1] Immunobiology Laboratory, Cancer Research UK, London Research Institute, London, UK [2] Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
EMBO J. 2013 Sep 11;32(18):2454-62. doi: 10.1038/emboj.2013.163. Epub 2013 Jul 19.
SAMHD1 is a host restriction factor for human immunodeficiency virus 1 (HIV-1) in cultured human cells. SAMHD1 mutations cause autoimmune Aicardi-Goutières syndrome and are found in cancers including chronic lymphocytic leukaemia. SAMHD1 is a triphosphohydrolase that depletes the cellular pool of deoxynucleoside triphosphates, thereby preventing reverse transcription of retroviral genomes. However, in vivo evidence for SAMHD1's antiviral activity has been lacking. We generated Samhd1 null mice that do not develop autoimmune disease despite displaying a type I interferon signature in spleen, macrophages and fibroblasts. Samhd1(-/-) cells have elevated deoxynucleoside triphosphate (dNTP) levels but, surprisingly, SAMHD1 deficiency did not lead to increased infection with VSV-G-pseudotyped HIV-1 vectors. The lack of restriction is likely attributable to the fact that dNTP concentrations in SAMHD1-sufficient mouse cells are higher than the KM of HIV-1 reverse transcriptase (RT). Consistent with this notion, an HIV-1 vector mutant bearing an RT with lower affinity for dNTPs was sensitive to SAMHD1-dependent restriction in cultured cells and in mice. This shows that SAMHD1 can restrict lentiviruses in vivo and that nucleotide starvation is an evolutionarily conserved antiviral mechanism.
SAMHD1 是一种宿主限制因子，可限制培养的人类细胞中的人类免疫缺陷病毒 1（HIV-1）。SAMHD1 突变会导致自身免疫性 Aicardi-Goutières 综合征，并存在于包括慢性淋巴细胞白血病在内的癌症中。SAMHD1 是一种三磷酸水解酶，可耗尽细胞内的脱氧核苷三磷酸池，从而阻止逆转录病毒基因组的逆转录。然而，体内缺乏 SAMHD1 抗病毒活性的证据。我们生成了 Samhd1 缺失的小鼠，尽管在脾脏、巨噬细胞和成纤维细胞中显示出 I 型干扰素特征，但它们不会发生自身免疫性疾病。Samhd1(-/-)细胞中的脱氧核苷三磷酸（dNTP）水平升高，但令人惊讶的是，SAMHD1 缺乏并没有导致 VSV-G 假型 HIV-1 载体感染增加。这种限制的缺乏可能归因于这样一个事实，即 SAMHD1 足够的小鼠细胞中的 dNTP 浓度高于 HIV-1 逆转录酶（RT）的 KM。这一观点与以下事实一致，即一种具有更低 dNTP 亲和力的 RT 的 HIV-1 载体突变体在培养细胞和小鼠中对 SAMHD1 依赖性限制敏感。这表明 SAMHD1 可以在体内限制慢病毒，核苷酸饥饿是一种进化保守的抗病毒机制。
