EFFICACY AND TOXICITY OF CSIC AND RETROCYCLIN IN THE SIV VAGINAL CHALLENGE MODEL

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。 本研究的总体目标是评价两种杀菌剂的毒性和有效性，一种是HIV进入抑制物(RC-101)，另一种是HIV非核苷逆转录酶抑制物(CSIC)，用于对抗RT-Shiv病毒的攻击。实现这一目标有五个具体目标。目的1评价RC-101和CSIC的阴道和全身毒性。杀微生物环将被放置在猕猴(Macaca Mulatta)的阴道穹隆中。将进行血液、组织采样和阴道镜检查，以确定阴道和全身的吸收和毒性，以及确定杀菌剂的释放率。目的2确定RT-SHV经阴道传播的最小感染剂量。六只恒河猴将通过阴道途径接种RT-SHV，并将采集血液样本以监测病毒感染。到目前为止，已经用Depo-Provera治疗了两只动物，并接种了10只TICD50 RT-Shiv。其余四只动物将根据前两只动物的结果接种疫苗。目标3、4和5将确定每种杀菌剂单独以及联合使用对抗RT-SHV攻击的效果。含有RC-101、CSIC、两者组合或仅含赋形剂(每组6只动物)的阴道环将被植入阴道。24小时后，这些动物将接受RT-SHV的阴道挑战。将收集血液样本、阴道活检和内窥镜下肠道挤压活检，以监测病毒感染。到目前为止，已指派6只动物测试CSIC的毒性和疗效(目标1和3)。

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. The overall objective of this study is to evaluate the toxicity and efficacy of two microbicides  an HIV entry inhibitor (RC-101) and an HIV non-nucleoside reverse transcriptase inhibitor (CSIC) against RT-SHIV virus challenge. There are five specific aims to achieve this objective. Aim 1 will assess the vaginal and systemic toxicity of RC-101 and CSIC. Microbicide rings will be placed in the vaginal vault of Rhesus macaques (Macaca mulatta). Blood, tissue sampling and colposcopies will be performed to determine vaginal and systemic absorption and toxicity as well as to determine the release rate of the microbicides. Aim 2 will determine the minimal infectious dose of RT-SHIV by the vaginal route. Six Rhesus macaques will be inoculated with RT-SHIV via the vaginal route and blood samples will be collected to monitor viral infection. To date, two animals have been treated with Depo-Provera and inoculated with 10 TICD50 RT-SHIV. The remaining four animals will be inoculated with the dose dependent upon the results of the first two animals. Aims 3, 4 and 5 will determine the efficacy of each microbicide individually, as well as in combination, against RT-SHIV challenge. Vaginal rings containing either RC-101, CSIC, a combination of the two or the vehicle only (6 animals in each group) will be implanted vaginally. The animals will be challenged vaginally 24 hours later with RT-SHIV. Blood samples, vaginal biopsies and endoscopic intestinal pinch biopsies will be collected to monitor for viral infection. Thus far, six animals have been assigned to test the toxicity and efficacy of CSIC (Aims 1 and 3).