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

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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.