Efficacy and Toxicity of CSIC abd Retrocylin in the SIV Virus Challenge Model

项目4将使用SHIV/雌性恒河猴模型评价2种候选药物的毒性和疗效 阴道杀菌剂RC-101和CSIC。需要两种不同的SHIV，因为RC-101是HIV-1 env CSIC是HIV-1 RT特异性的。SHIV 162 p4携带HIV-1 env，RT-SHIV携带HIV-1 env。 RT编码区。项目4将与项目1-3和执行项目1 - 3的核心密切互动， 需要进行体外研究以验证RC-101和CSIC在猴模型中的使用。有五个目标： 1.评估CSIC和RC-101在成年恒河猴中的阴道和全身毒性。阴道 阴道镜检查将评估与硅胶环中药物相关的炎症， 用于猕猴。将检测血清的药物吸收，并使用阴道冲洗液评估 药物释放到阴道穹窿。2.确定RT-SHIV经阴道感染的最小感染剂量 路线尽管SHIV 162 p4在阴道感染中有很好的特征，但还没有关于RT-SHIV的报道 通过粘膜途径感染。将使用6只猕猴确定RTSHIV的最小感染剂量 通过阴道途径3.测试RC-101作为阴道杀微生物剂对SHIV 162 p4的有效性。 12只雌性恒河猴将用于测试阴道硅胶环的传播预防 含有RC-101的应用4.为了测试CSIC，一种非核苷类RT抑制剂， 用RT-SHIV进行挑战。12只雌性恒河猴将被用来测试预防传播， CSIC含有硅胶环。5.为验证CSIC与RC-101联合应用的疗效， 是将两种药物以相同的环状制剂输送。目的是证明这两种药物可以用于 联合使用，比单独使用更能预防HIV-1阴道感染。 将监测所有动物6个月的感染情况。这是一个高度合作的项目， 与其他项目协调。

Project 4 will use the SHIV/female rhesus macaque model to evaluate the toxicity and efficacy of 2 candidate vaginal microbicides, RC-101 and CSIC. Two different SHIVs will be required because RC-101 is HIV-1 env specific and CSIC is HIV-1 RT specific. SHIV162p4 carries the HIV-1 env and RT-SHIV carries the HIV-1 RT coding region. Project 4 will interact closely with the projects 1-3 and the cores that will carry out the in vitro studies needed to validate RC-101 and CSIC for use in the monkey model. There are 5 aims: 1. To assess vaginal and systemic toxicity of CSIC and RC-101 in adult rhesus macaques. Vaginal colposcopy will assess inflammation associated with drugs in the silicone rings that will be specially made for use in macaques. Sera will be tested for absorption of drug(s) and vaginal washes will be used to assess release of drug into the vaginal vault. 2. To determine the minimal infectious dose for RT-SHIV by the vaginal route. Although SHIV162p4 is well characterized for vaginal infection, there are no reports on RT-SHIV infection by a mucosal route. Six macaques will be used to determine the minimal infectious dose of RTSHIV by the vaginal route. 3. To test the efficacy of RC-101 as a vaginal microbicide against SHIV162p4. Twelve female rhesus macaques will be used to test prevention of transmission by vaginal silicone ring application containing RC-101 4. To test the efficacy of CSIC, a non-nucleoside RT inhibitor against vaginal challenge with RT-SHIV. Twelve female rhesus macaques will be used to test prevention of transmission by CSIC containing silicone rings. 5. To test the efficacy of the combination of CSIC and RC-101.The final plan is to deliver both drugs in the same ring formulation. The goal is to show that these 2 drugs can be used together and will afford better protection against HIV-1 vaginal infection than either could alone. All animals will be monitored for infection for 6 months. This is a highly collaborative project that will closely coordinate with all other projects.