Speaker
Description
A characteristic feature of HIV-1 is its ability to develop a diverse population that can adapt to hostile environments. The source of this diversity is often attributed to its high mutation rate, estimated to be around 5.0x10-5 mutations per site per round of replication (mut/site/rep). However, there is high variation in the observed mutation rates across published studies. It remains unclear to what extent these differences are a product of different experimental methods or natural variation in the mutation rate. To address this question, we developed a transduction-based method, coined ERR-Seq (Error Rate of Replication Sequencing), which measures the in vivo mutation rate and mutational profiles of any HIV-1 GagPol on any template sequence.
We performed 53 transduction replicates of the ERR-Seq assay using the HIV-1 NL4-3 GagPol on an NL4-3 Env transgene template, and observed high variation in the mutation rate with a rate of 7.2x10-5 mut/site/rep and a 95% CI of 2.2x10-5 to 1.8 x10-4 mut/site/rep, mirroring the variation observed across previously published measurements of the NL4-3 mutation rate. Across all transgenes, fewer than 0.1% were hypermutated, providing a modest increase to the total mutation rate. We measured the mutation rate of 14 additional HIV-1 strains (GagPols) on the NL4-3 Env template, recapitulating a similar distribution of mutation rates across genotypes. We evaluated the impact of 3 different HIV-1 Env templates on mutation rate and observed significant mutation rate differences between the 3 Env templates in aggregate and across the different sites in the Env templates. Our data demonstrate high mutation rate variation across different HIV-1 strains and within replicate transductions of the same virus genotype. This suggests that molecular factors (aside from template sequence context) that may drive HIV-1 mutation rate variation are yet to be described.
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