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

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。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 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。 本研究的总体目的是评价两种杀微生物剂的毒性和有效性  HIV进入抑制剂（RC-101）和HIV非核苷逆转录酶抑制剂（CSIC）对抗RT-SHIV病毒攻击。 实现这一目标有五个具体目标。 目的1将评估RC-101和CSIC的阴道和全身毒性。 将杀微生物剂环置于恒河猴（Macaca mulatta）的阴道穹窿中。 将进行血液、组织取样和阴道镜检查，以确定阴道和全身吸收和毒性，以及确定杀微生物剂的释放速率。 目的2确定RT-SHIV经阴道途径的最小感染剂量。 将通过阴道途径对6只恒河猴接种RT-SHIV，并采集血样以监测病毒感染。 迄今为止，两只动物已接受Depo-Provera治疗并接种了10 TICD 50 RT-SHIV。其余4只动物将根据前两只动物的结果接种剂量。 目的3、4和5将确定每种杀微生物剂单独以及组合对抗RT-SHIV攻击的功效。 将阴道植入含有RC-101、CSIC、两者的组合或仅溶剂的阴道环（每组6只动物）。 24小时后用RT-SHIV对动物进行阴道攻毒。 将采集血样、阴道活检和内镜肠夹活检，以监测病毒感染。 到目前为止，已经分配了六只动物来测试CSIC的毒性和功效（目的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).