Molecular Epidemiology of Human Immunodeficiency Virus Type 1 (HIV-1) in Southern Africa and Northern California

Human immunodeficiency virus type 1 (HIV-1) exhibits extraordinary genetic diversity that is driven by high rates of mutation and recombination, coupled with elevated rates of viral turnover and the persistent nature of infection. Through these mechanisms, HIV-1 group M, the group largely responsible for the global pandemic, diversified into nine distinct subtypes and additional circulating recombinant forms. Subtype C HIV-1, which accounts for approximately 50% of the estimated 37 million individuals living with HIV/AIDS worldwide, predominates the epidemics in southern Africa and South / Southeast Asia. In contrast, subtype B HIV-1, predominant in the United States and Europe, comprises 12% of the global HIV-1 prevalence.Current US and, increasingly, international guidelines recommend that HIV genotypic sequencing be performed for newly-identified HIV-positive patients, in order to identify genetic mutations that may confer drug resistance and pose a barrier to effective antiretroviral therapy (ART). This practice has resulted in the generation of enormous amounts of genotypic data often linked with clinical, demographic, and geospatial information. Analyses of these large datasets, utilizing sophisticated statistical and computational methods, has enabled identification of important and previously unrecognized trends in epidemiologic and vertical transmission, persistence of HIV within and among distinct risk groups, and the accumulation and propagation of ART resistance. Results of these analyses, in turn, advance treatment and care for persons living with HIV.This thesis takes advantage of large, de-identified and anonymized datasets of HIV-1 genotypic and demographic information available through clinical testing and treatment programs in two distinct and epidemiologically important regions in the global HIV pandemic, northern California and southern Africa. Employing innovative and computationally intensive tools which combine experience from molecular biology, evolutionary biology and biostatistics, in-depth analyses were undertaken to explore and define risk factors, underlying epidemiologic features and clinical characteristics relevant to transmission and ART resistance. The final chapter provides a comprehensive literature review of the relevance of molecular epidemiologic principles and innovative biology to the complex and continued phenomenon of mother-to-child transmission of HIV, as a case study exemplifying the need for continued molecular studies grounded in solid epidemiologic principles. The findings presented here are ultimately intended to help guide domestic and global efforts to scale up ART treatment while considering well-known and lesser-known factors that may influence eventual clinical and epidemiologic outcomes