TESTING MARAVIROC AS A MICROBICIDE

测试马拉维罗作为杀菌剂

• 批准号: 8173008
• 负责人: Ronald S. Veazey
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173008
• 关键词: Binding; CCR5 gene; Cells; Clinical; Computer Retrieval of Information on Scientific Projects Database; Development; Dose; Funding; Gel; Grant; HIV-1; Infection; Institution; Macaca mulatta; Modeling; Pharmaceutical Preparations; Research; Research Personnel; Resources; Source; Testing; United States National Institutes of Health; Viral Load result; Viremia; Virus; Woman; microbicide; prevent; programs; receptor; small molecule; transmission process; vaginal microbicide

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. An effective vaginal microbicide could reduce human immunodeficiency virus type 1 (HIV-1) transmission to women. Among microbicide candidates in clinical development is Maraviroc (MVC), a small molecule drug that binds the CCR5 co-receptor and impedes HIV-1 entry into cells. Delivered systemically, MVC reduces viral load in HIV-1-infected people, but its ability to prevent transmission is untested. We have now evaluated MVC as a vaginal microbicide, using a stringent model involving challenge of rhesus macaques with a high-dose of a CCR5-using virus, SHIV-162P3. Gel-formulated, prescription-grade MVC provided dose-dependent protection, half-maximally at 0.5 mM (0.25 mg/ml). The duration of protection was transient; the longer the delay between MVC application and virus challenge, the less protection (T1/2 ~ 4 h). As expected, MVC neither protected against challenge with a CXCR4-using virus, SHIV-KU1, nor exacerbated post-infection viremia. These findings validate MVC development as a vaginal microbicide for women, and should guide clinical programs.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 有效的阴道杀菌剂可以减少 1 型人类免疫缺陷病毒 (HIV-1) 向女性的传播。 Maraviroc (MVC) 是处于临床开发阶段的候选杀菌剂之一，它是一种小分子药物，可结合 CCR5 共受体并阻止 HIV-1 进入细胞。 MVC 可以全身给药，降低 HIV-1 感染者的病毒载量，但其预防传播的能力尚未经过测试。我们现在已经使用严格的模型评估了 MVC 作为阴道杀微生物剂的效果，该模型涉及用高剂量的使用 CCR5 的病毒 SHIV-162P3 攻击恒河猴。凝胶配方的处方级 MVC 提供剂量依赖性保护，最大浓度为 0.5 mM (0.25 mg/ml)。保护的持续时间是短暂的； MVC应用和病毒攻击之间的延迟越长，保护越少（T1/2~4小时）。正如预期的那样，MVC 既不能抵御使用 CXCR4 的病毒 SHIV-KU1 的攻击，也不能加剧感染后病毒血症。这些发现证实了 MVC 作为女性阴道杀微生物剂的开发，并应指导临床计划。