This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.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.Previously we showed that elite control in our macaque cohort was associated with expression of the MHC class I (MHC-I) allele Mamu-B*17. The Mamu-B*17 protein presents peptide 'epitopes' derived from SIV proteins to CD8+ T cells, 'flagging' infected cells for destruction. Since Mamu-B*17 plays a role in the cellular immune response, we therefore hypothesized that the specific CD8+ T cell responses made by Mamu-B*17-positive animals 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, to immune containment of SIV in macaque ECs.By transiently depleting CD8+ T cells in a cohort of ECs, we showed that cellular immune responses are indeed crucial for the ongoing control of SIV replication seen in these animals. We devised a novel virus suppression assay to show that CD8+ T cells and NK cells both contribute to this immune containment in ECs. In the course of these studies, we discovered that an additional MHC-I gene, Mamu-B*08, is also associated with elite control. We determined which fragments of SIV proteins, or epitopes, are presented to CD8+ T cells by Mamu-B*08 molecules. We tested the ability of the cellular immune responses 'restricted' by these alleles to maintain control of virus replication by challenging animals with mutant viruses, into which we had introduced particular escape mutations. Surprisingly, the ECs controlled replication of these mutant viruses. We are now trying to understand how these animals maintain control of virus mutants that should 'knock out' their most important immune responses. Importantly, we have also found evidence that 'immunodominance,' the process by which immune responses to one viral epitope can inhibit responses that recognize different epitopes, may play a major role in determining animals' ability to control SIV replication. Our data suggest that AIDS vaccines may need to help modulate this immunodominance in immunized individuals if they are to successfully protect people from HIV.This research used Immunology & Virology Services, Genetics Services and Animal Services.
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