Mentoring in patient-oriented research to finding a cure for HIV-1 infection

指导以患者为导向的研究，寻找 HIV-1 感染的治疗方法

• 批准号: 10450089
• 负责人: Mathias Lichterfeld
• 金额: $ 19.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-13 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450089
• 关键词: Address; Adherence; Adult; Antigens; Area; Basic Science; Bioinformatics; Biological Assay; Birth; Botswana; Cells; Cellular Immunology; Characteristics; Childhood; Chromatin; Clinic; Clinical; Clinical Medicine; Clinical Research; Clinical Sciences; Clinical Trials; Clinical Trials Design; Collaborations; Communicable Diseases; Communities; Complement; Complex; Conduct Clinical Trials; Consensus; Creativeness; Development; Disease; Disease remission; Doctor of Philosophy; Educational workshop; Epigenetic Process; Evolution; Faculty; Funding; Future; General Hospitals; Genetic; Genetic Transcription; Genome; HIV; HIV-1; Home; Hospitals; Hour; Human; Immune response; Immune system; Immunologics; Individual; Infant; Infection; Institutes; Institution; Interruption; Intervention; Intervention Studies; Investigation; Knowledge; Laboratory Research; Length; Life; Life Expectancy; Massachusetts; Mentors; Mentorship; Molecular; Molecular Immunology; Monitor; National Institute of Allergy and Infectious Disease; Neonatal; Patients; Persons; Pharmaceutical Preparations; Physicians; Positioning Attribute; Predisposition; Principal Investigator; Procedures; Proteomics; Research; Research Activity; Research Infrastructure; Research Personnel; Research Project Grants; Residual state; Resources; Retrovirology; Sampling; Scientist; Subgroup; Systems Biology; Techniques; Technology; Therapeutic Intervention; Time; Training; Training Programs; Translating; Translational Research; United States National Institutes of Health; Universities; Viral; Viral Load result; Viral reservoir; Virus Diseases; Virus Integration; Woman; Work; antiretroviral therapy; bridge program; career; chromatin immunoprecipitation; clinical care; design; experience; genome analysis; global health; improved; infant infection; innovation; integration site; interest; member; multidimensional data; neonatal infection; neonate; neutralizing antibody; new technology; next generation; next generation sequencing; novel; novel therapeutic intervention; patient oriented; patient oriented research; patient population; pediatric human immunodeficiency virus; programs; protocol development; research study; skills; therapy development; training opportunity

Abstract Dr. Lichterfeld is an infectious disease physician-scientist with a strong record of mentoring research fellows in high-profile, patient-oriented research studies related to HIV-1 cure and eradication. He conducts a broad and diverse research program of patient-oriented studies that include molecular and cellular immunologic studies with patient-derived cells, translational human investigations and interventional clinical trials designed to explore novel therapeutic approaches to reduce HIV-1 reservoirs. These research activities provide attractive and exciting training opportunities for physicians and scientists interested and invested in developing strategies for a functional or sterilizing cure for HIV-1 infection; in the past, several of his mentees and co-mentees have progressed to receive R-level funding, and have been offered independent faculty positions at highly-selective universities around the world. In the proposed K24 application, Dr. Lichterfeld will extend and expand his successful mentoring activities in the context of three cutting-edge research areas: He will mentor trainees in the conceptualization, design, implementation and conduct of interventional clinical trials designed to explore novel therapeutic strategies for HIV-1 eradication (Specific Aim 1). These activities will initially focus on an already ongoing, NIAID-funded clinical trial in which Dr. Lichterfeld serves as the PI, but will be expanded in the future to translate novel ideas and concepts into exploratory, proof-of-concept clinical trials. These studies take advantage of advanced clinical trial research infrastructure and a highly motivated HIV-1 patient population at the Brigham and Women’s Hospital and the Massachusetts General Hospital, the two hospitals Dr. Lichterfeld is affiliated with. In addition, Dr. Lichterfeld will train his mentees in innovative next-generation sequencing and proteomics approaches involving single-genome, near full-length viral sequencing, combined with viral integration site analysis, chromatin accessibility assays and chromatin immunoprecipitation assays to profile residual viral reservoirs in patient-derived cell samples at an unprecedented breadth (Specific Aim 2). This work will be facilitated by unique technical resources and cross-disciplinary collaborations at the Ragon Institute and the Broad Institute of MIT and Harvard, where Dr. Lichterfeld holds Associate Member status. Finally, Dr. Lichterfeld will offer a distinct training experience in pediatric HIV-1 infection, focusing on the development of interventions that may enable a long-term, drug free remission of HIV-1 infection in neonates from Botswana (Specific Aim 3). These collaborative investigations will be performed in the context of ongoing, NIAID-funded clinical trials investigating effects of standard antiretroviral therapy and broadly-neutralizing antibodies on viral reservoirs and antiviral immune responses in HIV-1-infected infants started on therapy within the first days after birth. Together, these studies provide distinct but interrelated training opportunities for physicians and scientists to acquire the knowledge, skills, creativity and collaborations that are needed for an independent career in patient-oriented studies focused on finding a cure for HIV-1 infection.

摘要 博士Lichterfeld是一位传染病医生兼科学家，在指导研究人员方面有着良好的记录， 与HIV-1治愈和根除相关的高调、面向患者的研究。他进行了广泛的， 包括分子和细胞免疫学研究在内的以患者为导向的多样化研究计划 与患者来源的细胞，翻译人类研究和干预性临床试验，旨在探索 减少HIV-1储库的新治疗方法。这些研究活动提供了有吸引力和 令人兴奋的培训机会，为有兴趣和投资于制定战略的医生和科学家， HIV-1感染的功能性或绝育治疗;在过去，他的几个学员和共同学员已经 进展到获得R级资金，并已提供独立的教师职位，在高度选择性 世界各地的大学。在拟议的K24应用程序中，Lichterfeld博士将扩展和扩展他的 在三个前沿研究领域的背景下成功的指导活动：他将指导学员在 干预性临床试验的概念化、设计、实施和实施，旨在探索新的 HIV-1根除的治疗策略（具体目标1）。这些活动最初将侧重于一个已经 正在进行的NIAID资助的临床试验，其中Lichterfeld博士担任PI，但将来将扩大 将新的想法和概念转化为探索性的、概念验证的临床试验。这些研究采取 先进的临床试验研究基础设施和高度积极的HIV-1患者群体的优势， 布里格姆妇女医院和马萨诸塞州总医院，这两家医院 隶属于。此外，Lichterfeld博士还将在创新的下一代测序方面培训他的学员， 蛋白质组学方法涉及单基因组、近全长病毒测序， 整合位点分析、染色质可及性测定和染色质免疫沉淀测定， 以前所未有的广度在患者来源的细胞样品中检测残留病毒储库（特定目标2）。这项工作 将通过Ragon研究所独特的技术资源和跨学科合作来促进， 麻省理工学院和哈佛的布罗德研究所，Lichterfeld博士在那里拥有准会员资格。最后，博士。 Lichterfeld将提供儿科HIV-1感染方面独特的培训经验，重点是开发 可能使博茨瓦纳新生儿HIV-1感染得到长期、无药物缓解的干预措施 （具体目标3）。这些合作调查将在国家艾滋病研究所资助的正在进行的 研究标准抗逆转录病毒治疗和广泛中和抗体对病毒感染的影响的临床试验 HIV-1感染婴儿在接受治疗后的头几天内开始出现抗病毒免疫应答， 出生总之，这些研究为医生和科学家提供了不同但相互关联的培训机会 获得独立职业所需的知识，技能，创造力和协作， 以病人为导向的研究集中于寻找治疗HIV-1感染的方法。