Structural and Therapeutic Insights from the HIV-1 RNA Genome


Infection with HIV currently affects an estimated 30-36 million people throughout the world. Due in part to the poor replication fidelity of this RNA virus, resistance to antiretrovirals develops rapidly. Finding new ways of targeting HIV is therefore an ever urgent need. However, despite the wealth of ongoing research in HIV drug development, most new drug candidates continue to target only a few well-defined protein domains, chosen for their functional importance in HIV replication. Targeting the RNA genome itself in a structure-directed manner presents an opportunity to greatly expand the repertoire of potential target sites for anti-HIV therapeutics. We use a high-resolution SHAPE-directed secondary structure model of an entire HIV-1 RNA genome (1) to refine existing models of the Gag-Pol frameshift element, an important regulatory element and promising therapeutic target, and (2) to investigate the structural determinants for RNAi-based inhibition of HIV-1. We show that the Gag-Pol frameshift element folds into a complex structure that is distinct from currently accepted models and capable of switching between two different conformations. Additionally, we discovered that there exists a strong correlation between shRNA-mediated inhibition of HIV-1 production in a quantitative cell-based assay and very simple thermodynamic features in the SHAPE-directed RNA genome structure model. Both of these results are highly dependent on having an accurate secondary structural model, as obtained by SHAPE data. We anticipate that these results will be broadly applicable to RNA-directed antiretroviral development efforts.Doctor of Philosoph

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