Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman Medical School and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
J Virol. 2013 Dec;87(23):12949-56. doi: 10.1128/JVI.02291-13. Epub 2013 Sep 25.
Macrophages play important roles in host immune defense against virus infection. During infection by herpes simplex virus 1 (HSV-1), macrophages acquire enhanced antiviral potential. Restriction of HSV-1 replication and progeny production is important to prevent viral spread, but the cellular mechanisms that inhibit the DNA virus in macrophages are unknown. SAMHD1 was recently identified as a retrovirus restriction factor highly expressed in macrophages. The SAMHD1 protein is expressed in both undifferentiated monocytes and differentiated macrophages, but retroviral restriction is limited to differentiated cells by modulation of SAMHD1 phosphorylation. It is proposed to block reverse transcription of retroviral RNA into DNA by depleting cellular deoxynucleotide triphosphates (dNTPs). Viruses with DNA genomes do not employ reverse transcription during infection, but replication of their viral genomes is also dependent on intracellular dNTP concentrations. Here, we demonstrate that SAMHD1 restricts replication of the HSV-1 DNA genome in differentiated macrophage cell lines. Depleting SAMHD1 in THP-1 cells enhanced HSV-1 replication, while ectopic overexpression of SAMHD1 in U937 cells repressed HSV-1 replication. SAMHD1 did not impact viral gene expression from incoming HSV-1 viral genomes. HSV-1 restriction involved the dNTP triphosphohydrolase activity of SAMHD1 and was partially overcome by addition of exogenous deoxynucleosides. Unlike retroviruses, restriction of HSV-1 was not affected by SAMHD1 phosphorylation status. Our results suggest that SAMHD1 functions broadly to inhibit replication of DNA viruses in nondividing macrophages.
巨噬细胞在宿主抗病毒感染的免疫防御中发挥重要作用。在单纯疱疹病毒 1（HSV-1）感染过程中，巨噬细胞获得了增强的抗病毒能力。限制 HSV-1 的复制和产生子代对于防止病毒传播很重要，但抑制巨噬细胞中 DNA 病毒的细胞机制尚不清楚。SAMHD1 最近被鉴定为高度表达于巨噬细胞中的逆转录病毒限制因子。SAMHD1 蛋白在未分化的单核细胞和分化的巨噬细胞中均有表达，但通过 SAMHD1 磷酸化的调节，逆转录病毒的限制仅限于分化细胞。据推测，SAMHD1 通过耗尽细胞中的脱氧核苷酸三磷酸（dNTPs）来阻断逆转录病毒 RNA 转化为 DNA。具有 DNA 基因组的病毒在感染过程中不进行逆转录，但它们的病毒基因组复制也依赖于细胞内的 dNTP 浓度。在这里，我们证明 SAMHD1 限制分化的巨噬细胞系中 HSV-1 的 DNA 基因组复制。在 THP-1 细胞中耗尽 SAMHD1 可增强 HSV-1 的复制，而在 U937 细胞中外源过表达 SAMHD1 则抑制 HSV-1 的复制。SAMHD1 不影响来自 HSV-1 病毒基因组的病毒基因表达。HSV-1 的限制涉及 SAMHD1 的 dNTP 三磷酸水解酶活性，并且通过添加外源脱氧核苷可部分克服。与逆转录病毒不同，HSV-1 的限制不受 SAMHD1 磷酸化状态的影响。我们的结果表明，SAMHD1 在非分裂巨噬细胞中广泛抑制 DNA 病毒的复制。
