Abstract
SAMHD1 restricts HIV-1 replication in myeloid andquiescent CD4+T cells. Here, we show that SAMHD1restriction activity is regulated by phosphorylation.SAMHD1 interacts with cyclin A2/cdk1 only in cyclingcells. Cyclin A2/CDK1 phosphorylates SAMHD1 atthe Threonine 592 residue both in vitro and in vivo.Phosphorylation of SAMHD1 Thr592 correlates withloss of its ability to restrict HIV-1. Indeed, whilePMA treatment of proliferating THP1 cells results inreduced Thr592 phosphorylation, activation ofresting peripheral blood mononuclear cells (PBMCs)and purified quiescent CD4+T cells results inincreased phosphorylation of SAMHD1 Thr592. Inter-estingly, we found that treatment of cells by type 1interferon reduced Thr592 phosphorylation, reinforc-ing the link between the phosphorylation of SAMHD1and its antiviral activity. Unlike wild-type SAMHD1,a phosphorylation-defective mutant was able torestrict HIV-1 replication in both PMA-treatedand untreated cells. Our results uncover the phos-phorylation of SAMHD1 at Thr592 by cyclin A2/CDK1 as a key regulatory mechanism of its antiviralactivity.