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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 耐药性是影响感染HIV-1的个体的治疗选择的重要问题。某些抗药性限制突变可以长期存在于宿主中，并且可以水平和/或垂直传播给新个体。尚不理解治疗期间的耐药性支配突变，特别是在血液以外的解剖部位，可能会影响耐药性HIV-1的传播以及病毒储量在整个体内的持久性。迄今为止，尚无研究纵向抽样的血液和不同的解剖区室，可以鉴定耐药性分离株的起源和出现，并在同一部位测量抗逆转录病毒药物浓度。在此分包合同中，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。该项目的具体目的是：（1）：纵向检查RT中耐药性限制突变突变的出现，这些突变是在RT-Shivmne感染的猕猴中出现的，该猕猴会用核苷类似物的单药疗法或非核苷酸类似物的单一疗法或非核苷RT抑制剂Efavirenz ，在血液和不同的解剖区； （2）：确定野生型病毒重新出现的组织起源和/或在RT-Shivmne感染的动物中抑制单一疗法和抗逆转录病毒疗法后抑制病毒血症后抗药性病毒的持久性； （3）：测量上述RT-Shivmne感染的猕猴的血液和组织室中抗逆转录病毒药物的浓度，并将其与耐药的出现相关。特定目标1中的体内研究始于2011年1月。