Abstract
We performed whole genome sequencing of a cidofovir {[(S)-1-(3-hydroxy-2-phosphonylmethoxy-propyl) cytosine] [HPMPC]}-resistant (CDV-R) strain of Monkeypoxvirus (MPV). Whole-genome comparison with the wild-type (WT) strain revealed 55 single-nucleotide polymorphisms (SNPs) and one tandem-repeat contraction. Over one-third of all identified SNPs were located within genes comprising the poxvirus replication complex, including the DNA polymerase, RNA polymerase, mRNA capping methyltransferase, DNA processivity factor, and poly-A polymerase. Four polymorphic sites were found within the DNA polymerase gene. DNA polymerase mutations observed at positions 314 and 684 in MPV were consistent with CDV-R loci previously identified in Vaccinia virus (VACV). These data suggest the mechanism of CDV resistance may be highly conserved across Orthopoxvirus (OPV) species. SNPs were also identified within virulence genes such as the A-type inclusion protein, serine protease inhibitor-like protein SPI-3, Schlafen ATPase and thymidylate kinase, among others. Aberrant chain extension induced by CDV may lead to diverse alterations in gene expression and viral replication that may result in both adaptive and attenuating mutations. Defining the potential contribution of substitutions in the replication complex and RNA processing machinery reported here may yield further insight into CDV resistance and may augment current therapeutic development strategies.
Highlights
Poxviruses are large, enveloped, pleomorphic dsDNA viruses that infect a diverse array of mammals, reptiles, and insects [1]
Over a third of all observed single-nucleotide polymorphisms (SNPs) occurred within genes involved in virus replication and DNA metabolism
Five early proteins are essential for poxvirus DNA replication, including the DNA polymerase (E9), DNA-independent nucleoside triphosphatase (NTPase, D5), uracil DNA glycosylase (D4), protein kinase B1, and DNA processivity factor (VPF/A20) [19,6]
Summary
Poxviruses are large, enveloped, pleomorphic dsDNA viruses that infect a diverse array of mammals, reptiles, and insects [1]. The causative agent of Smallpox, Variola virus (VARV) is a member of the OPV genus. Smallpox was declared eradicated in 1980, natural or illicit re-emergence poses a risk for a growing non-vaccinated population [2]. MPV is a re-emerging pathogen within the OPV genus that causes sporadic outbreaks in monkeys and humans in West and Central Africa and, recently, in North America [3]. MPV can cause human disease clinically similar to Smallpox but with lower morbidity and mortality rates [4]. Terrestrial and arboreal rodents and mammals are thought to play a role in MPV transmission, human to human transmission is known to occur [5]
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