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

项目总结 通过这个K23奖项，候选人，一位在结核病方面接受过高级培训的传染病医生 (结核病)和全球结核病/艾滋病毒研究，将成为连接临床和 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HIV、耐药结核病变异、结核病传播与临床的关系 结果，以便更好地有针对性地干预和指导治疗。为了实现这些目标，候选人 要求：1)分析大型临床队列的技能；2)熟练掌握现有的分子流行病学 分析和建模；3)下一代测序技术和分析的工作知识 渠道；4)招募和管理未来临床队列的经验；5)专业人员 发展和准备外部资金。这本K23课程概述了实际操作的五年课程计划 培训，并组建一个多学科的指导团队来解决这些能力问题。凯伦医生 雅各布森(首席导师)有10多年进行国际结核病研究的经验，并拥有 成功的美国国立卫生研究院资助的赠款组合。罗宾·沃伦教授和大卫·恩格塔勒博士(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中。戴维斯博士。 罗伯特·霍斯伯格和劳拉·怀特(顾问)以及海伦·考克斯教授(顾问)将提供临床 和分子流行病学专业知识以及生物统计模型支持。这个K23将针对我们的 对艾滋病毒与耐利福平/多药耐药结核病(RR/MDR- 结核病)。候选人将利用南部西开普省的一批RR/MDR-TB样本 非洲，以检查传播和获得性结核病耐药性在12年间的变化 艾滋病毒携带者和非艾滋病毒感染者(目标1)。接下来，结核病耐药补偿突变在 社区一级的RR/MDR-TB传播将在伍斯特的一个追溯队列中进行检查， 南非，包括艾滋病毒和其他风险因素的影响(目标2)。最后，在一个预期的飞行员队列中， 将使用全基因组和下一代测序技术来检查结核病药物 在结核病治疗期间，艾滋病毒携带者和非艾滋病毒携带者以及那些感染艾滋病毒的人的耐药性演变不同 并在南非伍斯特停止抗逆转录病毒治疗(目标3)。从这项研究中获得的知识将转化为 采取干预措施以降低RR/MDR-TB感染的风险并改善人们的长期结果 艾滋病毒携带者。根据她以前的研究经验和培训，利用RR/MDR-TB生物库 标本和完善的研究站点，以及方法学培训和专家指导， 应聘者能够很好地完成建议的培训和研究目标，然后申请 R01奖的重点是探索高负担结核病/艾滋病毒混合感染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.