SAMHD1 restricts HIV-1 infection in dendritic cells (DCs) by dNTP depletion, but its expression in DCs and primary CD4+T-lymphocytes cannot be upregulated by interferons

Corine St Gelais,Joseph A Hollenbaugh,Christopher M Coleman,Baek Kim,Suresh De Silva,Heather Hoy,Li Wu,Sarah M Amie

doi:10.1186/1742-4690-9-105

Corine St Gelais, Joseph A Hollenbaugh + Show 6 more

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https://doi.org/10.1186/1742-4690-9-105

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Abstract

BackgroundSAMHD1 is an HIV-1 restriction factor in non-dividing monocytes, dendritic cells (DCs), macrophages, and resting CD4+ T-cells. Acting as a deoxynucleoside triphosphate (dNTP) triphosphohydrolase, SAMHD1 hydrolyzes dNTPs and restricts HIV-1 infection in macrophages and resting CD4+ T-cells by decreasing the intracellular dNTP pool. However, the intracellular dNTP pool in DCs and its regulation by SAMHD1 remain unclear. SAMHD1 has been reported as a type I interferon (IFN)-inducible protein, but whether type I IFNs upregulate SAMHD1 expression in primary DCs and CD4+ T-lymphocytes is unknown.ResultsHere, we report that SAMHD1 significantly blocked single-cycle and replication-competent HIV-1 infection of DCs by decreasing the intracellular dNTP pool and thereby limiting the accumulation of HIV-1 late reverse transcription products. Type I IFN treatment did not upregulate endogenous SAMHD1 expression in primary DCs or CD4+ T-lymphocytes, but did in HEK 293T and HeLa cell lines. When SAMHD1 was over-expressed in these two cell lines to achieve higher levels than that in DCs, no HIV-1 restriction was observed despite partially reducing the intracellular dNTP pool.ConclusionsOur results suggest that SAMHD1-mediated reduction of the intracellular dNTP pool in DCs is a common mechanism of HIV-1 restriction in myeloid cells. Endogenous expression of SAMHD1 in primary DCs or CD4+ T-lymphocytes is not upregulated by type I IFNs.

Highlights

SAM domain and HD domain-containing protein 1 (SAMHD1) is an HIV-1 restriction factor in non-dividing monocytes, dendritic cells (DCs), macrophages, and resting CD4+ T-cells
Over-expression of SAMHD1 in HEK 293T cells or HeLa cells does not inhibit HIV-1 infection, but modestly decreases the intracellular deoxynucleoside triphosphate (dNTP) pool in HeLa cells Given that HEK 293T and HeLa cell lines are highly permissive to post-entry HIV-1 infection [33], and express lower SAMHD1 compared to primary DCs (Figure 7C), we investigated whether over-expression of SAMHD1 in these cells could cause an HIV-1-specific restriction phenotype and whether SAMHD1 retained its dNTP hydrolysis enzymatic activity
SAMHD1 over-expression in HeLa cells had a more pronounced effect on dNTP concentration and 1.8, 2.4, 1.5, and 2.2-fold decreases were observed for dATP, dCTP, dGTP, and dTTP, respectively (p

Summary

Introduction

SAMHD1 is an HIV-1 restriction factor in non-dividing monocytes, dendritic cells (DCs), macrophages, and resting CD4+ T-cells. Acting as a deoxynucleoside triphosphate (dNTP) triphosphohydrolase, SAMHD1 hydrolyzes dNTPs and restricts HIV-1 infection in macrophages and resting CD4+ T-cells by decreasing the intracellular dNTP pool. SAMHD1 has been reported as a type I interferon (IFN)-inducible protein, but whether type I IFNs upregulate SAMHD1 expression in primary DCs and CD4+ T-lymphocytes is unknown. Myeloid lineage cells such as monocytes, macrophages and dendritic cells (DCs) are important immune cells that elicit innate and adaptive immune responses to a variety of pathogens, including viruses. In contrast to HIV-1, HIV-2 and simian immunodeficiency virus (SIV) from the sooty mangaby lineage are able to efficiently infect myeloid lineage cells by a mechanism initially attributed to the Vpx protein mediating degradation of an unknown host cellular restriction factor [3]. The effect of SAMHD1 on regulating the dNTP pool in DCs remains to be investigated

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