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Abstract
HIV-1 has several mechanisms that can significantly impact its genetic diversity. A high rate of mutation coupled with a strong tolerance for sequence change has allowed HIV-1 to evolve a number of machineries to evade immune control. RNA secondary structure was recently found critical in directing recombination and replication mechanisms. In our work, we assessed existing RNA structure modeling technologies for HIV application and developed a novel RNA structure prediction pipeline. In our pipeline, to compliment different prediction strategies, we combined experimental and computational methods to optimize HIV RNA structure prediction accuracy. The pipeline was applied to examine recombination and replication mechanisms. Based on the comparison of B subtype derived from complete genomes and from the recombinants CRF07-08, we found RNA structure variations at VPR-ENV splice donor/acceptor sites and at the NEF/LTR region. To quantify the RNA structure space, we further developed a measurement that uses Shannon Entropy to capture the distribution of Boltzmann un-pairing probabilities. Through our quantification, we were able to estimate the ribosomal frameshift efficiency across various HIV subtypes. Our work revealed that the frameshift element can be clustered according to different subtypes, and recombinants of the two subtypes tend to have identical frameshift elements in both HIV populations. Potential association between frameshift efficiency and disease progression was observed. This work can help us address existing knowledge gaps on replication and recombination mechanisms that could lead to novel antiviral therapies and HIV/AIDS vaccines development.