The Human Immunodeficiency Virus (HIV) enters the nucleus to establish infection. The nuclear envelope is a physical barrier for HIV. The role of nuclear pore components in promoting HIV infection is well established. In contrast, the role of other proteins of the nuclear envelope is much less understood. SUN1 and SUN2 are inner nuclear membrane proteins that connect the nuclear Lamin proteins to the cytoskeleton. Increased levels of SUN1 or SUN2 proteins potently restrict HIV infection through an unresolved mechanism. Here, we identify a strain-specific antiviral activity of SUN1 and SUN2 against HIV-1 and HIV-2 that we leverage to investigate the cellular basis of the antiviral effect. SUN1 preferentially restricts HIV-1 in macrophages and HeLa cells. This specificity maps to the nucleoplasmic domain of SUN proteins, which associates with Lamin A/C and participates to the DNA damage response. We find that etoposide, a DNA-damaging drug, stimulates infection. Inhibition of ATR, which induces a DNA damage response, also enhances HIV-1 infection. The proviral effect of ATR inhibition on infection requires the Vpr gene in HIV-1. Depletion of endogenous Lamin A/C, which sensitize cells to DNA damage, also enhances HIV-1 infection in HeLa cells. SUN1 over-expression neutralizes these proviral effects, while the antiviral effect of SUN2 is rescued by etoposide treatment. Finally, we show that inhibition of HIV-1 infection by over-expressed SUN proteins and endogenous Lamin A/C is associated with reduced internal movements of chromatin and reduced rotations of the nucleus. Altogether, the results highlight distinct antiviral activities of SUN1 and SUN2 and they reveal an emerging role of nuclear movements and the DNA damage response in the control of HIV infection by structural components of the nuclear envelope.

中文翻译：

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内核膜结构蛋白抑制HIV感染与染色质动力学降低有关

人类免疫缺陷病毒（HIV）进入细胞核以建立感染。核膜是艾滋病毒的物理屏障。核孔成分在促进HIV感染中的作用是众所周知的。相反，人们对核膜其他蛋白的作用了解甚少。SUN1和SUN2是将核Lamin蛋白连接到细胞骨架的内部核膜蛋白。SUN1或SUN2蛋白水平的提高通过一种尚未解决的机制有效地限制了HIV的感染。在这里，我们确定了SUN1和SUN2对HIV-1和HIV-2的菌株特异性抗病毒活性，我们利用该活性来研究抗病毒作用的细胞基础。SUN1优先限制巨噬细胞和HeLa细胞中的HIV-1。这种特异性对应于SUN蛋白的核质结构域，与Lamin A / C相关联并参与DNA损伤反应。我们发现依托泊苷是一种破坏DNA的药物，可刺激感染。抑制ATR会诱导DNA损伤反应，也会增强HIV-1感染。ATR抑制对感染的前病毒作用需要HIV-1中的Vpr基因。使细胞对DNA损伤敏感的内源性Lamin A / C的消耗也增加了HeLa细胞中的HIV-1感染。SUN1的过表达中和了这些前病毒作用，而依托泊苷治疗可以挽救SUN2的抗病毒作用。最后，我们表明过度表达的SUN蛋白和内源性Lamin A / C对HIV-1感染的抑制作用与染色质内部运动的减少和细胞核旋转的减少有关。共，