Implications of HIV-1 Minority Variants for Virologic Failure and HIV Reservoirs

描述（由申请人提供）：这是一份申请K08导师职业发展奖的申请，申请对象是Jonathan Li博士，他是哈佛医学院和布莱根妇女医院的医学讲师。李博士是一名致力于转化艾滋病毒研究的医学科学家。他已经聚集了一个经验丰富的导师、合作者和顾问团队，并正在提出一个全面的研究、课程作业和职业发展计划，这将使他成为一名成功的独立研究者。李博士提出的研究的总体目标是确定HIV-1少数变异对抗逆转录病毒治疗失败风险的影响，并利用少数变异人群来提高我们对HIV库的理解。HIV在每个感染者体内以多种病毒云的形式存在，但目前商业化的HIV-1耐药性测试只考虑了至少15-25%的病毒群中存在的突变。然而，在Li博士最近发表的一项分析中，低于商业耐药基因分型测试检测极限的少数HIV-1耐药突变可使基于nnrti的治疗失败的风险增加两倍以上。K08提案建立在这些重要发现的基础上。主要目的是：1)确定HIV DNA库中耐药少数变异的流行率和临床影响；2)评价少数整合酶抑制剂耐药突变对治疗失败风险的影响；3)描述慢性未经治疗的HIV感染患者HIV-1 RNA和DNA群体动态的波动。从这些研究中获得的知识可以提高我们为每位患者选择最佳治疗方案的能力，并可能有助于指导根除艾滋病毒库的策略。

DESCRIPTION (provided by applicant): This is an application for a K08 mentored career development award for Dr. Jonathan Li, an Instructor in Medicine at Harvard Medical School and the Brigham and Women's Hospital. Dr. Li is a physician-scientist committed to a career in translational HIV research. He has gathered an experienced team of mentors, collaborators, and advisors and is proposing a comprehensive research, course work, and career development plan that will position him to be a successful independent investigator. The overall goal of Dr. Li's proposed research is to determine the effect of HIV-1 minority variants on the risk of antiretroviral treatment failure and to use minority variant populations to improve our understanding of HIV reservoirs. HIV exists as a diverse cloud of viruses within each infected individual, but current commercial HIV-1 drug resistance tests only take into account mutations present in at least 15-25% of the viral population. However, in a recently published analysis by Dr. Li, minority HIV-1 drug resistance mutations present below the limit of detection of commercial resistance genotyping tests can increase the risk of NNRTI-based therapy failure by more than two-fold. This K08 proposal builds upon these important findings. The main aims are to 1) Determine the prevalence and clinical impact of drug-resistant minority variants within the HIV DNA reservoir; 2) Evaluate the effect of minority integrase inhibitor resistance mutations on the risk of treatment failure; and 3) Characterize fluctuations in HIV-1 RNA and DNA population dynamics in patients with chronic, untreated HIV infection. The knowledge gained from these studies could improve our ability to choose the best treatment regimen for each patient and may help guide strategies for eradicating the HIV reservoir.