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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 H I V 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 H I V disease progression and treatment response in the era of Highly Active Antiretroviral Therapy ( H A A R T ) . Methods: Host genetic factors selected for investigation include polymorphisms in chemokine receptor genes known to play a role in H I V disease progression during untreated infection ( C C R 5 and C X 3 C R I ) , or genes involved in drug metabolism (MDR-1) . Vira l genetic factors selected for investigation include polymorphisms in H I V 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 H I V / A I D S Drug Treatment Program in British Columbia, Canada. Results: Naturally-occurring polymorphisms in human chemokine receptor genes C C R 5 and C X 3 C R I , 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 H I V envelope appears to significantly affect both short and longer-term clinical responses to H A A R T , supporting the use of H I V envelope genotypes as determinants of therapy response. A n investigation of the impact of antiretroviral resistance mutations on long-term clinical outcomes, in particular, mortality,