EVALUATION OF RANTES ANALOGUES FOR PROTECTION FROM SHIV

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 迫切需要有效的艾滋病毒预防战略，但最近关键疫苗和“杀微生物剂”临床试验的失败突显了在相关动物模型中验证新方法的必要性。在持续缺乏有效疫苗的情况下，一种可以局部应用于阴道的杀微生物剂可能是减缓HIV-1经阴道传播的最大希望。然而，这种杀微生物剂必须高效且廉价，这样才能将其分发到疫情传播最快的经济困难地区。我们之前已经证明，CCR5抑制剂PSC-RANTES可以完全阻止R5Shiv通过阴道传播给猕猴，但生产成本限制了其作为实用杀菌剂的潜力。因此，我们开发了两个新的RANTES类似物，承诺通过发酵生产低成本的重组产品。在这里，我们展示了这两种新的CCR5抑制剂，5P12-RANTES和6P4-RANTES，在恒河猴阴道攻击模型中完全保护免受感染。这些高效分子易于低成本生产，代表着杀菌剂流水线上有希望的新成员。

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. Effective strategies for HIV prevention are urgently needed, but recent failures in key vaccine and 'microbicide' clinical trials highlight the need for new approaches validated in relevant animal models. 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 that promise low cost recombinant production by fermentation. Here we show that these two new CCR5 inhibitors, 5P12-RANTES and 6P4-RANTES, protect fully against infection in the rhesus vaginal challenge model. These highly potent molecules, which are amenable to low-cost production, represent promising new additions to the microbicides pipeline.