This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.In the continued absence of an effective vaccine, a microbicide that can be topically applied to the vagina may be the best hope for slowing vaginal HIV-1 transmission. However, such a microbicide must be highly effective and also inexpensive, so that it may be distributed to economically challenged areas where the epidemic is spreading most rapidly. We have previously shown that the CCR5 inhibitor PSC-RANTES can completely prevent vaginal transmission of R5 SHIV to macaques, but the cost of production limits its potential for a practical microbicide. We have thus developed two novel RANTES analogs (6P4, 5P12) that promise low cost recombinant production by fermentation. We recently demonstrated that both 6P4 and 5P12 RANTES were equally as effective as PSC-RANTES in inhibiting viral replication of SIVmac251 in macaque PBMC. When applied intravaginally, both 6P4 and 5P12 RANTES completely prevented vaginal transmission of the R5 SHIV162P3 in 5/5 macaques as evidenced by undetectable viremia in plasma. Both PSC-RANTES treated macaques were also protected against transmission. In contrast, 4 of 5 macaques treated with placebo alone became infected, demonstrating high peak plasma viremia by 14-21 days after challenge. In conclusion, novel, potent CCR5 inhibitors (RANTES analogs) have been developed that promise reduced costs of production. These results demonstrate that topical application of these analogs can completely protect macaques against vaginal SHIV 162P transmission. Since CCR5- utilizing strains predominate in early mucosal transmission, targeting CCR5 with such an approach may prove to be an effective and economical strategy for preventing mucosal HIV-1 transmission.
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