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

ZCM：一种治疗性传播感染的新型广谱杀菌剂

• 批准号: 8358089
• 负责人: Melissa J Robbiani
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358089
• 关键词: Animals; Anti-Retroviral Agents; Cervical; Coitus; Dose; Drug Formulations; Funding; Future; Gel; Grant; HIV; HIV Infections; HIV therapy; Human; Immunologics; Infection; Macaca; Macaca mulatta; Measures; Modeling; National Center for Research Resources; Pharmaceutical Preparations; Placebos; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Safety; Sexually Transmitted Diseases; Source; Tissues; United States National Institutes of Health; Vagina; Viral; Zinc Acetate; cost; efficacy testing; microbicide; non-nucleoside reverse transcriptase inhibitors; novel; prevent; research clinical testing; simian human immunodeficiency virus; transmission process

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 背景技术背景：迫切需要反复使用的、不依赖于性交的杀微生物剂凝胶，这些凝胶不含抗逆转录病毒药物，也用作一线艾滋病毒治疗，以遏制艾滋病毒的传播。目前的制剂需要高剂量（毫摩尔范围）的抗逆转录病毒药物，通常只提供短期保护猕猴。我们使用猕猴模型来测试一种新的组合杀微生物剂凝胶的功效，该凝胶含有醋酸锌和微摩尔剂量的新型非核苷逆转录酶抑制剂MIV-150，在重复凝胶应用后长达24小时。 方法和结果：恒河猴阴道挑战与SHIV-RT至24小时后，反复给药的杀微生物剂与安慰剂凝胶。通过测量病毒学和免疫学参数确定感染状态。每日施用2周后，含有14 mM醋酸锌二水合物和50 µ M MIV-150的组合杀微生物剂凝胶可提供长达24 h的完全保护（21/21只动物）。用MIV-150凝胶实现了部分保护（在最后一次施用后8小时为对照的56%，在24小时为11%），而乙酸锌凝胶提供了更显著的保护（在8 - 24小时为67%）。当在最后一次凝胶给药后24小时攻毒前每隔一天施用醋酸锌或MIV-150/醋酸锌凝胶持续4周时，显著的保护作用持续存在（11/14例受保护）。与MIV-150相比，MIV-150/醋酸锌每日给药后8小时，更多的MIV-150与宫颈组织相关，而阴道组织和24小时的MIV-150水平相当。 结论：MIV-150/醋酸锌凝胶和醋酸锌凝胶组合可提供长达24 h的抗SHIV-RT感染的显著保护。这代表了一种新的进步，确定了不含用于治疗艾滋病毒感染的抗病毒药物的杀微生物剂，并且可以重复使用和独立于性交，并强调了未来对其安全性和预防人类艾滋病毒传播能力的临床测试的必要性。