Evolutionary Origins of Human Herpes Simplex Viruses 1 and 2

Abstract

Herpesviruses have been infecting and codiverging with their vertebrate hosts for hundreds of millions of years. The primate simplex viruses exemplify this pattern of virus-host codivergence, at a minimum, as far back as the most recent common ancestor of New World monkeys, Old World monkeys, and apes. Humans are the only primate species known to be infected with two distinct herpes simplex viruses: HSV-1 and HSV-2. Human herpes simplex viruses are ubiquitous, with over two-thirds of the human population infected by at least one virus. Here, we investigated whether the additional human simplex virus is the result of ancient viral lineage duplication or cross-species transmission. We found that standard phylogenetic models of nucleotide substitution are inadequate for distinguishing among these competing hypotheses; the extent of synonymous substitutions causes a substantial underestimation of the lengths of some of the branches in the phylogeny, consistent with observations in other viruses (e.g., avian influenza, Ebola, and coronaviruses). To more accurately estimate ancient viral divergence times, we applied a branch-site random effects likelihood model of molecular evolution that allows the strength of natural selection to vary across both the viral phylogeny and the gene alignment. This selection-informed model favored a scenario in which HSV-1 is the result of ancient codivergence and HSV-2 arose from a cross-species transmission event from the ancestor of modern chimpanzees to an extinct Homo precursor of modern humans, around 1.6 Ma. These results provide a new framework for understanding human herpes simplex virus evolution and demonstrate the importance of using selection-informed models of sequence evolution when investigating viral origin hypotheses.

Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2

“…Possible explanations for the differences in genome diversity between HSV-1 and HSV-2 could be (i) that HSV-2 entered the human population later than HSV-1 and has not borne the cumulative selection pressures that HSV-1 has endured or (ii) that differences between HSV-1 and HSV-2 infection rates and age at the time of infection could lead to fewer opportunities for divergence and recombination in HSV-2. Recent analysis of the evolutionary origins of HSV-1 and HSV-2 supports the idea that HSV-2 entered the human lineage through divergence from ChHV only around 1.6 million years ago, while HSV-1 diverged from ChHV about 6 million years ago (15). However, the increased worldwide prevalence of HSV-1 compared to HSV-2 (36) and subsequent interaction with host selective pressures could also account for the increased sequence diversity seen in HSV-1.…”

“…However, using molecular dating, a recent study concluded that HSV-1 diverged from ChHV about 6 million years ago but that HSV-2 diverged from ChHV only 1.6 million years ago. The authors hypothesized that the latter occurred in a second, independent transmission to humans (15).…”

Alphaherpesvirus: Isolation, Identification, Partial Characterisation, Associated Pathologic Findings and Epidemiology in Beluga Whales (Delphinapterus leucas) in Alaska and Arctic Canada

“…It is likely that BWHV is enzootic in beluga populations world-wide given that alphaherpesviruses are known to persistently infect their hosts and co-diverge with them over millions of years as is the case with the human herpes simplex viruses HV-1 and HV-2 (Wertheim et al 2014). Beluga populations have a circumpolar distribution and there is a likelihood of contact between individuals from different populations during migration to allow for the spread of the virus.…”

Ancient recombination events between human herpes simplex viruses

“…doi:10.1093/molbev/msx113 MBE a putative transmission from chimpanzees to the human lineage (Wertheim et al 2014), HSV-2 diversified in African populations before a single lineage characterized by recombinant HSV-1 fragments (the worldwide lineage) accompanied the migration of Homo sapiens out of Africa. African HSV-2 belonging to the worldwide lineage may be the result of later contacts to nonAfrican populations.…”

“…doi:10.1093/molbev/msx113 MBE My; Wertheim et al 2014) (Whole genome 2); or using the substitution rate derived from the analysis of Whole genome 2 (7 Â 10 À2 substitutions site À1 My À1 ; 95% highest posterior density: 6-8 Â 10 À2 substitutions site À1 My À1 ) to inform the clock rate with a normal distribution of mean 7 Â 10 À2 substitutions site À1 My À1 and standard deviation 7 Â 10 À3 substitutions site À1 My À1 (95% CI: 6-8 Â 10 À2 substitutions site À1 My À1 ). In both cases, the overall model also included a tree shape component, for which we used a coalescent model assuming a constant population size.…”