An investigation of human and viral genetic factors influencing HIV disease progression and response to treatment in the era of highly active antiretroviral therapy (HAART)

Objective: Host and viral genetic factors contribute significantly to the natural course of untreated HIV infection; however, the impact of these genetic factors on response to modern antiretroviral therapies remains poorly understood. The primary objective of this thesis is to establish the impact of specific host and viral genetic factors on HIV disease progression and treatment response in the era of Highly Active Antiretroviral Therapy (HAART). Methods: Host genetic factors selected for investigation include polymorphisms in chemokine receptor genes known to play a role in HIV disease progression during untreated infection (CCR₅ and CX₃CRI), or genes involved in drug metabolism (MDR-1). Viral genetic factors selected for investigation include polymorphisms in HIV genes known to influence untreated disease progression (HIV envelope), or mutations in the viral genome known or suspected to confer resistance to antiretroviral agents. The impact of host and viral genetic factors on short and longer-term clinical outcomes were assessed using retrospective, population-based cohort and case-control analyses of HIV-infected individuals enrolled in the HIV/AIDS Drug Treatment Program in British Columbia, Canada. Results: Naturally-occurring polymorphisms in human chemokine receptor genes CCR₅ and CX₃CRI, as well as genes involved in drug metabolism (MDR-1) appear to be associated with differential short and longer-term responses to antiretroviral therapy; however, the relative contribution of individual human genetic polymorphisms to therapy response is likely to be small. In contrast, genetic variation in the HIV envelope appears to significantly affect both short and longer-term clinical responses to HAART, supporting the use of HIV envelope genotypes as determinants of therapy response. An investigation of the impact of antiretroviral resistance mutations on long-term clinical outcomes, in particular, mortality, suggested that drug resistance, although associated with poor short-term therapy efficacy, is not yet a major factor contributing to mortality among HIV-infected persons in British Columbia, at least on a population basis. Conclusion: Results support the potential incorporation of HIV envelope genotyping as a monitoring tool for the clinical management of HIV-infected individuals. The impact of human genetic variation on therapy response, however, is likely to be mediated by the contributions of polymorphisms in many different genes; a more comprehensive approach may therefore be necessary before incorporating host genotypes into routine HIV clinical management.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat