HIV-1 5'UTR RNA structures: connections to infectious lifecycle and potential therapeutic applications
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Human immunodeficiency virus (HIV) is among the most sinister pathogens plaguing man. As of now, we do not yet have a method to "cure" infection once the virus has integrated into the host genome. It has the highest mutation rate of any known biological entity, necessitating a persistent need of novel therapeutic options. Structure: function relationships derived from biochemical approaches have been long-standing method to understand the mechanisms of HIV infection and identifying targets for treatment. This dissertation presents work utilizing a wide range of biochemical approaches to explore the importance of the HIV-1 5'untranslated region (5'UTR) RNA in infection and strategies utilizing this gained knowledge for screening of novel therapeutic agents. The HIV-1 5'UTR structure is highly structured, structurally dynamic, and the most conserved region of the genome. In this dissertation we reveal work demonstrating the existence of a novel, alternate translation pathway adopted by HIV-1 to promote virus fitness to the detriment of the host. We show evidence implicating the 5'UTR structure in determining fate of RNAs between translation pathways. Additionally, we demonstrate that folding of the upstream elements of the HIV-1 5'UTR influence folding of downstream elements, suggesting the fate of the mRNA transcripts are determined when they are nascently transcribed. This work sets the foundation for further investigation into mechanism of 5' UTR folding in early and late HIV-1 mRNAs and its relevance in the HIV-1 infectious lifecycle. In this dissertation, we map the binding interface of HIV-1 5'UTR TAR RNA with INI1, a core component of the SWI/SNF eukaryotic chromatin remodeling complex. This is the first example of HIV-1 RNA surface structure mimicking a host protein surface, and the modeled structure will be vital for development of novel therapeutics targeting the interaction between INI1 and TAR. We also show evidence that defective INI1 results in decreased transcriptional elongation and decreased virion particle production. We then outline future directions to monitor HIV-1 5'UTR folding for screening of novel therapeutics.
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Ph. D.