Recent discoveries on the origins of modern humans from multiple archaic hominin populations and the diversity of human papillomaviruses (HPVs) suggest a complex scenario of virus-host evolution. To evaluate the origin of HPV pathogenesis, we estimated the phylogeny, timing, and dispersal of HPV16 variants using a Bayesian Markov Chain Monte Carlo framework. To increase precision, we identified and characterized non-human primate papillomaviruses from New and Old World monkeys to set molecular clock models. We demonstrate specific host niche adaptation of primate papillomaviruses with subsequent coevolution with their primate hosts for at least 40 million years. Analyses of 212 HPV16 complete genomes and 3582 partial sequences estimated ancient divergence of HPV16 variants (between A and BCD lineages) from their most recent common ancestors around half a million years ago, roughly coinciding with the timing of the split between archaic Neanderthals and modern Homo sapiens, and nearly three times longer than divergence times of modern Homo sapiens. HPV16 A lineage variants were significantly underrepresented in present African populations, whereas the A sublineages were highly prevalent in European (A1-3) and Asian (A4) populations, indicative of viral sexual transmission from Neanderthals to modern non-African humans through multiple interbreeding events in the past 80 thousand years. Remarkably, the human leukocyte antigen B*07:02 and C*07:02 alleles associated with increased risk in cervix cancer represent introgressed regions from Neanderthals in present-day Eurasians. The archaic hominin-host-switch model was also supported by other HPV variants. Niche adaptation and virus-host codivergence appear to influence the pathogenesis of papillomaviruses.
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