There is growing evidence supporting the hypothesisthat differences in HIV/SIV coreceptor usage, expression and regulation are critical determinants of HIV-1 transmission and AIDS pathogenesis. For example, homozygosity for a 32-bp deletion leads to loss of expression of CCR5, a key coreceptor for HIV/SIVentry, serves as a powerful resistance factor. These investigators have recently demonstrated that haplotypes bearing specific polymorphisms in the regulatory regions of CCR5are associated with altered rates of HIV-1disease progression. Despite this new knowledge, it is impossible to conduct experimental studies in humans to test this hypothesis, and to address directly the role of genetic and viral factors that contribute to HIVpathogenesis. These investigators propose to examine the role of coreceptor (CCR5) expression in the progression to disease using the simian immunodeficiency virus (SIV) model. Specifically, they will exploit the model of natural resistance to SIV in African green monkeys (AGM) or the experimental model of disease susceptibility to SIV in pig-tailed macaques. In the proposed studies, the investigators propose three specific aims to determine if host-specific differences in viral coreceptor usage and chemokine/chemokine receptor expression patterns provide potential mechanisms for natural resistance or susceptibility to SIV-mediated disease. Finally, they will determine if potential mechanisms by which genetic variation in CCR5 mediates natural resistance or susceptibility to SIV-mediated disease.
