BackgroundMammalian cells harbour RNA quality control and degradative machineries such as nonsense-mediated mRNA decay that target cellular mRNAs for clearance from the cell to avoid aberrant gene expression. The role of the host mRNA decay pathways in macrophages in the context of human immunodeficiency virus type 1 (HIV-1) infection is yet to be elucidated. Macrophages are directly infected by HIV-1, mediate the dissemination of the virus and contribute to the chronic activation of the inflammatory response observed in infected individuals. Therefore, we characterized the effects of four host mRNA decay proteins, i.e., UPF1, UPF2, SMG6 and Staufen1, on viral replication in HIV-1-infected primary monocyte-derived macrophages (MDMs).ResultsSteady-state expression levels of these host mRNA decay proteins were significantly downregulated in HIV-1-infected MDMs. Moreover, UPF2 and SMG6 inhibited HIV-1 gene expression in macrophages to a similar level achieved by SAMHD1, by directly influencing viral genomic RNA levels. Staufen1, a host protein also involved in UPF1-dependent mRNA decay and that acts at several HIV-1 replication steps, enhanced HIV-1 gene expression in MDMs.ConclusionsThese results provide new evidence for roles of host mRNA decay proteins in regulating HIV-1 replication in infected macrophages and can serve as potential targets for broad-spectrum antiviral therapeutics.

中文翻译：

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宿主 mRNA 衰变蛋白影响原代单核细胞衍生巨噬细胞中 HIV-1 的复制和病毒基因表达

背景哺乳动物细胞具有 RNA 质量控制和降解机制，例如无义介导的 mRNA 衰变，其靶向细胞 mRNA 从细胞中清除以避免异常基因表达。在人类免疫缺陷病毒 1 (HIV-1) 感染的背景下，宿主 mRNA 衰变途径在巨噬细胞中的作用尚待阐明。巨噬细胞直接被 HIV-1 感染，介导病毒的传播，并有助于在受感染个体中观察到的炎症反应的慢性激活。因此，我们表征了四种宿主 mRNA 衰变蛋白，即 UPF1、UPF2、SMG6 和 Staufen1，对 HIV-1 感染的原代单核细胞衍生巨噬细胞 (MDM) 中病毒复制的影响。结果这些宿主 mRNA 衰变蛋白的稳态表达水平在 HIV-1 感染的 MDM 中显着下调。此外，UPF2 和 SMG6 通过直接影响病毒基因组 RNA 水平，将巨噬细胞中 HIV-1 基因的表达抑制到与 SAMHD1 达到的相似水平。Staufen1 是一种宿主蛋白​​，也参与 UPF1 依赖性 mRNA 衰变，并在几个 HIV-1 复制步骤中起作用，增强了 MDM 中 HIV-1 基因的表达。结论这些结果为宿主 mRNA 衰变蛋白在调节 HIV-1 中的作用提供了新证据在受感染的巨噬细胞中复制，可以作为广谱抗病毒治疗的潜在靶点。