Relaxed molecular clock dating

We examined HIV-1 diversification patterns under immune selection from serial measures of HIV-1 envelope gene sequence diversity.We analyzed 1587 previously published HIV-1 whole envelope gene sequences obtained serially from 15 acutely infected individuals [27, 30–32].

Understanding the effect of strong immune selection on HIV-1’s molecular clock is of interest as selection is often thought to be a rate-changing factor [2, 29], driving a genealogy to depart from that of random evolution by placing preference for particular lineages and perturbing the molecular clock.While temporal diversification was consistent with evolution patterns in the absence of selection, mutations from the founder virus were highly clustered on statistically identified selection sites, which diversified more than 65 times faster than non-selection sites.By mathematically quantifying deviations from the molecular clock under various selection scenarios, we demonstrate that the deviation from a constant clock becomes negligible as multiple escape lineages emerge.Around 1 month post infection, the first CD8 T cell responses targeting the founder viruses lead to rapid viral escapes with amino acid changes in CD8 T cell epitope sequences at a rate as fast as 0.42 per day [24, 25].This rate implies that a minor mutant present in 5 % of the total viral population could become the dominant lineage making up 95 % of the population in just 2 weeks.

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