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

描述（由申请人提供）：这是一个K 08辅导职业发展奖的乔纳森李博士，在哈佛医学院和布里格姆妇女医院医学讲师的申请。李博士是一位致力于HIV转化研究的医生兼科学家。他聚集了一个经验丰富的导师，合作者和顾问团队，并提出了一个全面的研究，课程工作和职业发展计划，这将使他成为一个成功的独立调查员。李博士提出的研究的总体目标是确定HIV-1少数变异体对抗逆转录病毒治疗失败风险的影响，并利用少数变异体人群来提高我们对HIV宿主的理解。HIV在每个感染者体内以不同的病毒云形式存在，但目前的商业HIV-1耐药性测试仅考虑至少15-25%的病毒群体中存在的突变。然而，在李博士最近发表的一项分析中，少数HIV-1耐药突变低于商业耐药基因分型检测的检测限，可使基于NNRTI的治疗失败的风险增加两倍以上。K 08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库中耐药少数变异体的患病率和临床影响; 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感染患者中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储存库的策略。 公共卫生相关性：拟议项目的重点是在每个患者的不同病毒云中发现的低频HIV变异。研究这些变异可能会提高我们为每个患者选择最佳治疗方案的能力，并可能有助于指导根除HIV储存库的策略。

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. PUBLIC HEALTH RELEVANCE: The proposed projects are focused on low-frequency HIV variants found within the diverse cloud of virus in each patient. Studying these variants may improve our ability to choose the best treatment regimen for each patient and may help guide strategies to eradicate the HIV reservoir.