ORIGIN AND EVOLUTION OF HIV-1 DRUG RESISTANCE

HIV-1 耐药性的起源和演变

• 批准号: 8357636
• 负责人: Shiu-Lok Hu
• 金额: $ 37.79万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357636
• 关键词: Affect; Animals; Anti-Retroviral Agents; Blood; Blood specimen; Drug resistance; Evolution; Family suidae; Funding; Grant; HIV-1; Individual; Infection; Macaca; Measures; Modeling; Mutation; National Center for Research Resources; Pharmaceutical Preparations; Primates; Principal Investigator; Research; Research Infrastructure; Resistance; Resources; Site; Source; Tail; Tissues; United States National Institutes of Health; Viral; Viremia; Virus; antiretroviral therapy; cost; drug resistant virus; efavirenz; in vivo; non-nucleoside reverse transcriptase inhibitors; nucleoside analog; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Drug resistance is a significant issue affecting the treatment options of individuals infected with HIV-1. Some drug resistance-conferring mutations can persist for long periods in the host and can be transmitted horizontally and/or vertically to new individuals. How drug resistance-conferring mutations arise during treatment, particularly in anatomical sites other than the blood, is not understood and may affect transmission of drug resistant HIV-1 and persistence of viral reservoirs throughout the body. To date, no studies have longitudinally sampled blood and different anatomical compartments to identify the origins and emergence of drug resistant isolates and to measure antiretroviral drug concentrations at those same sites. In this subcontract, we propose to use a RT-SHIVmne infection model in pig-tailed macaques to study the origin and evolution of HIV-1 drug resistance. The Specific Aims of this project are: (1): To examine longitudinally the emergence of drug resistance-conferring mutations in RT that arise in RT-SHIVmne-infected macaques receiving monotherapy with the nucleoside analog FTC , or the non-nucleoside RT inhibitor efavirenz, in blood and different anatomical compartments; (2): To determine the tissue origin of the re-emergence of wild-type virus and/or persistence of drug resistant virus after discontinuation of monotherapy and after suppression of viremia with combination antiretroviral therapy in the RT-SHIVmne-infected animals; (3): To measure the concentration of antiretroviral drugs in the blood and tissue compartments of RT-SHIVmne-infected macaques described above and correlate these with emergence of resistance. In vivo studies in Specific Aim 1 were initiated in January of 2011.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 耐药性是影响 HIV-1 感染者治疗选择的一个重要问题。一些赋予耐药性的突变可以在宿主体内持续很长时间，并且可以水平和/或垂直传播给新个体。治疗过程中产生耐药性的突变是如何产生的，特别是在血液以外的解剖部位，目前尚不清楚，并且可能影响耐药性 HIV-1 的传播和全身病毒库的持续存在。迄今为止，还没有研究对血液和不同的解剖区室进行纵向采样，以确定耐药菌株的起源和出现，并测量这些相同部位的抗逆转录病毒药物浓度。在这个分包合同中，我们建议在猪尾猕猴中使用RT-SHIVmne感染模型来研究HIV-1耐药性的起源和进化。该项目的具体目标是：(1)：纵向检查 RT-SHIVmne 感染的猕猴接受核苷类似物 FTC 或非核苷 RT 抑制剂依非韦伦单一疗法时出现的 RT 耐药突变的出现，在血液和不同的解剖室中； (2)：确定在RT-SHIVmne感染的动物中停止单一治疗后和联合抗逆转录病毒治疗抑制病毒血症后野生型病毒重新出现和/或耐药病毒持续存在的组织来源； (3)：测量上述感染 RT-SHIVmne 的猕猴血液和组织区室中抗逆转录病毒药物的浓度，并将其与耐药性的出现相关联。具体目标 1 的体内研究于 2011 年 1 月启动。