Project Summary While there are many public health strategies in place for reducing HIV-1 infection rates in drug users, an effective HIV-1 vaccine remains critical to this effort. Studies of HIV-1 transmission, pathogenesis, and vaccine development are mostly conducted in macaque monkeys, although this primate model of HIV-1 infection has many limitations. In the decades since the macaque model was established, we have learned a tremendous amount about the immune response against HIV-1 and SIV. However, this hard-earned knowledge has never been synthesized into an integrated, rational approach for reevaluating the nonhuman primate model for HIV-1 infection. We present a principled approach for re-evaluating the genetic background of different primate species, capitalizing on the enormous knowledge base in the field, and on the substantial genetic diversity that exists. We will genotype restriction factor alleles from thousands of nonhuman primates representing several key primate species (rhesus macaques, pigtailed macaques, owl monkeys, baboons, marmosets, and squirrel monkeys) and test all discovered restriction factor alleles against HIV-1 in cell culture-based assays. Each discovered allele will be given an HIV-compatibility score, allowing systematic and rational determination of which species, and which specific individuals within those species, have restriction factor genotypes most compatible with HIV-1. As part of our approach, we will also evaluate MHC, KIR, and antibody receptor (FcR) gene content and allelic diversity in these primate species. We will specifically test discovered alleles against transmitted/founder (T/F) HIV-1, the variants that an effective vaccine needs to recognize. We will test T/F viruses previously isolated after both sexual and intravenous infection in humans, the two main modes by which drug users acquire HIV-1 infection. Ultimately, our research could open up exciting new avenues in the study of HIV-1 pathogenesis and transmission, and in the development of drugs and vaccines.