Simulating persistence and elimination of the HIV reservoir

模拟 HIV 病毒库的持续存在和消除

• 批准号: 10083066
• 负责人: Daniel Reeves
• 金额: $ 12.3万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10083066
• 关键词: Acquired Immunodeficiency Syndrome; Address; Advisory Committees; Anatomy; Antigens; Archives; Automobile Driving; Award; Biological Assay; Biological Markers; CD4 Positive T Lymphocytes; Cell Proliferation; Cells; Collaborations; Communication; DNA; DNA Sequence; DNA-Directed DNA Polymerase; Data; Data Set; Development; Ecology; Ensure; Epidemic; Evolution; Excision; Face; Financial Hardship; Foundations; Future; Genes; Genetic; Goals; HIV; HIV Infections; Human; Immunologics; Immunology; Individual; Infection; Knowledge; Laboratories; Laws; Learning; Lymphocyte; Maintenance; Memory; Mentors; Mentorship; Methods; Modeling; Modernization; Nature; Non-linear Models; Persons; Phylogenetic Analysis; Physics; Play; Population Dynamics; Primary Infection; Process; Program Sustainability; Publishing; RNA-Directed DNA Polymerase; Regimen; Research; Research Institute; Research Personnel; Research Training; Resolution; Resources; Role; Sampling; San Francisco; Sequence Analysis; Statistical Models; Structure; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Training; Training Programs; Trees; Universities; Viral; Viral Load result; Virus Latency; Virus Replication; Work; antiretroviral therapy; biological research; biomarker discovery; career; cohort; curative treatments; design; diverse data; gene therapy; human data; improved; in silico; infectious disease model; integration site; mathematical model; memory CD4 T lymphocyte; mortality; novel; response; side effect; skills; social stigma; standard of care; statistics; success; symposium; tool; virology

PROJECT SUMMARY/ABSTRACT This proposal describes a five-year research training program that will allow Dr Reeves to transition from a quantitative researcher in physics and achieve his long-term goal of becoming an independent biomedical researcher. Dr Reeves will develop a phylodynamic mathematical model, validated on diverse experimental data, to improve the understanding of the creation, persistence, and elimination of the HIV reservoir. The training program incorporates the expertise of an outstanding group of mentors and collaborators. Dr Reeves’s scientific advisory committee includes experts in modeling infectious diseases (Dr Josh Schiffer), HIV cure (Dr Keith Jerome), viral evolution (Drs Morgane Rolland and Trevor Bedford), HIV reservoirs (Drs Robert Siliciano and Peter Hunt), and statistics (Dr Peter Gilbert). This group is dedicated to ensuring the success of this project and the development of Dr Reeves’ career as an independent researcher. The proposal also contains professional mentorship (Dr Karen Peterson). The specific learning goals required for a successful transition to biological research will be accomplished through didactic coursework in virology, immunology, and phylogenetics as well as conferences and professional training in the skills of a successful mentor and group leader. Currently, no cure for HIV exists. Individuals living with HIV face the difficult prescription of a lifetime of daily antiretroviral therapy (ART). Understanding the persistence of HIV during ART is the paramount scientific question standing between standard of care treatment and cure. Aim 1 is directed at developing a phylodynamic model of primary infection and the creation of the HIV reservoir. The model will be validated against viral load and sequence data from the RV217 trial, the highest-resolution primary infection cohort recorded (shared by Dr Rolland). Dr Reeves has recently published a model in Nature Communications that suggests the majority of reservoir persistence is due to cellular proliferation of infected cells. Aim 2 is a logical continuation of this work. Dr Reeves will model T cell subset and phylogenetic data (shared by Drs Hunt and Siliciano) to refine the mechanism as predominantly homeostatic vs antigenic proliferation. For Aim 3 Dr Reeves will use the phylodynamic model as a biomarker discovery tool for curative interventions including latency reversing agents, anti-proliferative therapy, and gene therapy. Through accomplishing the aims of this proposal, Dr Reeves will address critical gaps in our knowledge of the HIV reservoir’s persistence and provide a framework to study HIV cure regimens in silico. Ultimately, this proposal will allow Dr Reeves to influence the future of HIV cure research as well as build a self-sustaining program at the interface of mathematical modeling, immunology, and viral evolution.

项目摘要/摘要 该建议描述了一项为期五年的研究培训计划，该计划将使里夫斯博士从 物理学的定量研究人员，并实现了成为独立生物医学的长期目标 研究员。里夫斯博士将开发一个系统动力学数学模型，并在潜水员实验中验证 数据，以提高对艾滋病毒储层的创造，持久性和消除的理解。 该培训计划结合了杰出的导师和合作者的专业知识。 里夫斯博士的科学咨询委员会包括建模传染病（Josh Schiffer博士）的专家， HIV治疗（Keith Jerome博士），病毒进化（Morgane Rolland博士和Trevor Bedford博士），HIV水库（博士 罗伯特·塞利西亚诺（Robert Siliciano）和彼得·亨特（Peter Hunt）和统计（彼得·吉尔伯特（Peter Gilbert）博士）。该小组致力于确保 这个项目的成功以及Reeves博士作为独立研究人员的事业的发展。提案 还包含职业心态（Karen Peterson博士）。一个特定的学习目标 成功过渡到生物学研究将通过病毒学的教学课程来完成， 免疫学，系统发育学以及成功技能的会议和专业培训 导师和小组负责人。 目前，尚无治愈艾滋病毒的治疗方法。患有艾滋病毒的人面临着一生的艰难处方 每日抗逆转录病毒疗法（ART）。了解艺术期间艾滋病毒的持久性是最重要的科学 问题在护理标准治疗和治愈之间。 AIM 1致力于开发 原发性感染的系统动力学模型和HIV储层的创造。该模型将得到验证 针对RV217试验的病毒载荷和序列数据，最高分辨率的原发性感染队列 记录（由Rolland博士共享）。里夫斯博士最近发表了一种自然传播模型 表明大多数储备持续性是由于感染细胞的细胞增殖。 AIM 2是合乎逻辑的 继续这项工作。 Reeves博士将建模T细胞子集和系统发育数据（由Drs Hunt和 硅）以优化该机制，主要是稳态与抗原增殖。对于AIM 3 DR 里夫斯将使用系统动力学模型作为生物标志物发现工具，用于治疗干预措施 潜伏期逆转剂，抗增殖疗法和基因疗法。 通过完成该提案的目标，里夫斯博士将解决我们所知的关键差距 艾滋病毒水库的持久性，并提供了研究硅疗法治疗方案的框架。最终，这个 提案将使里夫斯博士能够影响艾滋病毒治疗研究的未来，并建立自我维持的 在数学建模，免疫学和病毒进化的界面上的程序。