Institut de Recherches Cliniques de Montréal, Montreal, QC, H2W 1R7, Canada.
Axe des Maladies Infectieuses et Immunitaires, CR-CHU de Québec-Université Laval, Pavillon CHUL, Quebec City, QC, G1V 4G2, Canada.
Cell Rep. 2017 Oct 3;21(1):141-153. doi: 10.1016/j.celrep.2017.09.030.
Macrophages are heterogeneous immune cells with distinct origins, phenotypes, functions, and tissue localization. Their susceptibility to HIV-1 is subject to variations from permissiveness to resistance, owing in part to regulatory microRNAs. Here, we used RNA sequencing (RNA-seq) to examine the expression of >400 microRNAs in productively infected and bystander cells of HIV-1-exposed macrophage cultures. Two microRNAs upregulated in bystander macrophages, miR-221 and miR-222, were identified as negative regulators of CD4 expression and CD4-mediated HIV-1 entry. Both microRNAs were enhanced by tumor necrosis factor alpha (TNF-α), an inhibitor of CD4 expression. MiR-221/miR-222 inhibitors recovered HIV-1 entry in TNF-α-treated macrophages by enhancing CD4 expression and increased HIV-1 replication and spread in macrophages by countering TNF-α-enhanced miR-221/miR-222 expression in bystander cells. In line with these findings, HIV-1-resistant intestinal myeloid cells express higher levels of miR-221 than peripheral blood monocytes. Thus, miR-221/miR-222 act as effectors of the antiviral host response activated during macrophage infection that restrict HIV-1 entry.
巨噬细胞是具有不同起源、表型、功能和组织定位的异质性免疫细胞。它们对 HIV-1 的易感性因允许性到抗性的变化而有所不同，部分原因是调节 microRNA。在这里，我们使用 RNA 测序（RNA-seq）来检查 HIV-1 暴露的巨噬细胞培养物中受感染和旁观者细胞中超过 400 种 microRNA 的表达。在旁观者巨噬细胞中上调的两种 microRNA，miR-221 和 miR-222，被鉴定为 CD4 表达和 CD4 介导的 HIV-1 进入的负调节剂。两种 microRNA 均受肿瘤坏死因子 alpha（TNF-α）增强，TNF-α 是 CD4 表达的抑制剂。miR-221/miR-222 抑制剂通过增强 CD4 表达恢复 TNF-α 处理的巨噬细胞中的 HIV-1 进入，并通过抵消 TNF-α 增强旁观者细胞中 miR-221/miR-222 表达来增加 HIV-1 在巨噬细胞中的复制和扩散。与这些发现一致的是，HIV-1 抗性肠道髓样细胞比外周血单核细胞表达更高水平的 miR-221。因此，miR-221/miR-222 作为巨噬细胞感染期间激活的抗病毒宿主反应的效应物发挥作用，限制了 HIV-1 的进入。
