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: 10447769
• 负责人: Daniel Reeves
• 金额: $ 12.3万
• 依托单位: FRED HUTCHINSON CANCER 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/10447769
• 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/文摘