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.

项目总结/摘要 该提案描述了一个为期五年的研究培训计划，该计划将使里夫斯博士从一个 定量研究员在物理学和实现他的长期目标，成为一个独立的生物医学 研究员Reeves博士将开发一个动态数学模型，并在各种实验中进行验证。 数据，以提高对艾滋病毒库的创建，持久性和消除的理解。 该培训计划结合了一组优秀的导师和合作者的专业知识。 里夫斯博士的科学顾问委员会包括传染病建模专家（乔什·希弗博士）， 艾滋病毒治疗（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），艾滋病毒储存库（博士 Robert Siliciano和Peter Hunt）和统计学（Peter吉尔伯特博士）。该小组致力于确保 这个项目的成功和里夫斯博士作为一名独立研究人员的职业发展。该提案 还包含专业指导（卡伦彼得森博士）。A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教学课程完成， 免疫学和遗传学以及会议和专业培训的技能，成功的 导师和组长。 目前还没有治愈艾滋病毒的方法。艾滋病毒感染者面临着终生的困难处方， 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期间的持续存在是最重要的科学 标准治疗和治愈之间的问题。目标1旨在发展一个 原发性感染的动态模型和HIV库的创建。该模型将得到验证 与来自RV 217试验的病毒载量和序列数据相比，RV 217试验是最高分辨率的原发性感染队列， 记录（由Rolland博士分享）。里夫斯博士最近在《自然通讯》杂志上发表了一个模型， 表明大多数储库持续性是由于受感染细胞的细胞增殖。目标2是一个逻辑 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）以将机制细化为主要的稳态相对于抗原增殖。为目标3博士 Reeves将使用生物动力学模型作为治疗干预的生物标志物发现工具，包括 潜伏期逆转剂、抗增殖治疗和基因治疗。 通过实现这一建议的目标，里夫斯博士将解决我们的知识的关键差距 艾滋病病毒库的持久性，并提供了一个框架，研究艾滋病病毒的治疗方案在硅片。最终这 这项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 在数学建模，免疫学和病毒进化的接口程序。