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

项目4将使用SIV/雌性恒河猴模型来评估2个候选药物的毒性和疗效 阴道杀菌剂RC-101和CSIC。将需要两个不同的SHIV，因为RC-101是HIV-1环境 而CSIC是HIV-1RT特异性的。SHIV162p4携带HIV-1 env，RT-Shiv携带HIV-1 RT编码区。项目4将与项目1-3以及将执行项目3的核心密切互动。 体外研究需要验证RC-101和CSIC在猴子模型中的使用。有5个目标： 1.评价CSIC和RC-101对成年恒河猴的阴道和全身毒性。阴道 阴道镜检查将评估硅胶环中与药物相关的炎症，这种硅胶环将专门为 在猕猴身上使用。将对血清进行药物吸收测试(S)，并使用阴道冲洗液来评估 将药物释放到阴道穹隆。2.确定RT-SHV经阴道感染的最小剂量 路线。尽管SHIV162p4很好地表征了阴道感染，但还没有关于RT-SHV的报道 通过粘膜途径感染。六只猕猴将被用来确定RTSHIV的最小感染量 通过阴道途径。3.检测RC-101作为阴道杀菌剂对SHIV162p4的杀灭效果。 12只雌性恒河猴将被用来测试通过阴道硅环传播的预防 含RC-101的应用4.检测非核苷类RT抑制剂CSIC对阴道的疗效 用RT-Shiv挑战。12只雌性恒河猴将被用来测试通过 CSIC包含硅胶密封圈。5.测试CSIC和RC-101的组合效果。最终方案 就是将两种药物放在同一环配方中。其目的是证明这两种药物可以用于 与单独使用相比，这两种药物都能提供更好的预防艾滋病毒-1阴道感染的效果。 所有动物都将接受6个月的感染监测。这是一个高度协作的项目，将密切 协调所有其他项目。

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.