""""""""Elite controllers"""""""" (ECs), rare individuals who effectively control HIV replication in the absence of treatment, may help guide AIDS vaccine development by providing us a chance to define successful host immune responses. Unfortunately, however, it is challenging to study virological and immunological parameters associated with control in these subjects. ? ? We have identified a unique cohort of 13 rhesus macaques that spontaneously controlled SIVmac239 replication to extremely low levels for up to 5 years. The MHC class I allele Mamu-B*17 is present in 9 of 13 ECs (69%), while it occurs in just 19% of normal progressors, suggesting that this allele might restrict particularly effective CD8 T cell responses. Recently, we transiently depleted peripheral CD8 cells in 4 Mamu-B*17- positive ECs. CD8 depletion was associated with a brief 100-10,000-fold increase in viremia, which rapidly diminished as CD8 counts rebounded. Strikingly, when CD8 cells returned, only a small subset of Mamu-B*17-restricted, SIV-specific CD8 populations had expanded up to 250-fold above pre-depletion levels. We hypothesize that this handful of CD8 T cell responses drives elite control of SIV replication in these animals. Here we propose to test this hypothesis in vitro and in vivo in two specific aims. ? ? In specific aim 1, we will construct mutant viruses bearing escape mutations in Mamu-B*17 epitopes and assay their fitness in vitro. We will also test the capacity of epitope-specific CD8 cells from ECs to suppress the growth of these escape variants and wild type SIVmac239 in a newly developed in vitro culture system. ? ? In specific aim 2, we will challenge ECs with escape variant viruses. We predict that the escape mutations will """"""""knock out"""""""" crucial CD8 T cell responses in ECs expressing Mamu-B*17, and therefore these animals will fail to control this challenge. In contrast, B*17-negative ECs should suppress the mutant virus. ? ? ?
