SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates

Hichem Lahouassa et al. 2012. Nat. Immunol. 13, 223-228

Speaker: Li-Jie Kao (高力捷)                                                Time: 15:00~16:00, Dec. 5, 2012

Commentator: Shainn-Wei Wang, Ph. D. (王憲威老師)     Place: Room 601

Abstract

Human immunodeficiency virus type 1 (HIV-1) can infect macrophages and dendritic cells with limited virus replication. SAMHD1 has been found in macrophages and dendritic cells to restrict HIV-1 infection, but the mechanism is unclear. Simian immunodeficiency virus expresses a viral accessory protein, Vpx, to induce SAMHD1 degradation by proteasome^{1, 2}. SAMHD1 has weak homology with a dNTPase, and its HD (His-Asp) domain possesses putative nucleotidase activity. These findings suggest that SAMHD1 may restrict HIV-1 replication by controlling intracellular dNTP concentration. This study shows that SAMHD1 had dGTP-dependent triphosphohydrolase activity. In monocyte-derived macrophages, treatment with Vpx-containing virus-like particles increased the cellular dNTPs and enhanced HIV-1 infectivity. This suggested that SAMHD1 decreasesdNTPs to inhibit viral DNA synthesis. Overexpressing SAMHD1 in a monocytoid cell line reduced the intracellular dNTP pool resulted in decreasing HIV-1 infectivity. If SAMHD1 was mutated in its HD domain sequence, there was no effect on dNTP pool and virus infection. The simian immunodeficiency virus with mutated Vpx had poor infectivity to monocyte-derived macrophages, but treatment with extracellular deoxynucleosides to increase dNTP concentration restored its infectivity. Accordingly, SAMHD1 restricts lentivirus replication by diminishing the intracellular pool of dNTPs. This is a previously unknown mechanism of innate immunity, and implicates depleting the nucleotide pool might be a therapeutic approach to treating virus infection.

References

1.      Hrecka, K. et al. Vpx relieves inhibition of HIV‑1 infection of macrophages mediated by the SAMHD1 protein. 2012. Nature 474, 658–661.

2.      Laguette, N. et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV‑1 restriction factor counteracted by Vpx. 2012. Nature 474, 654–657.