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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 背景：重复使用，不含抗逆转录病毒药物的不依赖性交的杀微生物剂凝胶也被用作一线艾滋病毒治疗，迫切需要遏制艾滋病毒的传播。目前的配方需要大剂量(毫摩尔范围)的抗逆转录病毒药物，通常只对猕猴提供短期保护。我们利用猕猴模型测试了一种含有醋酸锌和微摩尔剂量的新型非核苷类逆转录酶抑制剂MIV-150的新型组合杀菌剂凝胶在重复使用后持续24小时的效果。方法和结果：恒河猴在重复使用杀菌剂和安慰剂凝胶后，用SHIV-RT对猕猴进行阴道激发，持续时间长达24小时。通过测定病毒学和免疫学参数来确定感染状态。含有14 mM二水醋酸锌和50M MIV-150的复合杀微生物剂凝胶在每日使用2周后，可对21只动物中的21只提供长达24小时的完全保护。MIV-150凝胶具有部分保护作用(8h时为对照组的56%，24 h时为对照组的11%)，而醋酸锌凝胶具有更明显的保护作用(8~24h时为67%)。当每隔一天涂抹醋酸锌或MIV-150/醋酸锌凝胶，持续4周，在最后一次涂抹后24小时挑战前，显著的保护作用持续存在(14个保护中的11个)。与MIV-150相比，每天服用MIV-150/醋酸锌8小时后，宫颈组织中出现更多的MIV-150，而阴道组织和24小时时出现类似的MIV-150水平。结论：MIV-150/醋酸锌凝胶和醋酸锌凝胶联合使用可提供长达24小时的显著保护，防止Shiv-RT感染。这是一项新的进展，识别出不含用于治疗HIV感染的抗病毒药物，并且可以重复使用，并且可以独立于性交使用，这突显了未来临床测试其安全性和防止HIV在人类中传播的能力的必要性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. BACKGROUND: Repeated use, coitus-independent microbicide gels that do not contain antiretroviral agents also used as first line HIV therapy are urgently needed to curb HIV spread. Current formulations require high doses (millimolar range) of antiretroviral drugs and typically only provide short-term protection in macaques. We used the macaque model to test the efficacy of a novel combination microbicide gel containing zinc acetate and micromolar doses of the novel non-nucleoside reverse transcriptase inhibitor MIV-150 for up to 24 h after repeated gel application. METHODS AND FINDINGS: Rhesus macaques were vaginally challenged with SHIV-RT up to 24 h after repeated administration of microbicide versus placebo gels. Infection status was determined by measuring virologic and immunologic parameters. Combination microbicide gels containing 14 mM zinc acetate dihydrate and 50 ¿M MIV-150 afforded full protection (21 of 21 animals) for up to 24 h after 2 weeks of daily application. Partial protection was achieved with the MIV-150 gel (56% of control at 8 h after last application, 11% at 24 h), while the zinc acetate gel afforded more pronounced protection (67% at 8-24 h). Marked protection persisted when the zinc acetate or MIV-150/zinc acetate gels were applied every other day for 4 weeks prior to challenge 24 h after the last gel was administered (11 of 14 protected). More MIV-150 was associated with cervical tissue 8 h after daily dosing of MIV-150/zinc acetate versus MIV-150, while comparable MIV-150 levels were associated with vaginal tissues and at 24 h. CONCLUSIONS: A combination MIV-150/zinc acetate gel and a zinc acetate gel provide significant protection against SHIV-RT infection for up to 24 h. This represents a novel advancement, identifying microbicides that do not contain anti-viral agents used to treat HIV infection and which can be used repeatedly and independently of coitus, and underscores the need for future clinical testing of their safety and ability to prevent HIV transmission in humans.