Inhibition of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by HIV-1 Nef and Cellular MicroRNA hsa-miR-1258

被引:31
作者
Yan, Qin [1 ,2 ,3 ]
Ma, Xinting [3 ]
Shen, Chenyou [3 ]
Cao, Xu [3 ,4 ]
Feng, Ninghan [3 ,4 ]
Qin, Di [3 ]
Zeng, Yi [5 ]
Zhu, Jianzhong [6 ]
Gao, Shou-Jiang [7 ]
Lu, Chun [1 ,2 ,3 ]
机构
[1] Nanjing Med Univ, State Key Lab Reprod Med, Nanjing, Jiangsu, Peoples R China
[2] Nanjing Med Univ, Key Lab Pathogen Biol Jiangsu Prov, Nanjing, Jiangsu, Peoples R China
[3] Nanjing Med Univ, Dept Microbiol & Immunol, Nanjing, Jiangsu, Peoples R China
[4] Nanjing Med Univ, Affiliated Hosp 1, Dept Urol, Nanjing, Jiangsu, Peoples R China
[5] Youjiang Med Coll Nationalities, Dept Microbiol & Immunol, Bose, Peoples R China
[6] Univ Pittsburgh, Inst Canc, Canc Virol Program, Pittsburgh, PA USA
[7] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA
基金
中国国家自然科学基金; 中国博士后科学基金;
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVATED PROTEIN-KINASE; NF-KAPPA-B; CYCLE REPLICATION; TYPE-1; NEF; VIRAL REPLICATION; ENCODED MICRORNA; GENE-EXPRESSION; DNA-SEQUENCES; IN-VITRO;
D O I
10.1128/JVI.00025-14
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several AIDS-related malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. The interaction of human immunodeficiency virus type 1 (HIV-1) and KSHV has a central role in promoting the aggressive manifestations of AIDS-KS. We have previously shown that negative factor (Nef), a secreted HIV-1 protein, synergizes with KSHV viral interleukin-6 (vIL-6) to promote angiogenesis and tumorigenesis by activating the AKT pathway (X. Zhu, et al., Oncogene, 22 April 2013, http://dx.doi.org/10.1038/onc.2013.136). Here, we further demonstrated the role of soluble and ectopic Nef in the regulation of KSHV latency. We found that both soluble Nef protein and ectopic expression of Nef by transfection suppressed the expression of KSHV viral lytic mRNA transcripts and proteins and the production of infectious viral particles. MicroRNA (miRNA) microarray analysis identified a number of Nef-regulated miRNAs. Bioinformatics and luciferase reporter analyses showed that one of the Nef-upregulated miRNAs, cellular miRNA 1258 (hsa-miR-1258), directly targeted a seed sequence in the 3' untranslated region (UTR) of the mRNA encoding the major lytic switch protein (RTA), which controls KSHV reactivation from latency. Ectopic expression of hsa-miR-1258 impaired RTA synthesis and enhanced Nef-mediated inhibition of KSHV replication, whereas repression of hsa-miR-1258 has the opposite effect. Mutation of the seed sequence in the RTA 3' UTR abolished downregulation of RTA by hsa-miR-1258. Collectively, these novel findings demonstrate that, by regulating cellular miRNA, Nef may inhibit KSHV replication to promote viral latency and contribute to the pathogenesis of AIDS-related malignancies.
引用
收藏
页码:4987 / 5000
页数:14
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