Aicardi-Goutières Syndrome Gene and HIV-1 Restriction Factor SAMHD1 Is a dGTP-regulated Deoxynucleotide Triphosphohydrolase

The SAMHD1 protein is an HIV-1 restriction factor that is targeted by the HIV-2 accessory protein Vpx in myeloid lineage cells. Mutations in the SAMHD1 gene cause Aicardi-Goutières syndrome, a genetic disease that mimics congenital viral infection. To determine the physiological function of the SAMHD1 protein, the SAMHD1 gene was cloned, recombinant protein was produced, and the catalytic activity of the purified enzyme was identified. We show that SAMHD1 contains a dGTP-regulated deoxynucleotide triphosphohydrolase. We propose that Vpx targets SAMHD1 for degradation in a viral strategy to control cellular deoxynucleotide levels for efficient replication. Background: Mutations in SAMHD1 cause Aicardi-Goutières syndrome. SAMHD1 is the HIV-1 restriction factor preventing replication in myeloid cells. Results: The SAMHD1 HD domain contains a dGTP-regulated deoxynucleotide triphosphohydrolase. Conclusion: SAMHD1 catalytic activity reduces deoxynucleotide precursor levels, restricting HIV-1 replication. Significance: The HIV-2 Vpx accessory protein targets SAMHD1 for degradation in a viral strategy to control cellular deoxynucleotide levels for efficient replication.