Mutations in the monkeypox virus replication complex: Potential contributing factors to the 2022 outbreak. Issue 133 (December 2022)

• Record Type: Journal Article
• Authors: Kannan, Saathvik R.; Sachdev, Shrikesh; Reddy, Athreya S.; Kandasamy, Shree Lekha; Byrareddy, Siddappa N.; Lorson, Christian L.; Singh, Kamal
• Is Part Of: Journal of autoimmunity. Issue 133(2022)
• Publication Date: 2022-12
• Subjects: Monkeypox virus -- Mutations -- DNA replication complex -- F8L -- G9R -- Family B polymerase; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2022.102928
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: L108F in MPXV DNA polymerase emerged in the 2022 outbreak. L108F can enhance DNA binding affinity, processivity and drug sensitivity of F8L. Mutation L108F can change the fidelity and sensitivity to nucleoside inhibitors. G9R mutations that emerged in 2022, are likely to affect interaction of G9R with E4R.