HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFNγ signaling
HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFNγ signaling
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DOI：
10.1182/blood-2008-10-183525
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发表时间：
2009-05-21
期刊：
影响因子：
20.3
通讯作者：
Lau, Allan S. Y.
中科院分区：
文献类型：
--
作者：
Cheng, Sherman M.;Li, James C. B.;Lau, Allan S. Y.
艾滋病毒感染仍然是一个全球性的威胁。HIV-1反式激活蛋白达特（Tat）是一种逆转录病毒蛋白，在艾滋病的发病机制中起着重要的免疫调节作用。虽然达特的主要功能是调节HIV-1在感染细胞中的复制，但它也失调细胞因子的产生，导致宿主免疫应答的干扰和逆转录病毒存活的增强。由于干扰素-γ（IFN-γ）是一种具有强效抗病毒和免疫调节作用的多效性细胞因子，我们研究了达特是否干扰初级单核细胞中的IFN-γ信号转导。我们证明，达特在STAT1活化水平上损害IFN γ受体信号传导途径，可能是通过细胞因子信号传导抑制因子-2（SOCS-2）活性的塔特依赖性诱导。我们通过在HEK293细胞中过表达外源性SOCS-2来阐明SOCS-2在IFN γ信号通路中的抑制作用。结果表明，SOCS-2抑制IFN γ激活的STAT1磷酸化和随后IFN γ调节的特定基因的转录。为了证实SOCS 2在Tat诱导过程中的作用，我们证明了人血液单核细胞中的SOCS-2 siRNA消除了IFN γ信号转导的Tat依赖性抑制。我们的数据表明，SOCS-2介导HIV-1诱导的免疫逃避和干扰素γ信号在原代人单核细胞中的失调的作用的可能机制。（血。2009; 113：5192 - 5201）
HIV infection remains a worldwide threat. HIV-1 transactivator protein Tat is one of the retroviral proteins identified as a key immunomodulator in AIDS pathogenesis. Although the primary function of Tat is to regulate HIV-1 replication in the infected cell, it also dysregulates cytokine production resulting in perturbation of the host immune response and enhancement of the retrovirus survival. Because interferon-gamma (IFN gamma) is a pleiotropic cytokine with potent antiviral and immunoregulatory effects, we investigated whether Tat interferes with the IFN gamma signal transduction in primary monocytes. We demonstrated that Tat impaired the IFN gamma-receptor signaling pathway at the level of STAT1 activation, possibly via Tat-dependent induction of suppressor of cytokine signaling-2 (SOCS-2) activity. We delineated the inhibitory role of SOCS-2 in IFN gamma signaling pathway by overexpression of exogenous SOCS-2 in HEK293 cell. The results showed that SOCS-2 suppressed the IFN gamma-activated STAT1 phosphorylation and consequent IFN gamma-regulated transcription of specific genes. To confirm the role of SOCS2 in the Tat-induced process, we demonstrated that SOCS-2 siRNA in human blood monocytes abrogated the Tat-dependent inhibition of IFN gamma signaling. Our data suggested a possible mechanism implicating the role of SOCS-2 in mediating HIV-1-induced immune evasion and dysregulation of IFN gamma signaling in primary human monocytes. (Blood. 2009; 113: 5192-5201)