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

尽管进行了有效的抗逆转录病毒治疗，艾滋病毒仍在患者中持续存在。HIV潜伏感染的CD4+T细胞可能是病毒根除的主要障碍，并已被广泛研究。然而，其他一些因素也可能有助于艾滋病毒的持久性。该项目的目标是在数学建模和实验数据分析方面开发新的方法，以解决艾滋病毒持久性问题。虽然HIV主要感染CD4+T细胞，但它也会感染其他细胞，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。在吞噬感染艾滋病毒的CD4+T细胞的过程中，巨噬细胞也会受到感染，从而促进病毒的产生和持续。除了病毒感染CD4+T细胞外，HIV还可以直接从感染的CD4+T细胞转移到未感染的CD4+T细胞。这种细胞间的传播可以发生在相同的细胞类型中，也可以发生在不同的细胞群体中，如巨噬细胞。这些来源对艾滋病毒持久性的相对贡献在很大程度上仍不清楚，但这些信息对于找到治愈或控制艾滋病毒感染的方法至关重要。研究生将在这个项目中接受培训。在这个项目中，基于机理的数学模型将被开发、分析，并与实验数据进行比较，以研究在高效抗逆转录病毒治疗期间不同来源对HIV持续的相对贡献。在第一部分中，将建立巨噬细胞感染模型，分析不同小鼠模型中巨噬细胞感染合并/不合并CD4+T细胞感染的数据。将评估CD4+T细胞感染、巨噬细胞感染和CD4-巨噬细胞传播对HIV持久性的相对贡献。第二部分研究细胞间传播是否可以解释抗逆转录病毒治疗期间病毒的持久性，以及它是否也有助于多重艾滋病毒感染。PI应开发一种新的细胞间传播模型，包括根据感染细胞的激活状态连续构建的感染细胞。这为研究HIV潜伏期、低病毒载量持久性和抑制治疗期间出现的病毒斑点提供了一个新的细胞到细胞建模框架。从这个项目中获得的结果将提供有关艾滋病毒持续存在的来源的定量信息，这有助于制定针对艾滋病毒根除或控制的治疗战略。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.