Using Phylogenetics to Elucidate HIV Transmission Patterns and Inform Prevention

描述（由申请人提供）：本申请是为北卡罗莱纳大学传染病学系医学助理教授Ann Dennis MD申请的K08奖，她正在接受培训，成为艾滋病毒传播、流行病学和预防方面的独立研究者。尽管艾滋病毒的治疗和预防取得了显著进展，但在美国东南部，新的艾滋病毒诊断仍在继续，在少数民族和男男性行为者之间仍然存在显著差异。需要创新的方法来成功地减少这些弱势群体中的艾滋病毒感染事件。系统发育性艾滋病毒传播网络或“聚类”的鉴定，即来自共享艾滋病毒传播的个体的高度相关序列，提供了对人群水平上艾滋病毒传播结构的独特见解，这是无法通过接触者追踪或其他患者报告的病史获得的。结合临床和人口统计数据，这些传播聚集可能为指导艾滋病毒预防工作提供新的目标，针对持续传播风险最高的群体。总体研究目标是描述北卡罗莱纳州当地系统发育集群的特征，并调查系统发育在公共卫生环境中的应用，以确定未来的干预措施。拟议的研究将采用分子流行病学的创新方法，利用从常规临床护理中发送的抗逆转录病毒耐药性测试中提取的大量HIV pol序列库来重建传播集群。该研究的目的是：(1)在一个由新发和确诊的HIV病例组成的大型临床队列中，确定新发或扩大的HIV传播集群的时间和临床特征；2)评估高密度HIV流行病例抽样对发现传播聚集性的影响，并表征全州范围内的流行结构；3)确定在限定地理区域内将HIV序列分析纳入常规HIV监测的可行性。Dennis博士的指导团队将包括主要导师Joseph Eron，医学博士，北卡罗来纳大学医学教授，在艾滋病临床和流行病学研究方面拥有超过20年的经验。两位共同导师将在艾滋病毒流行病学和系统发育方面提供互补的专业领域：威廉·米勒，医学博士，博士，公共卫生硕士，UNC流行病学和医学副教授，其研究重点是艾滋病毒流行病学；Stephane Hue博士，伦敦大学学院病毒学家，国际公认的HIV系统发育专家和UNC自2010年以来的合作者。丹尼斯博士的培训计划与拟议的研究目标有关：在艾滋病毒流行病学方面建立坚实的基础，包括监测和疫情调查；扩展系统发育分析的技能，整合时间尺度和地理数据；并探讨艾滋病预防系统发育的伦理问题。培训将通过教学课程、研讨会和实习相结合的方式完成。这些培训和研究活动将使丹尼斯博士成熟为一名独立的研究者，并提供基础

DESCRIPTION (provided by applicant): This application is for a K08 award for Ann Dennis MD, an Assistant Professor of Medicine in the Division of Infectious Diseases at the University of North Carolina, who is training to become an independent investigator in HIV transmission, epidemiology, and prevention. Despite marked advances in HIV treatment and prevention, new HIV diagnoses continue in the southeastern US where significant disparities still exist among racial minorities and men who have sex with men. Innovative methods are needed to successfully decrease incident HIV infections among these vulnerable groups. The identification of phylogenetic HIV transmission networks or "clusters", which are highly related sequences from individuals with shared HIV transmission, offers unique insight into the structure of HIV transmission on a population level that cannot be obtained through contact tracing or other patient-reported history. Paired with clinical and demographic data, these transmission clusters may provide new targets to direct HIV prevention efforts for groups at highest risk for ongoing transmission. The overall research objective is to characterize local phylogenetic clusters in North Carolina and investigate the use of phylogeny in the public health setting to target future interventions. The proposed study will employ innovative methods in molecular epidemiology to reconstruct transmission clusters using large repositories of HIV pol sequences extracted from antiretroviral resistance testing sent during routine clinical care. The aims of the study are to: ) Identify the temporal and clinical features of emerging or expanding HIV transmission clusters in a large clinical cohort of new and established HIV cases; 2) Assess the effect of higher density sampling of prevalent HIV cases on the detection of transmission clusters and characterize the statewide epidemic structure; and 3) Determine feasibility of incorporating HIV sequence analysis into routine HIV surveillance in a circumscribed geographic area. Dr. Dennis's mentoring team will consist of primary mentor Joseph Eron, MD, Professor of Medicine at UNC with over 20 years of experience in HIV clinical and epidemiologic research. Two co-mentors will offer complementary areas of expertise in HIV epidemiology and phylogenetics: William Miller, MD, PhD, MPH, Associate Professor of Epidemiology and Medicine at UNC whose research focuses on HIV epidemiology; and Stephane Hue, PhD, virologist at University College London, an internationally recognized expert in HIV phylogenetics and UNC collaborator since 2010. Dr. Dennis' training plan links to the proposed research aims: establish a solid foundation in HIV epidemiology including surveillance and outbreak investigation; expand skills in phylogenetic analyses integrating time- scaled and geographic data; and explore ethical issues surrounding phylogenetics in HIV prevention. Training will be accomplished through a combination of didactic courses, workshops, and practicums. These training and research activities will allow Dr. Dennis to mature into an independent investigator and provide a basis for an R01 to implement real-time phylogeny to direct prevention interventions and track trends in HIV incidence.