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Abstract
This work aimed to define the diversity of human immunodeficiency virus in the brain and the consequences of viral compartmentalization in the brain on both viral evolution and on brain processes. A knowledge gap in this area exists due to both limited sample availability and due to presence of the blood brain barrier, an interface between the central nervous system and the rest of the body that limits movement of virus and antiretroviral drugs into the brain. In order to help fill this gap, this dissertation work focused on neuropathogenesis due to viral presence in the brain. In chapters one and two of this dissertation we compiled and analyzed the HIV-1 brain-related repertoire of information available from publically accessible databases in order to understand, first, the mechanisms that shape viral genomic diversity in the brain, and second, viral perturbation of molecular signaling pathways in the brain. In the first chapter we developed and employed a computational pipeline that revealed general viral diversity as shaped primarily by pressures unique to the individual host, and secondarily by diagnosis of HIV-1-associated neurocognitive disorder in the host. In addition, we discovered multiple novel HAND-associated viral amino acid markers. This work also resulted in the development of a comprehensive and carefully curated compilation of viral sequence data and associated clinical information from HIV-1 individuals assessed for HAND available online for continued use by researchers. In the second chapter of this dissertation, comparison of HIV-1 infected brains to both healthy brains and to brains with the brain tumor, glioblastoma multiforme, led to the identification of signaling pathways both unique to HIV presence in the brain and in common with glioblastoma multiforme. In all, our studies have shown the significant impact of HIV presence in the brain on both evolution of the viral genome and on molecular-level changes in the brain. We hope this work will ultimately help shed light on treatment options for the nearly 50% of the HIV-1 population suffering from neurocognitive impairment due to viral presence in the brain.