HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-kappaB Signaling.
HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-kappaB Signaling.
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HIV-1 Vpr 通过诱导 MicroRNA miR-942-5p 和激活 NF-kappa B 信号传导抑制卡波西肉瘤相关疱疹病毒裂解复制
DOI：
10.1128/jvi.00797-16
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发表时间：
2016
影响因子：
5.4
通讯作者：
Lu Chun
中科院分区：
文献类型：
--
作者：
Yan Qin;Shen Chenyou;Qin Jie;Li Wan;Hu Minmin;Lu Hongmei;Qin Di;Zhu Jianzhong;Gao Shou-Jiang;Lu Chun
卡波西肉瘤相关疱疹病毒（KSHV）感染是几种艾滋病相关恶性肿瘤（包括卡波西肉瘤（KS）和原发性渗出性淋巴瘤（PEL））发生所必需的。KSHV和HIV-1的相互作用导致了AIDS-KS的高发。我们以前已经表明，HIV-1分泌的蛋白质达特和Nef调节KSHV的生命周期，并与KSHV癌基因协同作用，以促进血管生成和肿瘤发生。在这里，我们研究了HIV-1病毒蛋白R（Vpr）对KSHV潜伏期的调节。我们发现可溶性Vpr抑制KSHV裂解转录物和蛋白质的表达，以及通过激活NF-κB信号转导进入PEL细胞后抑制病毒颗粒的产生。通过分析microRNA的表达谱，结合生物信息学和荧光素酶报告基因分析的靶标搜索，我们鉴定了一种Vpr上调的细胞microRNA（miRNA），miR-942- 5 p，其直接靶向IκBα。抑制miR-942- 5 p可减轻IκBα的表达，降低Vpr对KSHV裂解性复制的抑制作用，而过表达miR-942- 5 p可增强Vpr对KSHV裂解性复制的抑制作用。我们的研究结果共同表明，通过上调细胞miRNA以靶向IκBα，激活NF-κB信号传导，内化的HIV-1 Vpr抑制KSHV裂解复制。这些结果表明Vpr在KSHV的生命周期中起着重要作用。重要提示HIV-1共感染可促进Kaposi肉瘤相关疱疹病毒（KSHV）相关恶性肿瘤的侵袭性生长，包括Kaposi肉瘤（KS）和原发性渗出性淋巴瘤（PEL）。在这项研究中，我们已经表明，可溶性HIV-1 Vpr抑制KSHV裂解复制激活NF-κB信号转导后内化到PEL细胞。机制研究显示，Vpr上调的细胞microRNA miR-942- 5 p直接靶向IκBα。抑制miR-942- 5 p可减轻IκBα表达，降低Vpr对KSHV复制的抑制作用，而过表达miR-942- 5 p可增强Vpr对KSHV复制的抑制作用。这些结果表明，通过上调靶向IκBα的细胞miRNA激活NF-κB信号，内化Vpr抑制KSHV裂解性复制。这项工作阐明了HIV-1分泌的调节蛋白Vpr调节KSHV潜伏期和艾滋病相关恶性肿瘤发病机制的分子机制。
Kaposi's sarcoma-associated herpesvirus (KSHV) infection is required for the development of several AIDS-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The high incidence of AIDS-KS has been ascribed to the interaction of KSHV and HIV-1. We have previously shown that HIV-1-secreted proteins Tat and Nef regulate the KSHV life cycle and synergize with KSHV oncogenes to promote angiogenesis and tumorigenesis. Here, we examined the regulation of KSHV latency by HIV-1 viral protein R (Vpr). We found that soluble Vpr inhibits the expression of KSHV lytic transcripts and proteins, as well as viral particle production by activating NF-κB signaling following internalization into PEL cells. By analyzing the expression profiles of microRNAs combined with target search by bioinformatics and luciferase reporter analyses, we identified a Vpr-upregulated cellular microRNA (miRNA), miR-942-5p, that directly targeted IκBα. Suppression of miR-942-5p relieved the expression of IκBα and reduced Vpr inhibition of KSHV lytic replication, while overexpression of miR-942-5p enhanced Vpr inhibition of KSHV lytic replication. Our findings collectively illustrate that, by activating NF-κB signaling through upregulating a cellular miRNA to target IκBα, internalized HIV-1 Vpr inhibits KSHV lytic replication. These results have demonstrated an essential role of Vpr in the life cycle of KSHV.IMPORTANCECoinfection by HIV-1 promotes the aggressive growth of Kaposi's sarcoma-associated herpesvirus (KSHV)-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). In this study, we have shown that soluble HIV-1 Vpr inhibits KSHV lytic replication by activating NF-κB signaling following internalization into PEL cells. Mechanistic studies revealed that a cellular microRNA upregulated by Vpr, miR-942-5p, directly targeted IκBα. Suppression of miR-942-5p relieved IκBα expression and reduced Vpr inhibition of KSHV replication, while overexpression of miR-942-5p enhanced Vpr inhibition of KSHV replication. These results indicate that by activating NF-κB signaling through upregulating a cellular miRNA to target IκBα, internalized Vpr inhibits KSHV lytic replication. This work illustrates a molecular mechanism by which HIV-1-secreted regulatory protein Vpr regulates KSHV latency and the pathogenesis of AIDS-related malignancies.