Comparison of HSV-1 strains circulating in Finland demonstrates the uncoupling of whole-genome relatedness and phenotypic outcomes of viral infection

Bowen, Christopher D.; Paavilainen, Henrik; Renner, Daniel W.; Palomäki, Jussi; Lehtinen, Jenni; Vuorinen, Tytti; Norberg, Peter; Hukkanen, Veijo; Szpara, Moriah L.

doi:10.1101/424408

Cited by 9 publications

(12 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, given that transgenic s17 also fails to spread extracellularly, it follows that any viruses built in to this backbone are also likely to have this release phenotype. should be noted that recent studies on ten random clinical HSV1 strains isolated in Finland indicated that while these viruses replicated with lower efficiencies than strain 17 syn+ in all cell types tested, and therefore also released fewer virions, the overall proportion of released virus was similar and in some cases higher than strain 17 syn+ [33]. While the nature of the assays carried out in those studies was different to our own (high multiplicity versus spread at low multiplicity respectively), further studies will be required to determine the relationship between efficient virus release and propagation in cell culture.…”

Section: Resultsmentioning

confidence: 82%

“…Such analyses do not prove that either or both of these variations are responsible for the defective release phenotype of these viruses, but it is interesting to note that UL26 encodes a protease which although characterized to be involved in capsid assembly, may nonetheless has the potential to have other activities during infection such as facilitating virus release from the cell surface. Although it has not yet been possible to directly correlate intrastrain genetic changes with phenotypic changes in these viruses, it should be noted that a recent study of clinical isolates also failed to identify sequences that would be predictive for phenotypic differences of virus replication and release [33], suggesting that these phenotypes are complex and multifactorial.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Genetic and phenotypic intrastrain variation in herpes simplex virus type 1 Glasgow strain 17 syn+-derived viruses

Jones

Depledge

Breuer

et al. 2019

Journal of General Virology

View full text Add to dashboard Cite

The Glasgow s17 syn+ strain of herpes simplex virus 1 (HSV1) is arguably the best characterised strain and has provided the reference sequence for HSV1 genetic studies. Here we show that our original s17 syn+ stock was a mixed population from which we have isolated a minor variant that, unlike other strains in the laboratory, fails to be efficiently released from infected cells and spreads predominantly by direct cellto-cell transmission. Analysis of other s17-derived viruses that had been isolated elsewhere revealed a number with the same release phenotype. Second generation sequencing of eight plaque-purified s17-derived viruses revealed sequences that vary by 50 SNPs including approximately 10 coding SNPs. This compared to interstrain variations of around 800 SNPs in strain Sc16, of which a quarter were coding changes. Amongst the variations found within s17, we identified thirteen variants of glycoprotein C within the original stock of virus which were predominantly a consequence of altered homopolymeric runs of C residues. Characterisation of seven isolates coding for different forms of gC indicated that all were expressed, despite six of them lacking a transmembrane domain. While the release phenotype did not correlate directly with any of these identified gC variations, further demonstration that nine clinical isolates of HSV1 also fail to spread through extracellular release raises the possibility that propagation in tissue culture had altered the HSV1 s17 transmission phenotype. Hence, this s17 intrastrain variation identified here offers an excellent model for understanding both HSV1 transmission and tissue culture adaptation.

show abstract

Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Genetic and phenotypic intrastrain variation in herpes simplex virus type 1 Glasgow strain 17 syn+-derived viruses

Jones

Depledge

Breuer

et al. 2019

Journal of General Virology

View full text Add to dashboard Cite

show abstract

“…These and other circulating HSV-1 strains have numerous genetic differences [83][84][85], which have been proposed to impact observed phenotypic differences in HSV pathogenesis [86][87][88] and spread [89]. Many TUs containing HSV-1 glycoprotein transcripts (e.g., US5, US6, US7, US8, and UL44) demonstrated higher expression in F-and McKrae-infected neurons versus KOS-infected neurons (Figs 3B and 4).…”

Section: Plos Pathogensmentioning

confidence: 99%

Viral infection of human neurons triggers strain-specific differences in host neuronal and viral transcriptomes

et al. 2021

Self Cite

View full text Add to dashboard Cite

Infection with herpes simplex virus 1 (HSV-1) occurs in over half the global population, causing recurrent orofacial and/or genital lesions. Individual strains of HSV-1 demonstrate differences in neurovirulence in vivo, suggesting that viral genetic differences may impact phenotype. Here differentiated SH-SY5Y human neuronal cells were infected with one of three HSV-1 strains known to differ in neurovirulence in vivo. Host and viral RNA were sequenced simultaneously, revealing strain-specific differences in both viral and host transcription in infected neurons. Neuronal morphology and immunofluorescence data highlight the pathological changes in neuronal cytoarchitecture induced by HSV-1 infection, which may reflect host transcriptional changes in pathways associated with adherens junctions, integrin signaling, and others. Comparison of viral protein levels in neurons and epithelial cells demonstrated that a number of differences were neuron-specific, suggesting that strain-to-strain variations in host and virus transcription are cell type-dependent. Together, these data demonstrate the importance of studying virus strain- and cell-type-specific factors that may contribute to neurovirulence in vivo, and highlight the specificity of HSV-1–host interactions.

show abstract

“…Minor variants (MVs) within each genome were detected using VarScan 2.4.2 [60], in a similar manner as previously described [11,12,61]. We used parameters intended to eliminate sequencing-induced errors from the initial calling of MVs.…”

Section: Methodsmentioning

confidence: 99%

In vitroevolution of herpes simplex virus 1 (HSV-1) reveals selection for syncytia and other minor variants in Vero cell culture

Kuny

Bowen

Renner

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

AbstractThe large dsDNA virus HSV-1 is often considered to be genetically stable, however it is known to rapidly evolve in response to strong selective pressures such as antiviral drug treatment. Deep sequencing analysis has revealed that clinical and laboratory isolates of this virus exist as populations that contain a mixture of minor alleles or variants, similar to many RNA viruses. Classical virology methods often used plaque-purified virus populations to demonstrate consistent genetic inheritance of viral traits. Plaque purification represents a severe genetic bottleneck which may or may not be representative of natural transmission of HSV-1. Since HSV-1 has a low error rate polymerase but exhibits substantial genetic diversity, the virus likely uses other mechanisms to generate genetic diversity, including recombination, contraction and expansion of tandem repeats, and imprecise DNA repair mechanisms. We sought to study the evolution of HSV-1 in vitro, to examine the impact of this genetic diversity in evolution, in the setting of standard laboratory conditions for viral cell culture, and in the absence of strong selective pressures. We found that a mixed population of HSV-1 was more able to evolve and adapt in culture than a plaque-purified population, though this adaptation generally occurred in a minority of the viral population. We found that certain genetic variants appeared to be positively selected for rapid growth and spread in Vero cell culture, a phenotype which was also observed in clinical samples during their first passages in culture. In the case of a minor variant that induces a visually observable syncytial phenotype, we found that changes in minor variant frequency can have a large effect on the overall phenotype of a viral population.Author SummaryHerpes simplex virus type 1 (HSV-1) is a common virus, affecting over half of the adult human population, although it presents variable levels of disease burden and frequency of symptomatic recurrence. Antiviral treatments for HSV-1 infections are available, but thus far attempts at vaccine development have been foiled by insufficient immunity and/or viral escape. As a virus with a double-stranded DNA genome, HSV-1 is generally considered to be genetically stable and to have limited evolutionary potential. As these two statements are in conflict, we examined the ability of HSV-1 to evolve in a standardized cell culture setting. We utilized two HSV-1 isolates in this experiment, one with multiple viral genotypes present, which is similar to the viral populations seen in clinical settings, and one with a highly clonal viral population, which is similar to those often used in laboratory settings. After multiple rounds of replication, we analyzed the sequences of each passaged population. We found that the mixed viral population changed substantially over passage, and we were able to track specific genetic variants to phenotypic traits. By comparison, evolution in the clonal virus population was more limited. These data indicate that HSV-1 is capable of evolving rapidly, and that this evolution is facilitated by diversity in the viral population.

show abstract

Comparison of HSV-1 strains circulating in Finland demonstrates the uncoupling of whole-genome relatedness and phenotypic outcomes of viral infection

Cited by 9 publications

References 50 publications

Genetic and phenotypic intrastrain variation in herpes simplex virus type 1 Glasgow strain 17 syn+-derived viruses

Genetic and phenotypic intrastrain variation in herpes simplex virus type 1 Glasgow strain 17 syn+-derived viruses

Viral infection of human neurons triggers strain-specific differences in host neuronal and viral transcriptomes

In vitroevolution of herpes simplex virus 1 (HSV-1) reveals selection for syncytia and other minor variants in Vero cell culture

Contact Info

Product

Resources

About