Viral, immune, and host genetic factors influence both a person's risk of becoming infected with HIV-1, and the rate at which the disease progresses once infected. We have recently determined that macrophage- tropic primary isolates of HIV-1 will not infect CD4+ peripheral blood mononuclear cells from some multiply-exposed seronegative persons. We have now identified the mechanism underlying this in vitro and in vivo resistance to infection. These individuals have inherited a homozygous 32-base-pair deletion within the gene encoding CCR-5, the major co- receptor for macrophage-tropic virus. Our most recent studies suggest that up to 25% of Caucasian high-risk seronegative homosexual men may have resisted HIV-1 infection because they inherited this allele. We hypothesize that this and other CCR-5 polymorphisms influence both one's risk of becoming infected with HIV-1 and the rate at which the disease progresses once infected. The overall goal of this proposal is to determine the extent to which naturally-occurring CCR-5 polymorphisms affect susceptibility to HIV-1 infection and disease progression world-wide. In addition, the immunologic function of cells expressing these CCR-5 polymorphisms will be tested. The specific aims of the proposal are to: 1. Determine the role of the 32-bp deleted allele in HIV-1 transmission and disease progression. 2. Find other polymorphisms of CCR-5, determine their role in transmission and disease progression, and understand their evolution. 3. Determine the mechanism by which CCR-5 polymorphisms control resistance to infection and rates of disease progression. 4. Determine the immunologic consequences of inheritance of CCR-5 polymorphisms.