Human immunodeficiency virus type 1 induces lytic cycle replication of Kaposi's-sarcoma-associated herpesvirus: role of Ras/c-Raf/MEK1/2, PI3K/AKT, and NF-κB signaling pathways.
Human immunodeficiency virus type 1 induces lytic cycle replication of Kaposi's-sarcoma-associated herpesvirus: role of Ras/c-Raf/MEK1/2, PI3K/AKT, and NF-κB signaling pathways.
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DOI：
10.1016/j.jmb.2011.03.055
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发表时间：
2011-07
影响因子：
5.6
通讯作者：
Xiaolei Zhu;Feng Zhou;D. Qin;Yi Zeng;Z. Lv;S. Yao;Chun Lu
中科院分区：
文献类型：
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作者：
Xiaolei Zhu;Feng Zhou;D. Qin;Yi Zeng;Z. Lv;S. Yao;Chun Lu
人类免疫缺陷病毒1型（HIV-1）感染可显著增加卡波西肉瘤（KS）相关疱疹病毒（KSHV）感染者发生KS的风险和发展。以前，我们报道了HIV-1达特蛋白通过调节Janus激酶/信号转导和转录激活因子信号通路诱导KSHV复制。在此，我们进一步研究了HIV-1诱导的KSHV再激活的可能信号通路。我们发现，HIV-1感染的原发性渗出性淋巴瘤细胞系触发KSHV的重新激活，表现为KSHV的复制和转录激活因子，早期病毒裂解蛋白vIL-6和ORF 59的表达和后代病毒体的产生。通过基因芯片分析、筛选一系列显性失活突变体和加入药物抑制剂，我们鉴定了一组不同的细胞信号蛋白，发现HIV-1感染BCBL-1细胞激活磷脂酰肌醇3-激酶/AKT（也称为蛋白激酶B，PK B）途径和失活的磷酸酶和张力蛋白同源物，在染色体10上缺失，糖原合成酶激酶-3 β，其部分调节HIV-1诱导的KSHV再活化。Ras/c-Raf/MAPK/ERK激酶1/2通路的激活参与了HIV-1诱导的KSHV复制。最后，我们发现HIV-1感染激活了核因子κB信号，这对BCBL-1细胞中KSHV的再激活具有抑制作用。总的来说，我们的数据表明，HIV-1感染刺激这些细胞信号通路，反过来，有助于KSHV再激活，这可能是获得性免疫缺陷综合征相关KS患者的治疗价值。
Human immunodeficiency virus type 1 (HIV-1) infection significantly increases the risk and development of Kaposi's sarcoma (KS) in individuals infected with KS-associated herpesvirus (KSHV). Previously, we reported that HIV-1 Tat protein induced KSHV replication by modulating the Janus kinase/signal transducers and activators of transcription signaling pathway. Here, we further investigated the possible signaling pathways involved in HIV-1-induced reactivation of KSHV. We showed that HIV-1 infection of primary effusion lymphoma cell lines triggered the reactivation of KSHV, as demonstrated by the expression of KSHV replication and transcription activator, the early viral lytic protein vIL-6 and ORF59 and the production of progeny virions. By utilizing microarray gene expression analyses, transfecting a series of dominant negative mutants, and adding pharmacologic inhibitors, we identified a group of diverse cellular signaling proteins and found that HIV-1 infection of BCBL-1 cells activated phosphatidylinositol 3-kinase/AKT (also called protein kinase B, PKB) pathway and inactivated phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase-3β, which partially modulated HIV-1-induced KSHV reactivation. Furthermore, activation of Ras/c-Raf/MAPK/ERK kinase1/2 pathway contributed to HIV-1-induced KSHV replication. Finally, we discovered that HIV-1 infection activated nuclear factor κB signaling, which exhibits an inhibitory effect on KSHV reactivation in BCBL-1 cells. Collectively, our data demonstrated that HIV-1 infection stimulated these cell signaling pathways that, in turn, contributed to KSHV reactivation, which may be of therapeutic value in acquired immunodeficiency syndrome-related KS patients.