Understanding HIV's impact on RR/MDR-TB development and transmission through genomics

项目摘要 通过这个K23奖，候选人，一个在结核病方面受过高级培训的传染病医生， (TB)和全球结核病/艾滋病毒研究，将成为一个独立的医生，科学家桥梁临床和 分子流行病学和耐药基因组学。候选人的长期目标是改善我们的 了解艾滋病毒、耐药结核病突变、结核病传播和临床 结果，以便更好地针对干预措施并指导治疗。为了实现这些目标，候选人 要求：1）大型临床队列分析技能; 2）现有分子流行病学流利 分析和建模; 3）下一代测序技术和分析的工作知识 管道; 4）招募和管理前瞻性临床队列的经验; 5）专业 发展和准备校外资金。这个K23概述了课程的5年计划，动手 培训，并组建了一个多学科的导师团队，以解决这些能力。卡伦博士 雅各布森（主要导师）有超过10年的国际结核病研究经验， 成功的NIH资助的赠款组合。罗宾·沃伦教授和大卫恩格尔塔勒博士（共同导师）是专家 分别在结核分枝杆菌耐药性和下一代测序技术方面。Drs. C. Robert Horsburgh和Laura白色（顾问）以及Helen考克斯教授（顾问）将提供临床 和分子流行病学专业知识沿着生物统计建模支持。K23将解决我们的 缺乏对艾滋病毒与利福平耐药/耐多药结核病（RR/MDR）之间关系的了解， TB）。候选人将利用来自南非西开普省的RR/MDR-TB样本库， 非洲，研究如何传播和获得性结核病耐药性的变化，在12年的时间内， 艾滋病毒感染者和非感染者（目标1）。其次，结核病耐药补偿突变在 将在伍斯特的一个回顾性队列中检查社区一级的RR/MDR-TB传播， 南非，包括艾滋病毒和其他风险因素的影响（目标2）。最后，在一个前瞻性的试点队列中， 全基因组和下一代测序技术将用于检测结核病药物 在结核病治疗过程中，艾滋病毒感染者和非艾滋病毒感染者以及 在南非的伍斯特，艾滋病毒/艾滋病患者停止了抗逆转录病毒治疗（目标3）。从本研究中获得的知识将转化为 降低RR/MDR-TB感染风险和改善人们的长期结果的干预措施 感染了艾滋病毒通过利用她先前的研究经验和培训， 标本和一个完善的研究基地，沿着方法培训和专家指导， 候选人有能力完成拟议的培训和研究目标，然后申请 R 01奖的重点是探索结核病/艾滋病毒合并感染高负担环境中结核病耐药性的演变。

PROJECT SUMMARY Through this K23 award, the candidate, an infectious disease physician with advanced training in tuberculosis (TB) and global TB/HIV research, will become an independent physician-scientist bridging clinical and molecular epidemiology and drug-resistance genomics. The candidate’s long-term goal is to improve our understanding of the relationship between HIV, drug-resistant TB mutations, TB transmission and clinical outcomes in order to better target interventions and guide treatment. To meet these goals, the candidate requires: 1) Skills in the analysis of large clinical cohorts; 2) Fluency with existing molecular epidemiology analysis and modelling; 3) Working knowledge of next generation sequencing techniques and analysis pipelines; 4) Experience in the recruitment and management of prospective clinical cohorts; 5) Professional development and preparation for extramural funding. This K23 outlines a 5-year plan of coursework, hands on training, and assembles a multidisciplinary mentorship team to address these competencies. Dr. Karen Jacobson (primary mentor) has over 10 years’ experience conducting international tuberculosis studies and a successful NIH-funded grant portfolio. Prof. Robin Warren and Dr. David Engelthaler (co-mentors) are experts in Mycobacterium tuberculosis drug resistance and next generation sequencing techniques, respectively. Drs. C. Robert Horsburgh and Laura White (advisors), together with Prof. Helen Cox (advisor) will provide clinical and molecular epidemiology expertise along with biostatistical modelling support. This K23 will address our lack of understanding of the association between HIV and rifampin-resistant/multidrug-resistant TB (RR/MDR- TB). The candidate will leverage a bank of RR/MDR-TB specimens from the Western Cape Province, South Africa, to examine how transmitted and acquired TB drug resistance varies over a twelve-year period among people living with and without HIV (aim 1). Next, the role of TB drug-resistance compensating mutations in RR/MDR-TB transmission at the community-level will be examined in a retrospective cohort in Worcester, South Africa, including the impact of HIV and other risk factors (aim 2). Finally, in a prospective pilot cohort, whole genome and next generation sequencing techniques will be used to examine whether TB drug resistance evolves differently during TB treatment in people with and without HIV, and in those presenting on and off antiretroviral therapy in Worcester, South Africa (aim 3). Knowledge gained from this study will translate into interventions to decrease the risk of RR/MDR-TB infection and improve long-term outcomes for people with HIV. By building upon her prior research experience and training, utilizing the biobank of RR/MDR-TB specimens and a well-established research site, along with methodologic training and expert mentorship, the candidate is well positioned to accomplish the proposed training and research aims and to then apply for an R01 award focused on exploring evolution of TB drug resistance in high burden TB/HIV coinfection settings.