Background:  Viral escape from cytotoxic T lymphocytes (CTL) has been shown to undermine immune control of HIV-1 and may prove a major limitation of CTL-based AIDS vaccine strategies. It is therefore important to determine whether viruses with mutations in dominant CTL epitopes can be stably transmitted to naïve hosts and to identify the mechanism by which these mutations are maintained.

Methods:  We infected naïve Mamu-A*01-positive (N=4) and Mamu-A*01-negative (N=5) rhesus monkeys with SIVsmE660 variants carrying mutations in the dominant Mamu-A*01-restricted Gag p11C epitope. The inoculum consisted of premorbid plasma from previously vaccinated and challenged Mamu-A*01-positive monkeys that exhibited breakthrough viral replication as a result of viral escape from p11C-specific CTL. We monitored viral RNA levels, clinical disease progression, cellular and humoral immune responses, and viral sequence evolution in the newly infected animals for 2 years.

Results:  Following transmission of the SIV variants to naïve rhesus monkeys, set-point viral RNA levels were 10⁵-10⁶ copies/mL, and 8 of 9 monkeys were euthanized for clinical disease progression during the 2-year follow-up period. Viral sequencing at multiple time points during chronic infection revealed permanent reversions to wild type (WT) sequences in 4 of 5 Mamu-A*01-negative monkeys with a median time to reversion of 30 weeks. In contrast, mutations in the p11C epitope persisted in all the Mamu-A*01-positive monkeys. Interestingly, we detected transient reversions to WT sequences during chronic infection in 3 of 4 of the Mamu-A*01-positive monkeys. The transiently reverted wild type viruses rapidly elicited p11C-specific CTL responses, which in turn exerted sufficient immunologic pressure to re-select the mutant viruses. The SIV variants thus persisted in these animals despite a virologic fitness cost.

Conclusions:  These data suggest that viruses with mutations in dominant CTL epitopes can prove highly pathogenic when transmitted to naïve hosts. Moreover, mutations in dominant HIV-1 CTL epitopes may accumulate in human populations with limited major hystcompatibility complex heterogeneity by a mechanism involving dynamic CTL control of transiently reverted WT viruses.

Keywords: vaccine; CTL; escape