P21 Regulates The Hiv-1 Restriction Factor Samhd1

Allouch et al. (1) have shown that CDKN1A (p21) restricts HIV-1 replication in monocyte-derived macrophages (MDM) by controlling the expression of the ribonucleotide reductase subunit R2 (RNR2) of the ribonucleotide reductase enzyme that, in turn, controls the intracellular deoxynucleotide (dNTP) pool required for HIV-1 reverse transcription. dNTP levels are also tightly controlled by the dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1), which is constitutively expressed in myeloid and lymphoid cells and is counteracted by the lentiviral virus protein x (Vpx) (reviewed in ref. 2). SAMHD1 is deactivated in proliferating cells by a mechanism that requires phosphorylation of SAMHD1 (3). Allouch et al. (1) conclude that p21-driven HIV-1 restriction in macrophages is independent of SAMHD1 because (i) p21 did not affect SAMHD1 expression and (ii) Vpx did not affect p21 expression. Here, we show that M-CSF induces monocyte differentiation into macrophages and cell proliferation (Fig. 1A), and RNA interference of p21 leads to an increase in the number of proliferating cells (Fig. 1B). Macrophages become susceptible to HIV-1 replication (Fig. 1C) because SAMHD1 is inactivated as measured by specific SAMHD1 phosphorylation at residue T592 (Fig. 1D). Delivery of simian immunodeficiency virus (SIV) mac Vpx-induced SAMHD1 degradation (Fig. 1E) and subsequently increased virus infection (Fig. 1F) (2, 4, 5). Of importance, siRNA-induced down-regulation of p21 (Fig. 2A) strongly enhanced the phosphorylation of SAMHD1 (Fig. 2 B and C), followed by an increase in …