Mutations in the monkeypox virus replication complex: Potential contributing factors to the 2022 outbreak

Saathvik R Kannan; Shrikesh Sachdev; Athreya S Reddy; Shree Lekha Kandasamy; Siddappa N Byrareddy; Christian L Lorson; Kamal Singh

doi:10.1016/j.jaut.2022.102928

Mutations in the monkeypox virus replication complex: Potential contributing factors to the 2022 outbreak

J Autoimmun. 2022 Dec:133:102928. doi: 10.1016/j.jaut.2022.102928. Epub 2022 Oct 14.

Authors

Saathvik R Kannan¹, Shrikesh Sachdev¹, Athreya S Reddy¹, Shree Lekha Kandasamy¹, Siddappa N Byrareddy², Christian L Lorson³, Kamal Singh⁴

Affiliations

¹ Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.
² Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
³ Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA.
⁴ Bond Life Sciences Center, University of Missouri, Columbia, MO, USA; Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden. Electronic address: singhka@missouri.edu.

Abstract

Attributes contributing to the current monkeypox virus (MPXV) outbreak remain unknown. It has been established that mutations in viral proteins may alter phenotype and pathogenicity. To assess if mutations in the MPXV DNA replication complex (RC) contribute to the outbreak, we conducted a temporal analysis of available MPXV sequences to identify mutations, generated a DNA replication complex (RC) using structures of related viral and eukaryotic proteins, and structure prediction method AlphaFold. Ten mutations within the RC were identified and mapped onto the RC to infer role of mutations. Two mutations in F8L (RC catalytic subunit), and two in G9R (a processivity factor) were ∼100% prevalent in the 2022 sequences. F8L mutation L108F emerged in 2022, whereas W411L emerged in 2018, and persisted in 2022. L108 is topologically located to enhance DNA binding affinity of F8L. Therefore, mutation L108F can change the fidelity, sensitivity to nucleoside inhibitors, and processivity of F8L. Surface exposed W411L likely affects the binding of regulatory factor(s). G9R mutations S30L and D88 N in G9R emerged in 2022, and may impact the interaction of G9R with E4R (uracil DNA glycosylase). The remaining six mutations that appeared in 2001, reverted to the first (1965 Rotterdam) isolate. Two nucleoside inhibitors brincidofovir and cidofovir have been approved for MPXV treatment. Cidofovir resistance in vaccinia virus is achieved by A314T and A684V mutations. Both A314 and A684 are conserved in MPXV. Therefore, resistance to these drugs in MPXV may arise through similar mechanisms.

Keywords: DNA replication complex; F8L; Family B polymerase; G9R; Monkeypox virus; Mutations.

MeSH terms

Mutation
Nucleosides*
Virus Replication* / genetics

Substances

Nucleosides