Dynamical systems analysis of HIV immunopathogenesis and the effects of antiretroviral treatment interruption

Rose, Jessica (2006) Dynamical systems analysis of HIV immunopathogenesis and the effects of antiretroviral treatment interruption. Masters thesis, Memorial University of Newfoundland.

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Abstract

In the absence of a successful vaccine against HIV-1, alternative means to cope with the HIV pandemic have been explored. Antiretroviral (ARV) treatment is commonly prescribed to HIV-infected individuals in an attempt to control the infection. However, ARV treatment is very rigorous and generally comprises a highly toxic and costly multi-drug regimen designed for strict, life-long adherence. ARV treatment interruption is an alternative treatment strategy designed to maximize clinical benefits and alleviate some of the complications associated with continuous treatment. It is theorized that treatment interruption can reset the virological setpoint by inducing controlled resurgences of virus to boost HIV -specific CD8+ T cell activity to control viral replication. -- Dynamical systems analysis is a mathematical tool used to describe the behavior of complex systems. This allows an unobtrusive, safe way to test treatment interruption regimens. I have developed a novel mathematical model that describes the dynamical interactions between HIV-specific T cell and virus populations for two clinically-defined subgroups of HIV-1-infected individuals called fast and slow progressors. The model is based on antiviral activity imposed by HIV-specific CD8+ T cells that specifically target the virus by removing virally-infected cells and the model accurately mimics clinical dis ease progression patterns in these subgroups. Model results accurately predict that treatment interruption induces resurgence of virus to boost HIV-specific CD8+ T cell activity in both subgroups, but does not reset the virological setpoint in either. These results are experimentally corroborated through an assessment of quantitative and qualitative changes in HIV-specific CD8+ T cell activities when virus loads are high (off-treatment) and low/ undetectable (on-treatment). -- In this thesis, I provide an introduction to HIV and dynamical systems, a complete analysis of the model derived to describe HIV immunopathogenesis, a report on clinical and experimental observation of a small cohort of HIV-1-infected individuals and a description of the integration of the mathematical, clinical and experimental results.

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