Appearance and Disappearance of Drug Resistance Mutations

耐药突变的出现和消失

• 批准号: 7592967
• 负责人: Frank Maldarelli
• 金额: $ 21.58万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/7592967
• 关键词: Alleles; Appearance; Biological Assay; Collaborations; Detection; Dose; Drug resistance; Evolution; Frequencies; Gagging; Goals; HIV; Human; Infant; Infection; Macaca nemestrina; Modeling; Mothers; Mutation; NNRTI-resistance; Nevirapine; Patients; Pharmaceutical Preparations; Polymerase Chain Reaction; Population; Reporting; Research Design; Research Personnel; Resistance; SIV; Site Visit; South Africa; Treatment Failure; Virus; Woman; base; efavirenz; falls; non-nucleoside reverse transcriptase inhibitors; prevent; programs; transmission process; virus host interaction

Using our allele-specific PCR assay, which allows detection and quantification of rare mutations at levels as low as 0.1% in a virus population, we are performing studies designed to understand the dynamics of appearance and disappearance of NNRTI resistance mutations in patients starting and stopping therapy as well as in drug-naive patients. In collaboration with Dr. Mellors, we are assessing the impact of low-frequency mutations on subsequent treatment failure. In collaboration with Drs. Lynn Morris (South Africa) and Pat Robertson (Boehringer Ingelheim), we are also analyzing the rise and fall of NNRTI resistance mutations in women exposed to single-dose nevirapine to prevent mother-to-infant transmission, and to assess the consequences of these mutations for subsequent nevirapine-based therapy. The assay is also being used for collaborative studies with DRP investigators. With Dr. Vineet KewalRamani, we are assessing the appearance of NNRTI resistance mutations in a pigtail macaque model of infection with SIV containing HIV RT (RT-SHIV) and treated with efavirenz, as a model for the evolution of resistance in humans so treated. In collaboration with Dr. Eric Freed, we are developing a sensitive assay for the duplication of the PTAP motif in the p6 portion of Gag frequently found in association with drug resistance. [Corresponds to Project 3 in the April 2007 site visit report of the Host-Virus Interaction Unit, HIV Drug Resistance Program]

使用我们的等位基因特异性PCR分析，该测定法可以在病毒群中检测和定量稀有的突变水平低至0.1％的稀有突变，我们正在进行研究，旨在了解开始和停止治疗的患者中NNRTI耐药性突变的外观和消失的动力学，以及药物不接受药物的患者。与Mellors博士合作，我们正在评估低频突变对随后的治疗失败的影响。与Drs合作。林恩·莫里斯（Lynn Morris）（南非）和帕特·罗伯逊（Pat Robertson）（Boehringer ingelheim），我们还分析了暴露于单剂量奈韦拉平的女性中NNRTI耐药性突变的兴衰，以防止母亲到侵入性传播，并评估这些基于Nevirapine基于Nevirapine的治疗的后果。该测定法也用于与DRP研究人员的合作研究。借助Vineet Kewalramani博士，我们正在评估使用含有HIV RT（RT-SHIV）的SIV的粘尾猕猴感染模型中NNRTI抗性突变的外观，并用Efavirenz处理，作为人类耐药性进化的模型。通过与Eric Freed博士的合作，我们正在开发一种敏感测定法，以重复PTAP图案的P6部分与耐药性相关的GAG部分。 [对应于2007年4月的宿主病毒互动部门的现场访问报告，艾滋病毒抗药性计划的项目3]