BLOCKING VIRUS SPREAD BY DCS WITH CARRAGEENAN-BASED COMPOUNDS

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 而子项目的主要调查员可能是由其他来源提供的， 包括其它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。 背景资料：阴道环是杀微生物剂的一种有前景的递送载体，因为它们可以提高粘附性，不依赖于性交，并且消除了每日应用的需要。乙烯-醋酸乙烯酯（伊娃）环的MIV-150释放效果优于硅胶。在当前的研究中，我们用100 mg MIV-150配制了一个伊娃环，并比较了猕猴在24小时（24小时）或2周PRI激发时对SHIV-RT的保护作用。 研究方法：Depo-Provera处理的恒河猴（n=18）在阴道内插入伊娃/MIV-150（每种n=7）或伊娃/对照（每种n=2）环，然后用103 TCID 50 SHIV-RT（SIVmac 239与HIV-1 RT）经阴道激发24小时或2周PRI。从血浆病毒RNA和SIV特异性抗体（Ab）应答确定感染。通过放射免疫测定法测量MIV-150吸收。用Fisher精确检验确定统计学显著性。结果：在试验组中，攻毒24 h和攻毒2 wk的动物中分别有1/7和1/7的动物发生感染（共2/14，14.3%）。在对照组中，2/2只攻毒24 h PRI的动物和1/2只攻毒2 wks PRI的动物发生感染（共3/4，75%）。SIV RNA和SIV特异性抗体在所有感染（但不是未感染）动物的血浆中检测到。这些数据表明，伊娃/MIV-150环对阴道SHIV-RT感染具有显著保护作用（p 0.044）。在血浆30 min-72 h PRI中未检测到MIV-150，表明保护不需要显著水平的全身药物吸收。 结论：阴道环释放NNRTI（MIV-150）能够阻断猕猴的SHIV感染，值得进一步开发用于预防HIV感染。未来的研究将优化MIV-150的剂量和相对于病毒暴露的环插入时间。

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: Vaginal rings are a promising delivery vehicle for microbicides because they may improve adherence, are coitally independent, and eliminate the need for daily application. Ethylene-vinyl-acetate (EVA) rings have been shown to release MIV-150 better than silicone. In the current study, we formulated an EVA ring with 100mg of MIV-150 and compared protection against SHIV-RT when macaques were challenged either 24 hours (24h) or 2wks PRI. Methods: Depo-Provera treated rhesus macaques (n=18) had either EVA/MIV-150 (n=7 each) or EVA/control (n=2 each) rings inserted vaginally before being challenged vaginally either 24h or 2wks PRI with 103 TCID50 SHIV-RT (SIVmac239 with HIV-1 RT). Infection was determined from plasma virus RNA and SIV-specific antibody (Ab) responses. MIV-150 absorption was measured by radioimmunoassay. Statistical significance was determined with Fisher's exact test. Results: In the test groups, 1/7 animals challenged 24h PRI and 1/7 animals challenged 2wks PRI became infected (2/14 total, 14.3%). In the control groups, 2/2 animals challenged 24h PRI and 1/2 animals challenged 2wks PRI became infected (3/4 total, 75%). SIV RNA and SIV-specific Abs were detected in the plasma of all infected (but not uninfected) animals. These data indicate that EVA/MIV-150 rings provided significant protection (p0.044) against vaginal SHIV-RT infection. MIV-150 was undetectable in the plasma 30min-72h PRI, suggesting that significant levels of systemic drug absorption were not required for protection. Conclusions: Vaginal rings releasing an NNRTI, MIV-150, are capable of blocking SHIV infection in macaques and warrant further development for the prevention of HIV infection. Future studies will optimize the dose of MIV-150 and the timing of ring insertion relative to virus exposure.