Correlates of elite control of SIV

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DESCRIPTION (provided by applicant): "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.