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 这项提案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 在物理学上从事定量研究，并实现成为独立生物医学人员的长期目标 研究员。里夫斯博士将开发一个系统动力学数学模型，并在各种实验中进行验证 数据，以提高对艾滋病毒宿主的创建、持续和消除的理解。 该培训计划融合了一批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传染病建模专家(乔希·希弗博士)， 艾滋病毒治愈(基思·杰罗姆博士)、病毒进化(摩根·罗兰博士和特雷弗·贝德福德博士)、艾滋病毒宿主(DRS 罗伯特·西里西亚诺和彼得·亨特)和统计(彼得·吉尔伯特博士)。该小组致力于确保 该项目的成功和里夫斯博士作为独立研究人员的职业发展。这项建议 还包含专业指导(Karen Peterson博士)。课程所需的具体学习目标 成功地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、系统发生学以及会议和专业技能培训的成功 导师和小组组长。 目前，还没有治愈艾滋病毒的方法。艾滋病毒携带者面临一生难开的处方 每日抗逆转录病毒治疗(ART)。了解艾滋病毒在抗逆转录病毒治疗中的持久性是最重要的科学 介于护理标准、治疗标准和治愈标准之间的问题。目标1旨在开发一种 初次感染的系统动力学模型和艾滋病毒储备库的创建。该模型将得到验证 针对RV217试验的病毒载量和序列数据，最高分辨率的初次感染队列 录制(由罗兰博士分享)。里夫斯博士最近在《自然通讯》上发表了一个模型 这表明，大多数储存库的持久性是由于感染细胞的细胞增殖所致。目标2是合乎逻辑的 这项工作的继续。里夫斯博士将对T细胞亚群和系统发育数据进行建模(由DRS Hunt和 Siliciano)，以完善机制，主要是动态平衡与抗原性增殖。对于AIM 3灾难恢复 里夫斯将使用系统动力学模型作为生物标记物发现工具，用于治疗性干预，包括 潜伏期逆转药物、抗增殖治疗和基因治疗。 通过实现这项建议的目标，里夫斯博士将解决我们知识中的关键差距 并为在硅胶中研究艾滋病毒的治疗方案提供了一个框架。归根结底，这 这项提案将使里夫斯博士能够影响未来的艾滋病毒治疗研究，并建立一个自我维持的 在数学建模、免疫学和病毒进化的界面上进行编程。