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Transcriptome Profiling of Human Monocyte-Derived Macrophages Upon CCL2 Neutralization Reveals an Association Between Activation of Innate Immune Pathways and Restriction of HIV-1 Gene Expression
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2020-08-05 , DOI: 10.3389/fimmu.2020.02129
Daniela Angela Covino , Karolina Elżbieta Kaczor-Urbanowicz , Jing Lu , Maria Vincenza Chiantore , Gianna Fiorucci , Maria Fenicia Vescio , Laura Catapano , Cristina Purificato , Clementina Maria Galluzzo , Roberta Amici , Mauro Andreotti , Maria Cristina Gauzzi , Matteo Pellegrini , Laura Fantuzzi

Macrophages are key targets of human immunodeficiency virus type 1 (HIV-1) infection and main producers of the proinflammatory chemokine CC chemokine ligand 2 (CCL2), whose expression is induced by HIV-1 both in vitro and in vivo. We previously found that CCL2 neutralization in monocyte-derived macrophages (MDMs) strongly inhibited HIV-1 replication affecting post-entry steps of the viral life cycle. Here, we used RNA-sequencing to deeply characterize the cellular factors and pathways modulated by CCL2 blocking in MDMs and involved in HIV-1 replication restriction. We report that exposure to CCL2 neutralizing antibody profoundly affected the MDM transcriptome. Functional annotation clustering of up-regulated genes identified two clusters enriched for antiviral defense and immune response pathways, comprising several interferon-stimulated, and restriction factor coding genes. Transcripts in the clusters were enriched for RELA and NFKB1 targets, suggesting the activation of the canonical nuclear factor κB pathway as part of a regulatory network involving miR-155 up-regulation. Furthermore, while HIV-1 infection caused small changes to the MDM transcriptome, with no evidence of host defense gene expression and type I interferon signature, CCL2 blocking enabled the activation of a strong host innate response in infected macrophage cultures, and potently inhibited viral genes expression. Notably, an inverse correlation was found between levels of viral transcripts and of the restriction factors APOBEC3A (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 A), ISG15, and MX1. These findings highlight an association between activation of innate immune pathways and HIV-1 restriction upon CCL2 blocking and identify this chemokine as an endogenous factor contributing to the defective macrophage response to HIV-1. Therapeutic targeting of CCL2 may thus strengthen host innate immunity and restrict HIV-1 replication.



中文翻译:

CCL2中和后人类单核细胞衍生巨噬细胞的转录组分析揭示了先天免疫途径的激活与HIV-1基因表达的限制之间的关联。

巨噬细胞是人类免疫缺陷病毒1型(HIV-1)感染的主要靶标,也是促炎性趋化因子CC趋化因子配体2(CCL2)的主要生产者,其表达均由HIV-1诱导 体外体内。我们以前发现单核细胞衍生的巨噬细胞(MDMs)中的CCL2中和作用强烈抑制了HIV-1复制,影响了病毒生命周期的进入后步骤。在这里,我们使用RNA测序来深入表征MDM中CCL2阻断调节的细胞因子和途径,并参与HIV-1复制限制。我们报告,暴露于CCL2中和抗体深刻影响了MDM转录组。上调基因的功能注释聚类确定了两个富含抗病毒防御和免疫反应途径的聚类,包括几个干扰素刺激的和限制性因子编码基因。簇中的转录本富含RELA和NFKB1靶标,提示规范核因子κB通路的激活是涉及miR-155上调的调控网络的一部分。此外,虽然HIV-1感染引起MDM转录组的微小变化,但没有宿主防御基因表达和I型干扰素签名的迹象,但CCL2阻断能够激活被感染巨噬细胞培养物中强烈的宿主先天反应,并有效抑制病毒基因表达。值得注意的是,发现病毒转录物水平与限制因子APOBEC3A(载脂蛋白B mRNA编辑酶催化多肽样3A),ISG15和MX1的水平成反比。这些发现凸显了先天性免疫途径的激活与HIV-1对CCL2阻断的限制之间的关联,并将这种趋化因子确定为导致对HIV-1的巨噬细胞应答缺陷的内源性因子。因此,治疗性靶向CCL2可能会增强宿主固有免疫力并限制HIV-1复制。

更新日期:2020-09-20
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