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.

Keywords: co-divergence; cross-species transmission; homo; molecular clock; selection; zoonosis.

Fig. 1.

General pattern of codivergence for primate herpes simplex viruses and their Simiiforme hosts. Underlined viral taxa indicate phylogenetic incongruence, implying cross-species transmission events. Dashed lines connect virus to host species.

Fig. 2.

Evolutionary scenarios that could produce the human and chimpanzee herpes simplex virus phylogeny via viral duplication within a host lineage. Hypothetical unobserved viruses are shown in gray. Nodes representing the common ancestor of humans and chimpanzees, around 6 Ma, are indicated with asterisks. All scenarios imply a 6 Ma tMRCA for HSV-2/ChHV and a tMRCA >6 Ma for HSV-1/ChHV. (A) Viral duplication prior to the diversification of apes. (B) Viral duplication prior to the diversification of the great apes. (C) Viral duplication prior to the diversification of the African apes. (D) Viral duplication prior to the split between the Homo and Pan genera.

Fig. 3.

Evolutionary scenarios that could produce the human and chimpanzee herpes simplex virus phylogeny via viral cross-species transmission. Hypothetical unobserved viruses are shown in gray. Nodes representing the common ancestor of humans and chimpanzees, around 6 Ma, are indicated with asterisks. Scenarios A–C imply a 6 Ma tMRCA for HSV-2/ChHV and a tMRCA >6 Ma for HSV-1/ChHV, whereas scenarios D–F imply a 6 Ma tMRCA for HSV-1/ChHV and a tMRCA <6 Ma for HSV-2/ChHV. (A) Cross-species transmission of a gibbon virus to a human ancestor, giving rise to HSV-1. (B) Cross-species transmission of an orangutan virus to a human ancestor, giving rise to HSV-1. (C) Cross-species transmission of a gorilla virus to a human ancestor, giving rise to HSV-1. (D) Cross-species transmission of a virus infecting a Pan ancestor to a human ancestor, giving rise to HSV-2. (E) Cross-species transmission of a chimpanzee virus to a human ancestor, giving rise to HSV-2. (F) Cross-species transmission of a bonobo virus to a human ancestor, giving rise to HSV-2.

Fig. 4.

Posterior distributions of the tMRCAs for HSV-1/ChHV and HSV-2/ChHV in BMCMC analysis. (A) Concatenated glycoprotein tMRCA estimates. (B) gB tMRCA estimates. Shaded regions depict the 95% highest posterior densities. The vertical dashed line represents the divergence between humans and chimpanzees around 6 Ma.

Fig. 5.

Branch length expansion under BSREL relative to GTR + Γ₄ substitution model in the gB phylogeny. (A) Maximum likelihood tree with branch lengths estimated under GTR + Γ₄. HSV-1 and HSV-2 clades are collapsed. (B) Maximum likelihood tree with branch lengths re-estimated under BSREL. Branches determined by cAIC to support multiple dN/dS classes are colored, and the HSV-1 and HSV-2 clades are collapsed. Both trees are shown on the same scale. (C) Comparison of branches inferred under BSREL and GTR + Γ₄. Branches determined by cAIC to support multiple dN/dS classes are filled. All other branches supported only a single dN/dS class. The dashed line depicts x = y.