Intracellular tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus: Role of JAK/STAT signaling
Intracellular tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus: Role of JAK/STAT signaling
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DOI：
10.1128/jvi.02024-06
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发表时间：
2007-03-01
影响因子：
5.4
通讯作者：
Lu, Chun
中科院分区：
文献类型：
--
作者：
Zeng, Yi;Zhang, Xunhai;Lu, Chun
人类免疫缺陷病毒I型（HIV-1）感染显著增加卡波西肉瘤相关疱疹病毒（KSHV）感染者发生卡波西肉瘤（KS）的风险。KSHV感染似乎是必要的，但不足以KS发展没有其他辅助因子。然而，促进KSHV导致KS的因素尚未得到很好的定义。先前，我们确定人类疱疹病毒6是激活KSHV裂解周期复制的辅因子之一。在这里，我们证明了HIV-1的达特蛋白是KS发病机制中的一个潜在的重要因素，这是通过在BCBL-1细胞中产生裂解期mRNA转录物和病毒蛋白来确定的。机制研究表明，达特的异位表达诱导人白细胞介素6（船体，6）及其受体（huIL-6 Ra）的产生并激活STAT 3信号传导。huIL-6或huIL-6 R的中和或STAT 3信号传导的抑制增强了复制。此外，IL-4/STAT 6信号也部分促进了Tat诱导的KSHV复制。这些结果表明，达特可能参与KS的发病机制，诱导KSHV复制和增加KSHV病毒载量。这些数据还表明，JAK/STAT信号可能是治疗艾滋病相关的KS患者的价值。
Human immunodeficiency virus type I (HIV-1) infection significantly increases the risk of Kaposi's sarcoma (KS) occurrence in individuals infected with Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV infection appears to be necessary but not sufficient for KS development without other cofactors. However, factors that facilitate KSHV to cause KS have not been well defined. Previously, we determined that human herpesvirus 6 was one of the cofactors that activated lytic cycle replication of KSHV. Here, we demonstrate that the Tat protein of HIV-1 is a potentially important factor in the pathogenesis of KS, as determined by production of lytic phase mRNA transcripts and viral proteins in BCBL-1 cells. Mechanistic studies showed ectopic expression of Tat induced the production of human interleukin-6 (hull,6) and its receptor (huIL-6Ra) and activated STAT3 signaling. Neutralization of huIL-6 or huIL-6R or inhibition of STAT3 signaling enhanced the replication. In addition, IL-4/STAT6 signaling also partially contributed to Tat-induced KSHV replication. These findings suggest that Tat may participate in KS pathogenesis by inducing KSHV replication and increasing KSHV viral load. These data also suggest that JAK/STAT signaling may be of therapeutic value in AIDS-related KS patients.