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Vaccinia Virus Infection & Temporal Analysis of Virus Gene Expression: Part 2
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Mutations in the monkeypox virus replication complex: Potential contributing factors to the 2022 outbreak.

Saathvik R Kannan1, Shrikesh Sachdev1, Athreya S Reddy1

  • 1Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.

Journal of Autoimmunity
|October 17, 2022
PubMed
Summary

Mutations in the monkeypox virus (MPXV) DNA replication complex (RC) may drive the current outbreak. Specific RC mutations, particularly in F8L and G9R, are prevalent in recent MPXV sequences, potentially impacting viral pathogenicity and drug resistance.

Keywords:
DNA replication complexF8LFamily B polymeraseG9RMonkeypox virusMutations

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Area of Science:

  • Virology
  • Molecular Biology
  • Structural Biology

Background:

  • The drivers of the current monkeypox virus (MPXV) outbreak are not fully understood.
  • Viral protein mutations can significantly alter virus phenotype and pathogenicity.

Purpose of the Study:

  • To investigate if mutations in the MPXV DNA replication complex (RC) contribute to the ongoing MPXV outbreak.
  • To identify and characterize novel mutations within the MPXV RC.

Main Methods:

  • Temporal analysis of MPXV sequences to identify mutations.
  • In silico generation of the MPXV DNA replication complex (RC) using protein structures and AlphaFold.
  • Mapping identified mutations onto the RC structure to infer functional impact.

Main Results:

  • Ten mutations within the MPXV RC were identified and mapped.
  • Two mutations in F8L (catalytic subunit) and two in G9R (processivity factor) showed high prevalence in 2022 sequences.
  • Newly emerged mutations in F8L (L108F) and G9R (S30L, D88N) may affect DNA binding, fidelity, and interactions with other viral proteins.
  • Potential mechanisms for resistance to MPXV nucleoside inhibitors (brincidofovir, cidofovir) were suggested based on conserved residues.

Conclusions:

  • Specific mutations in the MPXV DNA replication complex (RC) are associated with the 2022 outbreak.
  • These mutations likely influence MPXV replication, pathogenicity, and potentially antiviral drug resistance.
  • Further research is warranted to elucidate the precise roles of these RC mutations in MPXV evolution and virulence.