EVALUATION OF RANTES ANALOGUES FOR PROTECTION FROM SHIV

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 迫切需要有效的艾滋病毒预防策略，但最近在关键疫苗和“杀微生物剂”临床试验中的失败突出表明需要在相关动物模型中验证的新方法。 在仍然缺乏有效疫苗的情况下，可以局部应用于阴道的杀微生物剂可能是减缓阴道HIV-1传播的最佳希望。 然而，这种杀微生物剂必须是高度有效的并且也是廉价的，以便它可以被分配到流行病传播最快的经济困难地区。我们以前已经表明，CCR 5抑制剂PSC-RANTES可以完全防止R5 SHIV经阴道传播给猕猴，但生产成本限制了其作为实用杀微生物剂的潜力。因此，我们已经开发了两种新的RANTES类似物，其承诺通过发酵进行低成本重组生产。在这里，我们表明，这两个新的CCR 5抑制剂，5 P12-RANTES和6P 4-RANTES，保护恒河猴阴道攻击模型完全免受感染。这些高效分子易于低成本生产，是杀微生物剂管道中有希望的新添加物。

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.