This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In two U19 grants, we are examining immune responses in the vagina of macaques. One project involves examining CTL responses after fusion inhibitors and the other is a new comparative study of the vaginal environment of women and macaques. Our lab has been testing microbicide candidates in nonhuman primates for several years. However, we still do not know how these data will translate into human clinical trials. Furthermore, there is some evidence suggesting that there are subtle differences in the anatomy, physiology, and immune responses between macaques and humans, as well as between different species of macaques, which may affect the efficacy or host responses to a microbicide. Thus, these studies are designed to carefully compare these issues between humans, rhesus, and pigtail macaques using identical methodology. We will compare the anatomy, immunology, and physiology of reproductive tissues of the non-human primate and human vaginal explant models of SIV/HIV/ and SHIV transmission to determine whether non-human primate systems parallel those of women, and if not, characterize these differences to better inform clinical microbicide development, and improve models of nonhuman primate testing. The objectives are to compare the anatomy, immunology, and physiology of normal macaque and human female reproductive tissues using identical methodology, compare the immune responses of cervical explants of women, rhesus, and pig-tailed macaques to mitogens, potential microbicide candidates (RANTES analogs), TLR agonists, and HIV/SIV/SHIV using identical methodology, and finally assess the depth of penetration, mechanisms of action of synthetic RANTES derivatives, and interactions with HIV/SIV/SHIV in human and macaque vaginal tissues. These studies will determine whether the immunophenotype, anatomy, and mucosal immune responses of rhesus or pigtailed macaques resemble those of women.
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