Human genetic polymorphism influences the occurrence and evolution of HIV-1 infection. This project addresses the Office of AIDS Research 2007 goal of identifying genetic factors that explain highly variable responses to the infection and its sequelae. Genetic determinants will be studied primarily in infectied and susceptible populations in Zambia, Rwanda and Uganda and secondarily in established HIV/AIDS cohorts of European ancestry. A unique assembly of 1200 heterosexually active African couples with one HIV -1 - positvie and one negative parnter permits powerful hypothesis testing for genetic effects in untreated individuals. Specific aims address genes in pathways critical fro the response to the virus: 1) the HLA class 1 antigen - presenting pathway (HLA-A, -B and -C), 2) the natural killer cell pathway (the KIR gene family and LILRB1), and 3) the chemokine co-receptor pathway (CCR2, CCR5, CCL3, CCL3L1, CCL4, CCL4L1, and CCL5). New candidate genes can be added. The investigators will use public bioinformatics databases, genome-level sequencing services, and state-of-the-art medium-throughput laboratory techniques to detect polymorphisms within the selected loci. Principal outcome measures include time to seroconversion in exposed HIV-1-negative partners and level of plasma viral RNA and CD4+ cell counts early in infection. The size of each African cohort will support independent hypothesis-testing, and powerful inferences may be drawn from data judiciously aggregated across the cohorts. With couples investigation, the behavior of two hosts successively infected with a closely related virus can be observed on a scale previously unequaled. Analyses will emphasize predicted interactions between receptor and ligand gene products. Simultaneous effects of multiple markers on outcomes will be examined, and statistical attention will be paid to haplotype tagging, to population heterogeneity and to potential false discovery. Functional correlations of immunogenetic relationships will be explored through collaboration. Discovery of polymorphisms that modify acquisition and control of the infection is likely to have clinical and public health relevance beyond prognostic value. Elucidation of key host genetic influences, particularly of HLA class 1 gene variants, will likely guide the design and application of HIV vaccines; the work could also inform the development of immunotherapeutic agents that exploit genetically mediated host-virus interaction.