The SAMHD1 knockout mouse model: in vivo veritas?

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; TRIM5a 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 SAMHD1 restriction, explaining why infection of myeloid cells and resting CD4þ T cells is a poorly efficient process (Baldauf et al, 2012; Descours et al, 2012). While it is unclear why HIV-1 did not evolve antiSAMHD1 strategies too, reduced HIV-1 infection of dendritic cells appears to be beneficial by allowing viral escape from immune detection (Puigdomenech et al, 2013). In addition to HIV-1, a large panel of other retroviruses (Gramberg et al, 2013) as well as DNA viruses such as vaccinia and herpes viruses (Hollenbaugh et al, 2013) are also restricted by SAMHD1 (Figure 1). Before being identified as an antiviral factor, SAMHD1 was already known to be mutated in the Aicardi-Goutières syndrome (AGS), an inherited autoimmune encephalopathy that can also be caused by mutations in other nucleic acid-processing enzymes (TREX1, ADAR1 and RNASEH2). This inflammatory disorder induces symptoms similar to those observed during a congenital infection, and is associated with exacerbated secretion of type-I interferon (IFN), probably caused by sensing of endogenous nucleic