Evolution and Diversity in Human Herpes Simplex Virus Genomes

Herpes simplex virus 1 (HSV-1) causes a chronic, lifelong infection in>60%of adults.Multiple recent vaccine trials have failed, with viral diversity likely contributing to these failures. To understandHSV-1 diversity better, we comprehensively compared 20 newly se-quenced viral genomes fromChina, Japan, Kenya, and SouthKoreawith six previously sequenced genomes from theUnited States, Europe, and Japan. In this diverse collection of passaged strains, we found that one-fifth of the newly sequencedmembers share a gene deletion and one-third exhibit homopolymeric frameshiftmutations (HFMs). Individual strains exhibit genotypic and potential phe-notypic variation viaHFMs, deletions, short sequence repeats, and single-nucleotide polymorphisms, although the protein sequence identity between strains exceeds 90%on average. In the first genome-scale analysis of positive selection inHSV-1, we found signs of selection in specific proteins and residues, including the fusion protein glycoproteinH.We also confirmedprevious results suggesting that recombination has occurredwith high frequency throughout theHSV-1 genome.Despite this, theHSV-1 strains analyzed clus-tered by geographic origin duringwhole-genomedistance analysis. These data shed light on likely routes ofHSV-1 adaptation to changing environments andwill aid in the selection of vaccine antigens that are invariantworldwide