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: 10226330
• 负责人: Daniel Reeves
• 金额: $ 5.89万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226330
• 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.

项目概要/摘要 该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能够从 物理学定量研究员并实现成为独立生物医学研究者的长期目标 研究员。里夫斯博士将开发一个系统动力学数学模型，并在各种实验中得到验证 数据，以增进对艾滋病毒储存库的产生、持久性和消除的了解。 该培训计划融合了优秀导师和合作者团队的专业知识。 里夫斯博士的科学顾问委员会包括传染病建模专家（乔希·希弗博士）， HIV 治疗（Keith Jerome 博士）、病毒进化（Morgane Rolland 博士和 Trevor Bedford 博士）、HIV 储存库（Drs Robert Siliciano 和 Peter Hunt），以及统计数据（Peter Gilbert 博士）。该小组致力于确保 该项目的成功以及里夫斯博士作为独立研究员的职业生涯的发展。提案 还包含专业指导（凯伦·彼得森博士）。所需的具体学习目标 向生物学研究的成功过渡将通过病毒学的教学课程来完成， 免疫学和系统发育学以及成功的技能会议和专业培训 导师和小组领导者。 目前，尚无治疗艾滋病毒的方法。艾滋病毒感染者面临着终生难以解决的难题 每日抗逆转录病毒治疗（ART）。了解 ART 期间艾滋病毒的持续存在是最重要的科学依据 护理治疗标准和治愈之间存在问题。目标 1 旨在开发 原发感染的系统动力学模型和艾滋病毒储存库的形成。该模型将被验证 对照来自 RV217 试验的病毒载量和序列数据，这是分辨率最高的原发感染队列 记录（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 表明大部分储存库的持续存在是由于受感染细胞的细胞增殖造成的。目标2是合乎逻辑的 继续这项工作。 Reeves 博士将对 T 细胞亚群和系统发育数据进行建模（由 Hunt 博士和 Siliciano）完善了主要是稳态增殖与抗原增殖的机制。为了目标3博士 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，包括 潜伏期逆转剂、抗增殖疗法和基因疗法。 通过实现该提案的目标，里夫斯博士将解决我们知识中的关键差距 艾滋病毒储存库的持久性，并提供一个框架来研究艾滋病毒治疗方案的计算机。最终，这 该提案将使里夫斯博士能够影响艾滋病毒治疗研究的未来，并建立一个自我维持的 数学建模、免疫学和病毒进化接口的程序。