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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 SIV/雌性恒河猴模型正在被用来评估两种候选阴道杀菌剂的毒性和疗效，RC-101是一种HIV共受体阻滞剂，CSIC是一种非核苷类逆转录酶抑制剂。SIV-HIV重组病毒RT-Shiv携带HIV-1 RT编码区。这种病毒在体外对这两种候选药物都很敏感。该项目将与其他项目1-3以及将开展验证RC-101和CSIC用于猴子模型所需的体外研究的核心密切互动。 研究的目的是： 1.评价CSIC和RC-101对成年恒河猴的阴道和全身毒性。阴道镜检查将评估与硅胶环相关的炎症，硅胶环将专门用于猕猴。将测试血清对药物的吸收(S)，并将使用阴道冲洗来评估药物进入阴道穹隆的释放情况。 2.确定RT-SHV经阴道感染的最小感染剂量。六只猕猴将被用来确定RT-SHV通过阴道途径的最小感染量。 3.检测RC-101作为阴道杀菌剂对RT-SHV的杀灭效果。12只雌性恒河猴将被用来测试含有RC-101的阴道硅环对预防传播的作用 4.检测非核苷类RT抑制剂CSIC对RT-SHV阴道攻击的保护作用。 12只雌性恒河猴将被用来测试含有硅胶环的CSIC预防传播。 5.检测CSIC与RC-101联合应用的效果。最终的计划是在相同的环配方中提供这两种药物。其目的是证明这两种药物可以一起使用，并将比单独使用其中任何一种药物更好地预防艾滋病毒-1阴道感染。 到目前为止，动物已经被要求参加目标1。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The SHIV/female rhesus macaque model is being used to evaluate the toxicity and efficacy of 2 candidate vaginal microbicides, RC-101, an HIV co-receptor blocker, and CSIC, a non-nucleoside reverse transcriptase inhibitor. The SIV-HIV recombinant virus, RT-SHIV, carries the HIV-1 RT coding region. This virus is susceptible in vitro to both candidate drugs. This project will interact closely with the other 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. The aims of the study are: 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. Six macaques will be used to determine the minimal infectious dose of RT-SHIV by the vaginal route. 3. To test the efficacy of RC-101 as a vaginal microbicide against RT-SHIV. 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. Thus far animals have been requested for aim 1.