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Simulating persistence and elimination of the HIV reservoir

模拟 HIV 病毒库的持续存在和消除

基本信息

批准号：
10668319
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
项目类别：
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/10668319
关键词：
Acquired Immunodeficiency Syndrome Advisory Committees Anatomy Antigens Archives Automobile Driving Award Binding Biological Assay Biological Markers CD4 Positive T Lymphocytes Cell Proliferation Cells Collaborations Communication DNA DNA Sequence DNA-Directed DNA Polymerase Data Data Set Dedications Development Ecology Ensure Epidemic Evolution Excision Face Financial Hardship 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 Proliferating Publishing RNA-Directed DNA Polymerase Regimen Research Research Institute Research Personnel Research Training Resolution Resource-limited setting Role 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 Integration 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

项目摘要

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