This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To understand the importance of breadth in CD8+ T cell immunity against HIV and SIV. Numerous lines of evidence suggest CD8+ T cells are important in the control of SIV/HIV. The STEP Trail vaccine was designed to elicit HIV-specific CD8+ T cells;however this trial was halted in 2007 after a failure to protect against HIV infection. It is possible that the failure of this vaccine is due, in part, to an inability to elicit a broad specificity of CD8+ T cells. We are challenging homozygous and heterozygous animals with SIVmac239 and closely following SIV-pathogenesis in these animals in order to determine whether CD8+ T cell breadth is an important component of HIV control. In specific aim 1 we will examine whether Mauritian cynomolgus macaques heterozygous for two common MHC haplotypes will control SIV more effectively than animals homozygous for either of the haplotypes. In order to complete this aim, 18 animals, six of each genetic background, will be infected with SIVmac239. In specific aim 2 we will examine whether reducing the breadth of potential CD8+ T cell responses increases the pathogenicity of SIV by infected animals with a virus that is depleted of epitopes from one of the haplotypes. In specific aim 3 we will define the impact of CD8+ T cell breadth to the protection afforded by live attenuated vaccines by challenging vaccinated animals with the virus from specific aim 2. We are currently in the process of completing specific aim 1. We have infected 18 animals with SIVmac239 and are monitoring these animals for differences in viral loads, CD4 counts, and the size and focus of their CD8 T cell response. Two potential manuscripts are being prepared with currently gathered data. We have also initiated specific aim 2 by beginning work to create the virus that will be used in that aim. This research used WNPRC Animal Services, Immunology &Virology Services, Research computing and Genetics Services.