Analysis of host immune responses involved in control of HIV infections

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In the natural courses of HIV infections, cytotoxic T lymphocyte (CTL) responses play a central role in resolution from primary infection but fail to control viral replication leading to establishment of persistent HIV infection. We have been examining the effect of vaccine-induced CTL responses on simian immunodeficiency virus (SIV) replication in macaques to elucidate the mechanism for persistent HIV infection. We have found a group of rhesus macaques sharing a major histocompatibility complex haplotype 90-120-a that show vaccine-based SIV control. Some of them have shown reappearance of plasma viremia after 1-year of viral control with accumulation of Gag CTL escape mutations. In this study, we have examined the replicative ability of SIV with these multiple CTL escape mutations.The mutant SIV had Gag mutations escaping from three epitope-specific CTLs and showed diminished replicative ability in vitro compared to the wild-type SIV and the SW with a single CTL escape mutation rapidly-selected in the early phase of infection. This indicates that the viruses reappeared by escaping from CTLs with viral fitness costs, suggesting involvement of these three epitope-specific CTL responses in viral control. Viral evasion from immune control with a single escape mutation from a dominant CTL has been reported only in one preclinical AIDS vaccine trial in an acute AIDS model (Nature 415 : 335, 2002). This report has not made it clear whether multiple epitope-specific CTLs can be involved in the vaccine-based control of immunodeficiency virus replication, but our results indicate that accumulation of multiple CTL escape mutations can result in viral breakthrough from the vaccine-based control of SIV replication.