Evolution and Diversity in Human Herpes Simplex Virus Genomes

Abstract

gHerpes 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 understand HSV-1 diversity better, we comprehensively compared 20 newly sequenced viral genomes from China, Japan, Kenya, and South Korea with six previously sequenced genomes from the United States, Europe, and Japan. In this diverse collection of passaged strains, we found that one-fifth of the newly sequenced members share a gene deletion and one-third exhibit homopolymeric frameshift mutations (HFMs). Individual strains exhibit genotypic and potential phenotypic variation via HFMs, 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 in HSV-1, we found signs of selection in specific proteins and residues, including the fusion protein glycoprotein H. We also confirmed previous results suggesting that recombination has occurred with high frequency throughout the HSV-1 genome. Despite this, the HSV-1 strains analyzed clustered by geographic origin during whole-genome distance analysis. These data shed light on likely routes of HSV-1 adaptation to changing environments and will aid in the selection of vaccine antigens that are invariant worldwide. Herpes simplex virus 1 (HSV-1; species Human herpesvirus 1, genus Simplexvirus, subfamily Alphaherpesvirinae, family Herpesviridae, order Herpesvirales) is among the most successful human pathogens in terms of its global distribution, longevity in the host, and mild symptoms among the great majority of those exposed (1-4). HSV-1 is a large, enveloped DNA virus that infects lytically at epithelial surfaces and establishes a lifelong, latent infection in sensory neurons. HSV-1 infection produces a wide range of symptoms, ranging from few or none in many seropositive individuals to periodic lesions on epithelial surfaces in a significant proportion of people and to lethal encephalitis as an extreme manifestation in a few. There is no vaccine at present (5, 6). Studies in animal models have characterized the ways in which genetic variation between viral strains can influence the symptoms of pathology, including lesion severity and rates of reactivation from latency. The most recent phase III vaccine trial for HSV failed to provide protection from infection (7, 8), and one contributing factor to this failure may well be variation among HSV isolates found in the field.Based on early restriction fragment length polymorphism (RFLP) analyses, HSV-1 has been described as more diverse than HSV-2 (9-11). In contrast to both HSV-1 and HSV-2, the related human alphaherpesvirus, varicella-zoster virus (VZV), has relatively low interstrain diversity (12-15). Decades of research comparing RFLP bands, polypeptide size, and PCR-based sequence analysis have revealed that HSV-1 strains vary between individuals, over sequential isolates from the s...

Genetic diversity of equine herpesvirus 1 isolated from neurological, abortigenic and respiratory disease outbreaks

“…High‐throughput genome sequencing has provided evidence of recombination between strains in other herpesviruses, namely HSV‐2, VZV, Marek's disease virus, HSV‐1, pseudorabies virus, human cytomegalovirus and infectious laryngotracheitis virus (Hughes & Rivailler, 2007; Kolb, Larsen, Cuellar, & Brandt, 2015; Lee et al., 2013; Norberg et al., 2011, 2015; Sijmons et al., 2015; Szpara et al., 2014; Szpara, Tafuri, et al., 2011; Zell et al., 2012). In the present study, network analysis suggested that recombination has also occurred between EHV‐1 strains.…”

Correlation between clinical signs of feline conjunctivitis and molecular detection of felid herpesvirus-1, feline calicivirus, chlamydophila felis and mycoplasma felis in cats from shelters in Rio de Janeiro

“…Overall, the high prevalence of viral agents was not unexpected, and can be understood by their efficient mechanisms to escape from the immune system (MOCHIZUKI et al, 2000;SZPARA et al, 2014). What was really unexpected was the high occurrence of FHV-1 on asymptomatic kittens; it was the most common pathogen on animals of G1, and was detected on barely half of them.…”

Ancient recombination events between human herpes simplex viruses

“…We note here that early studies focused on recombination used PCR-based approaches and typically covered 2-4% of the genome; to our knowledge, they did not target any of the coding sequences in which we identified recombinant HSV-1 fragments (Bowden et al 2004;Norberg et al 2004Norberg et al , 2007. More recently, a number of studies have produced several dozens of HSV-1 and HSV-2 complete (or nearly complete) genomes which were used to examine genome-wide patterns of recombination (Kolb et al 2011(Kolb et al , 2013(Kolb et al , 2015Szpara et al 2014;Newman et al 2015). However, it seems that these studies only used single species alignments, which of course prevents the identification of interspecies recombination.…”

“…org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Szpara et al 2014;;Newman et al 2015), we first performed recombination analyses to identify regions with low recombination rate for further analyses. Although we indeed observed intraspecific recombination events (data not shown), we also identified a minimum of four HSV-1 fragments recombined within HSV-2 genomes.…”

“…HSV-1, however, has accumulated more variation than HSV-2 (maximum overall divergence 1.1% vs. 0.4%; Kolb et al 2011Kolb et al , 2013Kolb et al , 2015Szpara et al 2014;Newman et al 2015). Most HSV-2 open reading frames (ORF) exhibit little (if any) variability.…”