Relaxed molecular clock dating updating ntext
The most recent common ancestor of a virus pair from distinct escape lineages is most likely the transmitted founder virus, indicating that HIV-1 molecular dating is feasible even after the founder viruses are no longer detectable.
The ability of HIV-1 to escape from immune surveillance in many different directions is the driving force of molecular clock persistence.
This finding advances our understanding of the robustness of HIV-1’s molecular clock under immune selection, implying the potential for molecular dating.
The molecular clock serves as a focal link between molecular evolution at a microscopic level and species evolution at a macroscopic level [1, 2].
Estimates on the timing of infection can help us define immune correlates for protection using data from HIV-1 vaccine and prevention trials; for instance, knowledge of the time of HIV-1 acquisition will be important in determining the antibody titer threshold for protection in the Antibody Mediated Prevention (AMP) study .
Furthermore, the ability to molecularly date the HIV-1 gene pool expands the opportunity to determine HIV-1 incidence using recently developed genomic assays [8, 9].
Figure 1a plots HIV-1 envelope gene sequence diversity dynamics during the 150 days following the first sample.
To avoid the uncertainty of when each subject’s first sample was taken, all subsequent data points are presented in terms of the increase in diversity and the time following the first sample. a Diversity increase as a function of time for the first 150 days since the first sample for 15 HIV-1 infected individuals, CAP045, CH040, CH042, CH058, CH077, CH131, CH159, CH162, CH164, CH185, CH198, CH256, CH505, SUMA0874 and WEAU0578.
This dynamic phase is a period of heightened immune selection pressure, which commences an evolutionary arms race between the virus and the immune system.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].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.
Search for relaxed molecular clock dating:
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.