ZCM:A NOVEL BROAD-SPECTRUM MICROBICIDE FOR SEXUALLY TRANSMITTED INFECTIONS

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。 我们最近证明了PC-815（一种由NNRTI MIV-150和Carraguard（CG）组成的杀微生物剂凝胶）对SHIV-RT（表达HIV-1逆转录酶的SIVmac 239）恒河猴阴道攻击的部分疗效。在这里，我们的目的是通过添加锌来进一步提高凝胶的效力，这增强了CG在小鼠中的抗HSV-2活性。我们测试了两种候选杀微生物剂：PC-707（CG中14 mM乙酸锌）和PC-1005（CG中50 mM MIV-150和14 mM乙酸锌）。 将治疗凝胶PC-707（n=14）和PC-1005（n=21）或甲基纤维素（MC）安慰剂（n=14）每日（2 ml/天）应用于Depo-Provera治疗的恒河猴的阴道上皮，持续14天。在最后一次凝胶应用后4、8或24小时，用103 TCID 50 SHIV-RT对动物进行阴道攻击。随访包括检测血浆病毒RNA和PBMC病毒DNA、血清转换和IFN-γ应答。用Fisher精确检验确定统计学显著性。 在MC组中，14只动物中有12只（85.7%）感染。在PC-707处理组中，分别在最终凝胶应用后8小时和24小时攻毒时，1/7只动物（14.3%）和2/7只动物（28.6%）感染。PC-1005处理的动物在任何时间点攻毒后均未感染SHIV-RT。这与单独研究的结果形成对比，我们发现在用CG治疗的动物中，8（5/7只动物或71.4%感染）或24小时（4/7只动物或57.1%感染）和PC-815（50 M MIV-150在CG中）在最后一次凝胶应用后8小时（7只动物中的2只或28.6%感染）或24小时（7只动物中的5只或71.4%感染）攻毒的动物中。PC-1005的保护作用显著高于CG（p <0.0003）。感染通常与SIV特异性抗体和T细胞反应的发展相关。 每天重复施用PC-1005（一种在CG中递送的含有MIV-150和醋酸锌的杀微生物剂）可提供长达24小时的针对阴道SHIV-RT攻击的完全保护。由PC-1005介导的增强的保护作用（与在CG中单独递送MIV-150或乙酸锌时观察到的部分活性相比）对于开发有效的、不依赖于性交的凝胶是有希望的。

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. We recently demonstrated partial efficacy of PC-815, a microbicide gel consisting of the NNRTI MIV-150 and Carraguard (CG) against vaginal challenge of rhesus macaques with SHIV-RT (SIVmac239 expressing HIV-1 reverse transcriptase). Here, we aimed to further improve the potency of the gels by adding zinc, which enhances the anti-HSV-2 activity of CG in mice. We tested two candidate microbicides: PC-707 (14mM zinc acetate in CG) and PC-1005 (50mM MIV-150 and 14mM zinc acetate in CG). Treatment gels PC-707 (n=14) and PC-1005 (n=21), or methyl cellulose (MC) placebo (n=14), were applied daily (2ml/day) for 14 days to the vaginal epithelium of Depo-Provera-treated rhesus macaques. Animals were vaginally challenged with 103 TCID50 SHIV-RT at 4, 8, or 24h after the last gel application. Follow-up included detection of plasma virus RNA and PBMC virus DNA, seroconversion, and IFN-¿ responses. Statistical significance was determined with Fisher's exact test. In the MC group, 12 of 14 animals (85.7%) became infected. Among the PC-707 treatment groups, 1 of 7 (14.3%) and 2 of 7 animals (28.6%), became infected when challenged 8 and 24h after final gel application, respectively. None of the animals treated with PC-1005 became infected with SHIV-RT after challenge at any time point. This contrasts findings from separate studies where we found that in animals treated with CG, 8 (5 of 7 animals or 71.4% infected) or 24h (4 of 7 animals or 57.1% infected) and PC-815 (50 M MIV-150 in CG) in animals challenged 8 (2 of 7 animals or 28.6% infected) or 24h (5 of 7 animals or 71.4% infected) after the last gel application. PC-1005 was significantly more protective than CG (p0.0003). Infection typically correlated with the development of SIV-specific Ab and T cell responses. Repeated daily application of PC-1005, a microbicide containing MIV-150 and zinc acetate delivered in CG, provided complete protection for up to 24h against vaginal SHIV-RT challenge. The enhanced protection mediated by PC-1005 (compared to the partial activity seen when either MIV-150 or zinc acetate alone were delivered in CG) is promising for the development of an effective, coitally-independent gel.