Host genetic factors are important in HIV infection and rate of progression, but the identification of operative genes that restrict infection or influence rate of progression to AIDS has proven difficult. Two approaches have proved useful: direct testing of specific candidate genes in HIV cohorts and Polymorphism Admixture Typing (PAT) to enhance disease associated linkage disequilibrium in HIV-exposed cohorts with a high frequency of mixed human groupings. Both of these methods require large numbers of individuals in the risk categories. We have established lymphoblastoid cell lines as a DNA source and collected clinical data from over 4000 exposed individuals in three major risk groups: intravenous drug users, homosexual males, and hemophiliacs. These reagents are an important resource for both immunological and genetic studies. Major findings of this project include: (1) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CC CKR5 structural gene in over 1900 patients studied. In the homozygous state, the CKR5 deletion allele prevents infection by HIV and in the heterozygote state progression to AIDS is delayed. (2) Different combinations of alleles of HLA loci and Tap variants contribute to the rate of progression to AIDS. Some combinations delay and others accelerate the onset of clinical symptoms of AIDS. (3) Several additional """"""""candidate genes"""""""" plus anonymous markers demonstrate allele and/or genotypic association with progression rate to clinical AIDS among HIV-1-infected individuals. The future objective is to identify host genetic components that significantly regulate disease progression to AIDS.
