A viral kinase counteracts in vivo restriction of murine cytomegalovirus by SAMHD1

Nat Microbiol. 2019 Dec;4(12):2273-2284. doi: 10.1038/s41564-019-0529-z. Epub 2019 Sep 23.


The deoxynucleotide triphosphate (dNTP) hydrolase SAMHD1 inhibits retroviruses in non-dividing myeloid cells. Although antiviral activity towards DNA viruses has also been demonstrated, the role of SAMHD1 during cytomegalovirus (CMV) infection remains unclear. To determine the impact of SAMHD1 on the replication of CMV, we used murine CMV (MCMV) to infect a previously established SAMHD1 knockout mouse model and found that SAMHD1 inhibits the replication of MCMV in vivo. By comparing the replication of MCMV in vitro in myeloid cells and fibroblasts from SAMHD1-knockout and control mice, we found that the viral kinase M97 counteracts SAMHD1 after infection by phosphorylating the regulatory residue threonine 603. The phosphorylation of SAMHD1 in infected cells correlated with a reduced level of dNTP hydrolase activity and the loss of viral restriction. Together, we demonstrate that SAMHD1 acts as a restriction factor in vivo and we identify the M97-mediated phosphorylation of SAMHD1 as a previously undescribed viral countermeasure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Colony-Stimulating Factors / metabolism
  • Disease Models, Animal
  • HEK293 Cells
  • Herpesviridae Infections / drug therapy
  • Herpesviridae Infections / virology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muromegalovirus / drug effects*
  • Muromegalovirus / enzymology
  • Muromegalovirus / growth & development
  • NIH 3T3 Cells
  • Phosphorylation
  • Phosphotransferases / metabolism*
  • Recombinant Proteins
  • SAM Domain and HD Domain-Containing Protein 1 / antagonists & inhibitors*
  • SAM Domain and HD Domain-Containing Protein 1 / genetics
  • SAM Domain and HD Domain-Containing Protein 1 / metabolism*
  • Transcriptome
  • Viral Proteins / metabolism
  • Virus Replication / drug effects


  • Antiviral Agents
  • Colony-Stimulating Factors
  • M97 protein, Mouse cytomegalovirus
  • Recombinant Proteins
  • Viral Proteins
  • Phosphotransferases
  • SAM Domain and HD Domain-Containing Protein 1
  • Samhd1 protein, mouse