Significant variability exists in the time between infection and death both in humans infected with HIV and macaques infected with SIV. Understanding why some individuals have the inherent capability of resisting the ravaging effects of virus infection would provide information crucial to the development of vaccines and chemotherapeutic agents. The recent discovery that HIV/SIV require, in addition to CD4, other cell surface determinants for virus infection has raised the issue of the role of these co-receptors in disease resistance. One of these, CCR-5, a beta chemokine receptor required for infection of macrophages with primary isolates of HIV, contains a naturally- occurring polymorphism in 1% of the caucasian population that renders the protein nonfunctional. In HIV-infected people, the incidence of heterozygosity of CCR-5 is 35% lower than in uninfected people; and homozygosity for the mutant gene is not seen. These data provide evidence for a role for co-receptor genes in resistance to infection and disease. We propose to use infection of rhesus macaques with the well-characterized primary isolate, SIV/DeltaB670, to address this relationship more directly: 1) Using the in vitro kinetic assay that we have shown predicts rapid and slow progressors, in vitro expression of MIPlalpha, MIP1beta, and RANTES will be determined by ELISA in culture supernatants of PBMC obtained pre- and post-in vivo infection to determine whether inherent differences in expression of these chemokines predict susceptibility to disease. 2) In collaboration with R. Doms and S. Peiper, the co-receptor(s) for the dominant SIV/DeltaB670 genotypes will be identified using a gene reporter fusion assay and target cells transfected with a battery of human and simian chemokine receptor genes. 3) The genetic composition of the chemokine receptors used by SIV/De1taB670 will be determined in progressor and nonprogressor monkeys to identify polymorphisms associated with the nonprogressor phenotype. The function of variant receptors will be determined in the Doms fusion assay and their distribution in the Tulane colony determined. 4) The transition from nonprogressive to progressive disease will be examined with respect to the interrelationship between emerging viral genotypes, changes in tropism, co-receptor usage, and resistance to serum neutralization. These studies will employ in situ hybridization using B670 clone-specific oligomeric probes by T. Reinhart, co-receptor analysis of variant genotypes by R. Doms, and serum blocking of fusion in the Doms assay.
