HIV Persistence During Antiretroviral Therapy: Mechanisms, Models, Computation, and Data Analysis

抗逆转录病毒治疗期间艾滋病毒的持续存在：机制、模型、计算和数据分析

基本信息

批准号：
1950254
负责人：
Libin Rong
金额：
$ 17.89万
依托单位：
University of Florida
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1950254&HistoricalAwards=false
关键词：
HIV Persistence During Antiretroviral Therapy

项目摘要

HIV persists in patients despite effective antiretroviral therapy. HIV latent infection of CD4+ T cells might be a major obstacle to viral eradication and has been extensively investigated. However, some other factors may also contribute to HIV persistence. The goal of this project is to develop new approaches in mathematical modeling and experimental data analysis to address questions of HIV persistence. Although HIV preferentially infects CD4+ T cells, it also infects other cells, such as macrophages. Macrophages are white blood cells that engulf and digest cellular debris and pathogens. During the engulfment of HIV-infected CD4+ T cells, macrophages can also get infected, contributing to viral production and persistence. In addition to the viral infection of CD4+ T cells, HIV can also be transferred directly from infected to uninfected CD4+ T cells. Such cell-to-cell transmission can take place within the same cell types and also in different cell populations such as macrophages. The relative contributions to HIV persistence from these sources remain largely unknown, but such information is crucial for finding a cure or control of HIV infection. Graduate students will be trained in this project.In this project, mechanism-based mathematical models will be developed, analyzed, and compared with experimental data to study the relative contributions of various sources to HIV persistence during highly active antiretroviral therapy. In the first part, models with macrophages will be developed to analyze the data of macrophage infection with/without CD4+ T cell infection in different mouse models. The relative contributions from CD4+ T cell infection, macrophage infection, and CD4-to-macrophage transmission to HIV persistence will be evaluated. The second part studies whether cell-to-cell transmission can explain viral persistence during antiretroviral therapy and whether it also contributes to multiple HIV infection. The PI shall develop a new cell-to-cell transmission model including infected cells structured continuously according to their activation status. This provides a new cell-to-cell modeling framework to study HIV latency, low viral load persistence, and emergence of viral blips during suppressive therapy. The results obtained from this project will provide quantitative information on the sources contributing to HIV persistence, which can help develop treatment strategies targeting HIV eradication or control.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

尽管有效的抗逆转录病毒疗法，患者的HIV仍然存在。 CD4+ T细胞的HIV潜在感染可能是消除病毒的主要障碍，并已广泛研究。但是，其他一些因素也可能导致艾滋病毒持久性。该项目的目的是开发数学建模和实验数据分析的新方法，以解决HIV持久性问题。尽管HIV优先感染CD4+ T细胞，但它也会感染其他细胞，例如巨噬细胞。巨噬细胞是吞噬和消化细胞碎片和病原体的白细胞。在感染HIV感染的CD4+ T细胞的过程中，巨噬细胞也会被感染，导致病毒生产和持久性。除了CD4+ T细胞的病毒感染外，HIV还可以直接从感染转移到未感染的CD4+ T细胞。这种细胞对细胞的传播可以发生在相同的细胞类型中，也可以在诸如巨噬细胞等不同细胞种群中进行。这些来源对艾滋病毒持久性的相对贡献在很大程度上尚不清楚，但是这种信息对于找到治愈或控制HIV感染至关重要。研究生将接受该项目的培训。在该项目中，将开发，分析基于机制的数学模型，并与实验数据进行比较，以研究高度活跃的抗逆转录病毒疗法期间各种艾滋病毒持久性的相对贡献。在第一部分中，将开发具有巨噬细胞的模型来分析不同小鼠模型中带有/没有CD4+ T细胞感染的巨噬细胞感染的数据。将评估CD4+ T细胞感染，巨噬细胞感染和CD4对巨噬细胞传播到HIV持久性的相对贡献。第二部分研究了细胞到细胞的传播是否可以解释抗逆转录病毒疗法期间的病毒持久性，以及它是否也导致多种HIV感染。 PI应开发出一个新的细胞到细胞传输模型，包括根据其激活状态连续结构的感染细胞。这提供了一个新的细胞间建模框架，以研究抑制性治疗期间的HIV潜伏期，低病毒负荷持久性和病毒叶片的出现。从该项目获得的结果将提供有关导致艾滋病毒持久性的来源的定量信息，该信息可以帮助制定针对消除艾滋病毒或控制的治疗策略。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的审查标准来通过评估来获得支持的。