The G1/S Specific Cyclin D2 Is a Regulator of HIV-1 Restriction in Non-proliferating Cells
The G1/S Specific Cyclin D2 Is a Regulator of HIV-1 Restriction in Non-proliferating Cells
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DOI：
10.1371/journal.ppat.1005829
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发表时间：
2016-08-01
期刊：
影响因子：
6.7
通讯作者：
Ballana, Ester
中科院分区：
文献类型：
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作者：
Badia, Roger;Pujantell, Maria;Ballana, Ester
巨噬细胞是一种受分化刺激强烈影响的异质细胞群，在限制因子SAMHD1被细胞周期蛋白依赖的激酶(CDK)灭活后，巨噬细胞对HIV-1感染变得易感。在这里，我们使用通过不同刺激分化的原代人单核细胞来源的巨噬细胞来评估巨噬细胞对细胞激活和增殖的异质性以及对HIV-1感染的易感性。GM-CSF刺激单核细胞可诱导一种对HIV-1感染高度限制性的非增殖性巨噬细胞群，其特征是G1/S特异的细胞周期蛋白D2上调，该蛋白控制细胞周期进程的早期步骤。Cyclin D2的敲除，通过磷酸化使SAMHD1限制因子失活，增强了HIV-1在GM-CSF巨噬细胞中的复制。免疫共沉淀实验表明，细胞周期蛋白D2与CDK4和p21形成复合体。CDK4和p21是一种已知的限制HIV-1复制的因子，它通过影响下游级联反应的功能而导致SAMHD1失活。因此，我们证明细胞周期蛋白D2在非增殖性巨噬细胞中作为细胞周期蛋白的调节器，影响SAMHD1介导的HIV-1限制。
Macrophages are a heterogeneous cell population strongly influenced by differentiation stimuli that become susceptible to HIV-1 infection after inactivation of the restriction factor SAMHD1 by cyclin-dependent kinases (CDK). Here, we have used primary human monocyte-derived macrophages differentiated through different stimuli to evaluate macrophage heterogeneity on cell activation and proliferation and susceptibility to HIV-1 infection. Stimulation of monocytes with GM-CSF induces a non-proliferating macrophage population highly restrictive to HIV-1 infection, characterized by the upregulation of the G1/S-specific cyclin D2, known to control early steps of cell cycle progression. Knockdown of cyclin D2, enhances HIV-1 replication in GM-CSF macrophages through inactivation of SAMHD1 restriction factor by phosphorylation. Co-immunoprecipitation experiments show that cyclin D2 forms a complex with CDK4 and p21, a factor known to restrict HIV-1 replication by affecting the function of the downstream cascade that leads to SAMHD1 deactivation. Thus, we demonstrate that cyclin D2 acts as regulator of cell cycle proteins affecting SAMHD1-mediated HIV-1 restriction in non-proliferating macrophages.