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The SAMHD1 knockout mouse model: in vivo veritas?

Ferdinand Roesch, Olivier Schwartz

Author Affiliations

  • Ferdinand Roesch, 1 Institut Pasteur, Department of Virology; CNRS; and Université Paris Diderot, Sorbonne Paris Cité, Paris, France
  • Olivier Schwartz, 1 Institut Pasteur, Department of Virology; CNRS; and Université Paris Diderot, Sorbonne Paris Cité, Paris, France

SAMHD1, a dNTP hydrolase mutated in the autoimmune encephalopathy Aicardi‐Goutières syndrome, restricts HIV replication in non‐dividing human cells by reducing intracellular deoxyribonucleotide pools. New work in The EMBO Journal unexpectedly finds neither autoimmune disease nor increased murine retrovirus infection in SAMHD1 knockout mice, but improved replication of a mutant HIV with increased sensitivity to low dNTP levels. Thus, while the new mouse model partially recapitulates known features of human SAMHD1, it represents a unique tool to study the role of dNTP regulation during inflammation, viral infection and other pathologies.

Upon entry into host cells, viruses encounter a powerful line of antiviral defence called intrinsic immunity, which includes proteins referred to as restriction factors. In the case of HIV‐1, several restriction factors have been identified that inhibit the viral life cycle in different ways: APOBEC3G induces G‐to‐A hypermutation of the viral genome; TRIM5α perturbs uncoating of viral cores; BST2/tetherin retains viral particles at the surface of infected cells; IFITM family proteins inhibit membrane hemifusion and viral entry; and Schlafen11 perturbs HIV protein synthesis by binding to tRNAs and altering codon usage. Finally, the dNTP hydrolase SAMHD1 acts to deplete the intracellular pool of nucleotides available for viral DNA synthesis by reverse transcriptase (RT) (Hrecka et al, 2011; Laguette et al, 2011; Lahouassa et al, 2012). HIV has evolved strategies to overcome the imposed replicative block by most of these restriction factors, often by triggering proteasomal degradation of the inhibitory factor. In the case of SAMHD1, the Vpx protein encoded by both HIV‐2 and SIV hijacks a host cell ubiquitin ligase complex to target SAMHD1 for degradation. In contrast, HIV‐1 lacks Vpx and is therefore unable to overcome …

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