, our observations proffer a conceptual model for viral evolution, which suggests that the propensity of HIV to escape from CTL responses could be harnessed in future HIV vaccines to drive the evolution of unfit variants, enhancing containment of viral replication.