CORRELATES OF ELITE CONTROL OF SIV

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To understand the "correlates of control" in macaque elite controllers (ECs). The "correlates of protection," i.e., the immune responses which will protect vaccinated individuals against HIV infection, are unknown. Because of this, there is intense interest in studying "elite controllers" (ECs), rare individuals who spontaneously control HIV replication. Over the past few years we have assembled a cohort of elite controller macaques that resemble human ECs in several important respects. This project is aimed at understanding the "correlates of control" in these macaque ECs. Previously we showed that elite control in our macaque cohort was associated with expression of particular MHC class I (MHC-I) alleles, Mamu-B*17 and Mamu-B*08. Strikingly, all macaque elite controllers in our cohort express at least one of these alleles. These proteins present peptide "epitopes" derived from SIV proteins to CD8+ T cells, "flagging" infected cells for destruction. Since Mamu-B*17 and B*08 play a role in the cellular immune response, we therefore hypothesized that the specific CD8+ T cell responses made by animals expressing these proteins made it possible for them to become ECs. This project has therefore probed the contribution of CD8+ T cell responses, particularly those "restricted" by Mamu-B*17 and B*08, to immune containment of SIV in macaque ECs. To our surprise, we recently found no apparent differences in either the strength of immune responses or number of viral epitopes recognized in ECs and progressors. To determine more directly whether particular CD8+ T cell responses enable Mamu-B*17-positive ECs to control SIV replication, we constructed a series of SIVmac239 derivatives bearing mutations in combinations of Mamu-B*17-restricted epitopes. We reasoned that one or more of these mutant viruses would cause breakthrough viremia in Mamu-B*17-positive ECs after intravenous inoculation. Again to our surprise, we found that ECs resisted superinfection, even with a virus bearing mutations in all 5 CD8+ T cell epitopes that constitute the Mamu-B*17-restricted repertoire. We devised a novel competing coculture assay to test the replicative capacity of these mutant viruses, which showed that the epitope mutations exact negligible costs to viral fitness, suggesting that growth defects cannot account for the ability of ECs to control the epitope mutant viruses. A manuscript describing these results is currently in preparation. This research used WNPRC Animal Services, Genetics Services, and Immunology & Virology Services.