This study will investigate host genetic influences on three aspects of HIV infection among homosexual/bisexual men: 1) the risk of becoming infected with HIV; 2) the rate of disease progression among HIV-infected men; 3) the development of specific conditions, such as Kaposi's sarcoma (KS), Pneumocystis carinii pneumonia (PC), or other opportunistic infections (OI). Subjects will be 619 gay men from three existing cohorts of men in San Francisco who have been followed prospectively for periods ranging from 2 - 10 years: San Francisco Mens' Health Study (SFMHS), San Francisco General Hospital Cohort (SFGHC), and Young Mens' Health Study (YMHS). To test the specific hypothesis relating to risk of infection and development of specific conditions, we will use case-control comparisons of genotypes at immune response loci among 1) 135 high-risk HIV- men and 144 high-risk HIV+ men from the YMHS; and 2) 134 men with KS and 165 men with PCP and/or OI from all three cohorts to study risk of developing specific conditions. Immune response genotypes will be compared among 432 HIV+ men from all three cohorts who will be ranked by CD4 cell slopes to define rate of disease progression. To control for natural genetic variation due to ethnicity, all men will be white, non-Hispanic. Molecular techniques will be used to type subjects for HLA class II genes (DRB1, DQA1, DQB1,DPB1, DPA1), complement C2 and C4, antigen processing genes (TAP 1 and 2), and T cell receptor variable region genes (TCRValpha and TCRVBeta). To maximize the information from the YMHS in risk of infection, a first series of patients will be tested to establish potentially alleles. A second series of patients will be used to test specific hypotheses generated by the first series. Extended haplotypes will be tested in the same way. Relevant genotypes will be tested in the same way. Relevant genotypes and known behavioral/environmental cofactors will be included in logistic regression to determine the relative contribution of genetics to these aspects of HIV infection. Subjects will be ranked by a probability score, based on non-genetic risk factors, and genotypes compared among ranked groups to assess interactions between genetic and other risk factors. Our earlier work on the SFMHS showed HLA associations with disease progression. The present study will add to this information to examine other immune response genes that interact with HLA, and extend it to provide important biologic insights of host genetic risk of HIV infection and development of specific AIDS-defining conditions.
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