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

Purpose of Review: This report broaches the topic of altered fidelity of DNA replication in herpesvirus mutants described over the past decades. Reduced genome replication fidelity of herpesvirus exonuclease mutants allows studying of virus population dynamics in the absence of exonucleolytic proofreading and can inform us on virus evolution in the face of error-prone genome replication. Recent Findings: We recently found that mutations previously described to be lethal for herpes simplex type 1 (HSV-1) caused error-prone genome replication in Marek’s disease virus. This has allowed us to study the influence of augmented genetic diversity on viral population dynamics, replicative fitness, and virulence. Summary: We conclude that the use of herpesvirus fidelity mutants allows unprecedented insights into virus evolution driven by low-fidelity replication. More than that, their use allows us to observe accelerated evolution, potentially enabling time-saving screens for the rise of drug- or vaccine-resistant mutants. In addition, we can infer that lethal or suicidal phenotypes observed in low-fidelity herpesvirus mutants are likely a consequence of error-prone genome replication, ultimately leading to lethal mutagenesis of small and isolated virus populations in cell culture.