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. To evaluate the impact of AIDS virus evolution on the design of vaccines, we will determine whether mutations ? that facilitate AIDS virus escape from CD8 T-cell responses also affect viral fitness in vitro and in vivo.? ? The prodigious ability of HIV to spawn new mutants presents a major obstacle to AIDS vaccine development. It is now ? well established that AIDS viruses evolve over the course of infection in most individuals, accumulating mutations that ? enable the viruses to """"""""escape"""""""" recognition by the immune system. If these escape mutations can arise in one patient ? and be transmitted to another, over time the virus could become less and less recognizable to immune responses. ? These studies were designed to assess the degree to which escape mutations in viral epitopes will persist in populations ? as the AIDS epidemic progresses. ? ? In the past year, we found a rhesus macaque gene, Mamu-B*17, to be associated with effective containment of the ? pathogenic virus SIVmac239. This work also identified a cohort of """"""""elite controllers"""""""" (ECs), animals that controlled ? chronic phase viremia to less than 1,000 viral RNA (vRNA) copy Eq/ml plasma. We began studies to determine the role ? played by CD8+ T cell responses in control of virus replication in these animals by transiently depleting their CD8+ ? lymphocytes, as we also reported last year.? ? We then built on these studies to better understand the functional significance of AIDS virus escape from cellular ? immune responses. We continued our study of virus containment in CD8-depleted ECs, devising a novel assay to ? distinguish between the antiviral effects of these animals' CD8+ T and NK cells ex vivo. We searched for responses to ? novel SIV antigens presented by Mamu-B*17 and found evidence for a """"""""cryptic"""""""" epitope recognized by high frequency ? CD8+ T cells that accumulates mutations consistent with escape. We took a new approach to examining the functional ? significance of escape from CTL by evaluating the ability of epitope-specific CTL lines to suppress replication of wild type ? and escape mutant viruses in an in vitro assay. Funds from this award also supported aspects of other studies on the ? ability of CD8+ T cells to control SIV in vitro and in vivo. This research used WNPRC Animal Services and Immunology & ? Virology Services.?
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