ORIGIN AND EVOLUTION OF HIV-1 DRUG RESISTANCE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 耐药性是影响艾滋病毒-1感染者治疗选择的一个重大问题。一些导致耐药性的突变可以在宿主中持续很长时间，并可以水平和/或垂直传播给新的个体。在治疗期间，特别是在血液以外的解剖部位，如何产生导致耐药性的突变尚不清楚，并可能影响耐药艾滋病毒-1的传播和整个身体的病毒库的持久性。到目前为止，还没有研究对血液和不同的解剖分区进行纵向采样，以确定耐药菌株的来源和出现，并测量这些部位的抗逆转录病毒药物浓度。在这项分包合同中，我们建议使用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)纵向检测RT-SHIVmne感染的猕猴在接受核苷类似物FTC或非核苷RT抑制剂efavirenz的单一治疗后，血液和不同解剖分区中出现的与RT耐药相关的突变；(2)确定RT-SHIVmne感染的动物在停止单一治疗和抑制病毒血症与联合抗逆转录病毒治疗后，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)：检测上述RT-SHIVmne感染猕猴血液和组织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。特定目标1的体内研究于2011年1月启动。

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.