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

CSIC abd Retrocylin 在 SIV 病毒攻击模型中的功效和毒性

• 批准号: 8317576
• 负责人: Preston A Marx
• 金额: $ 55.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8317576
• 关键词: Adult; Animal Husbandry; Animal Model; Animal Welfare; Animals; Clinical Trials; Code; Colposcopy; Dose; Drug Formulations; Drug resistance; Environment; Evaluation; Female; Genetic Recombination; Goals; HIV; HIV Entry Inhibitors; HIV-1; Head; Housing; Human; Hybrids; Implant; In Vitro; Infection; Inflammation; Laboratories; Macaca; Macaca mulatta; Modeling; Monitor; Monkeys; Personal Communication; Pharmaceutical Preparations; Phase; Prevention; Prevention approach; Primates; Principal Investigator; Procedures; Publishing; RNA-Directed DNA Polymerase; Reporting; Research; Resources; Reverse Transcriptase Inhibitors; Route; SIV; Serum; Sexual Transmission; Silicones; Surface; Technical Expertise; Testing; Time; Tissues; Topical application; Toxic effect; United States National Institutes of Health; Vagina; Virus; Virus Diseases; Washington; Work; absorption; base; clinical care; cost effective; data exchange; design; efficacy testing; evaluation/testing; experience; in vivo; inhibitor/antagonist; interest; microbicide; non-nucleoside reverse transcriptase inhibitors; nonhuman primate; novel strategies; programs; repository; research study; retrocyclin; simian human immunodeficiency virus; transmission process; vaginal microbicide; vaginal transmission

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.

项目4将使用SHIV/雌性恒河猴模型来评估2个候选药物的毒性和功效 阴道杀菌剂、RC-101 和 CSIC。需要两种不同的 SHIV，因为 RC-101 是 HIV-1 环境 特异性，CSIC 是 HIV-1 RT 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 以及执行项目的核心密切互动。 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. 评估CSIC和RC-101对成年恒河猴的阴道和全身毒性。阴道 阴道镜检查将评估与硅胶环中的药物相关的炎症，该硅胶环是专门为 用于猕猴。将测试血清的药物吸收情况，并使用阴道冲洗液进行评估 将药物释放到阴道穹窿中。 2. 确定阴道RT-SHIV的最小感染剂量 路线。尽管 SHIV162p4 对阴道感染有很好的特征，但目前还没有关于 RT-SHIV 的报道 通过粘膜途径感染。将使用六只猕猴来确定 RTSHIV 的最低感染剂量 通过阴道途径。 3. 测试RC-101作为阴道杀微生物剂对抗SHIV162p4的功效。 十二只雌性恒河猴将被用于测试阴道硅胶环预防传播的效果 含有RC-101的应用4.测试CSIC（一种非核苷RT抑制剂）对阴道的功效 RT-SHIV 挑战。将使用 12 只雌性恒河猴来测试传播预防措施 CSIC含有硅环。 5. 测试CSIC与RC-101结合的功效。最终方案 是在同一个环制剂中递送两种药物。目标是证明这两种药物可以使用 两者结合起来，比单独使用任何一种药物都能提供更好的预防 HIV-1 阴道感染的保护作用。 所有动物将接受为期 6 个月的感染监测。这是一个高度协作的项目，将密切 与所有其他项目协调。