Herpesvirus DNA Polymerase Mutants—How Important Is Faithful Genome Replication?

Trimpert, Jakob; Osterrieder, Nikolaus

doi:10.1007/s40588-019-00135-2

Cited by 4 publications

(1 citation statement)

References 70 publications

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“…The DNApol gene is thus one of the most conserved genes in herpesviral genomes and likely to be under strong purifying selection with a low substitution rate. Nevertheless, any mutations found in these domains are typically associated with lower replication fidelity (see review: [ 25 ]), contributing to higher mutation rates. If some of these mutations are beneficial to virus replication efficiency, they can, in turn, result in faster evolution rates [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Infection with a Recently Discovered Gammaherpesvirus Variant in European Badgers, Meles meles, is Associated with Higher Relative Viral Loads in Blood

et al. 2022

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Herpesviruses are ubiquitous pathogens infecting most animals. Although host immunity continually coevolves to combat virulence, viral variants with enhanced transmissibility or virulence occasionally emerge, resulting in disease burdens in host populations. Mustelid gammaherpesvirus 1 (MusGHV-1) is the only herpesvirus species identified thus far in European badgers, Meles meles. No MusGHV-1 associated pathomorbidity has been reported, but reactivation of MusGHV-1 in genital tracts is linked to impaired female reproductive success. An analysis of a short sequence from the highly conserved DNA polymerase (DNApol) gene previously identified two variants in a single host population. Here we compared genetic variance in blood samples from 66 known individuals of this same free-ranging badger population using a partial sequence comprising 2874 nucleotides of the DNApol gene, among which we identified 15 nucleotide differences resulting in 5 amino acid differences. Prevalence was 86% (59/66) for the common and 17% (11/66) for the novel variant, with 6% (4/66) of badgers presenting with coinfection. MusGHV-1 variants were distributed unevenly across the population, with individuals infected with the novel genotype clustered in 3 of 25 contiguous social groups. Individuals infected with the novel variant had significantly higher MusGHV-1 viral loads in their blood (p = 0.002) after adjusting for age (juveniles > adults, p < 0.001) and season (summer > spring and autumn, p = 0.005; mixed-effect linear regression), likely indicating higher virulence of the novel variant. Further genome-wide analyses of MusGHV-1 host resistance genes and host phenotypic variations are required to clarify the drivers and sequelae of this new MusGHV-1 variant.

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Section: Introductionmentioning

confidence: 99%

Infection with a Recently Discovered Gammaherpesvirus Variant in European Badgers, Meles meles, is Associated with Higher Relative Viral Loads in Blood

et al. 2022

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Evolutionary Dynamics of Accelerated Antiviral Resistance Development in Hypermutator Herpesvirus

Höfler,

Nascimento,

Zeitlow

et al. 2024

Molecular Biology and Evolution

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Antiviral therapy is constantly challenged by the emergence of resistant pathogens. At the same time, experimental approaches to understand and predict resistance are limited by long periods required for evolutionary processes. Here, we present a herpes simplex virus 1 mutant with impaired proofreading capacity and consequently elevated mutation rates. Comparing this hypermutator to parental wild type virus, we study the evolution of antiviral drug resistance in vitro. We model resistance development and elucidate underlying genetic changes against three antiviral substances. Our analyzes reveal no principle difference in the evolutionary behavior of both viruses, adaptive processes are overall similar, however significantly accelerated for the hypermutator. We conclude that hypermutator viruses are useful for modeling adaptation to antiviral therapy. They offer the benefit of expedited adaptation without introducing apparent bias and can therefore serve as an accelerator to predict natural evolution.

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Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus

et al. 2022

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Evolution relies on the availability of genetic diversity for fitness-based selection. However, most DNA viruses employ DNA polymerases capable of exonucleolytic proofreading to limit mutation rates during DNA replication. The relative genetic stability produced by high fidelity genome replication can make studying DNA virus adaptation and evolution an intensive endeavor, especially in slowly replicating viruses. Here, we present a proofreading impaired polymerase mutant (Y547S) of Marek’s disease virus that exhibits a hypermutator phenotype while maintaining unimpaired growth in vitro and wild-type (WT)-like pathogenicity in vivo. At the same time, mutation frequencies observed in Y547S virus populations are 2–5 fold higher compared to the parental WT virus. We find that Y547S adapts faster to growth in originally non-permissive cells, evades pressure conferred by antiviral inhibitors more efficiently, and is more easily attenuated by serial passage in cultured cells when compared to WT. Our results suggest that hypermutator viruses can serve as a tool to accelerate evolutionary processes and help identify key genetic changes required for adaptation to novel host cells and resistance to antiviral therapy. Similarly, the rapid attenuation achieved through adaption of hypermutators to growth in cell culture enables identification of genetic chances underlying attenuation and virulence, knowledge that could practically exploited, for example in the rational design of vaccines.

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Herpesvirus DNA Polymerase Mutants—How Important Is Faithful Genome Replication?

Cited by 4 publications

References 70 publications

Infection with a Recently Discovered Gammaherpesvirus Variant in European Badgers, Meles meles, is Associated with Higher Relative Viral Loads in Blood

Infection with a Recently Discovered Gammaherpesvirus Variant in European Badgers, Meles meles, is Associated with Higher Relative Viral Loads in Blood

Evolutionary Dynamics of Accelerated Antiviral Resistance Development in Hypermutator Herpesvirus

Fast-forwarding evolution—Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus

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