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Spontaneous Mutations in HIV-1 Gag, protease, RT p66 in the first replication cycle and how they appear: Insights from an in vitro BSL2 assay on mutation rates and types

By Joshua Yi Yeo, Darius Wen-Shuo Koh, Ping Yap, Ghin-Ray Goh, Samuel KE Gan

Posted 23 Jun 2019
bioRxiv DOI: 10.1101/679852

While drug resistant mutations in HIV-1 is largely credited to its error prone HIV-1 RT, host proteins such as deaminases may also play a role generating mutations. Many HIV-1 RT mutational in vitro studies utilize reporter genes (LacZ) as template, leaving out the possible contribution of HIV codon usage and gene-specific effects. To address this gap, we studied HIV-1 RT mutation rates and bias on its own Gag, protease, and RT p66 genes in an in-vitro selection pressure free system. We found rare clinical mutations with a general avoidance of crucial functional sites in the background mutations rates for Gag, protease and RT p66 at 4.71 x 10−5, 6.03 x 10−5, and 7.09 x 10−5 mutations/bp respectively. Gag and p66 genes showed a large number of ‘A to G’ hypermutations likely due to cellular adenosine deaminases. Comparisons with silently mutated p66 sequences showed an increase in mutation rates (1.88 x 10−4 mutations/bp) and that ‘A to G’ mutations occurred in regions reminiscent of ADAR neighbour preferences. Mutational free energies by the ‘A to G’ mutations revealed an avoidance of destabilizing effects with the natural p66 gene codon usage providing barriers to ADAR effects. Our study demonstrates the importance of studying mutation emergence in HIV genes to understand how fast drug resistance can emerge, sometimes with contributions of host deaminases, providing transferable applications to how new viral diseases and drug resistances can emerge. ### Competing Interest Statement The authors have declared no competing interest.

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