Human Immunodeficiency Virus Persistence Despite Prolonged Combination Therapy: Modeling and Control Strategies

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The major goal of this project is to develop mathematical models of human immunodeficiency virus (HIV) persistence and control strategies in the setting of highly active antiretroviral therapy (HAART). Although HAART can often suppress the plasma viral loads of HIV-infected individuals to below the detection limit of current standard assays, it cannot eradicate the virus from patients. HIV can be identified in resting memory CD4+ T cells (the latent reservoir) and persists at a low level in the presence of HAART for a prolonged period of time. These latently infected cells decay slowly, but can produce virions when activated by their relevant antigens. The mechanisms underlying low viral load persistence and extremely slow decay of the latent reservoir are not fully understood. The first part of this project is to develop novel mathematical models to study the long-term dynamics of both virus and the latent reservoir during HIV treatment. Models will be analyzed and predictions will be compared with data to test the mechanisms. Since HIV infection requires lifelong therapy at present, efficient control strategies are urgently needed to reduce treatment cost and toxicity associated with long-term drug use. The second part of the project is to develop control strategies using the models of HIV persistence we developed in the first part. Practical treatment schedules such as structured treatment interruptions are also obtained using the developed models. The project represents an effort to develop control strategies based on mathematical models whose predictions agree with much of our knowledge about HIV infection and prolonged treatment. Results improve our understanding of the biological events underlying HIV persistence and may have important implications for the management of HIV infection in the era of HAART. If the control strategies, particularly those interrupted treatment schedules, can be shown to provide similar treatment benefits as the continuous therapy with maximum drug use, they will significantly reduce the financial burden, minimize drug toxicity, and improve the life quality of HIV patients. Additionally, the project provides extensive interdisciplinary training opportunities for undergraduate and graduate students from the math and biology departments, as well as the new medical school at Oakland University. The research will be incorporated into a graduate mathematical biology course and a variety of undergraduate research programs, most of which place priority on involving minority students.