Publikationsdatenbank

On fidelity, adaptation and reproduction:
a study of hypermutation in herpes simplex virus 1 (2024)

Art

Hochschulschrift

Autor

Höfler, Thomas (WE 5)

Quelle

Berlin, 2024 — 144 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/45742

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Balancing mutation rates always comes with trade-offs. Often deleterious or even lethal, mutations also produce the necessary genetic diversity to fuel evolution by natural selection. Many factors influence viral mutation rates; however, replicative polymerases play an essential role. Large dsDNA viruses, like herpesviruses, encode a DNA-polymerase with intrinsic 3’-5’ exonuclease (Exo) activity, increasing replication fidelity by orders of magnitude. Abolishing this proofreading consequently yields viral populations with increased mutation rates. Here we described the first successful reconstitution of proofreading deficient herpes simplex type 1 viruses. Although those viruses are initially viable, we found that after a few passages they accumulate huge mutational loads that interfere with productive viral replication. Especially deleterious mutations in major variants map specifically to essential gene sets important for nucleic acid metabolism, structural proteins and others. Notably, mild effects on proofreading conferred by Exo III mutant Y557S (YS) did increase mutation rates but yielded populations with wild type (wt) like replication kinetics. To follow up on the adaptability of mild hypermutators we passaged both wt and YS under antiviral pressure to screen for resistance mutations. We observed faster resistance development in YS by about 5-10 passages. This increase in adaptability is due to 2-3 times more mutations occurring in YS populations compared to wt. Importantly, we could detect no general differences in the underlying evolutionary processes. Furthermore, changing selection pressures shed light on the importance of standing genetic variation, especially in populations that already plateaued in their phenotypes. Finally, within population diversity on a phenotypic and genetic level is vastly increased in YS populations. Taken together we managed to explore the limits of hypermutation in herpes simplex type 1. Marginal increases in their mutation rates lead to greater adaptability which in turn can be employed to speed up evolutionary processes for experimental applications without compromising the underlying mechanism. However, increases beyond that, mediated by abolishing proofreading completely, lead to lethal mutagenesis and suicidal phenotypes. So far lethal mutagenesis is a process exclusively described for RNA virus populations. Defining the circumstances for lethal mutagenesis in herpes simplex virus type 1 might be interesting for future antiviral developments. Especially combination of replicative in concert with Exo inhibitors might yield promising antiviral therapies.