Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages.
Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages.
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DOI：
10.4049/jimmunol.0903563
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发表时间：
2010-08-15
期刊：
影响因子：
--
通讯作者：
Benveniste EN
中科院分区：
文献类型：
--
作者：
Akhtar LN;Qin H;Muldowney MT;Yanagisawa LL;Kutsch O;Clements JE;Benveniste EN
HIV-1在中枢神经系统巨噬细胞内的复制通常导致认知和运动障碍，这被称为最严重形式的HIV相关性痴呆（HAD）。IFN-β在早期CNS感染期间抑制这些细胞内的病毒复制，但效果是短暂的。HIV-1最终克服了这种保护性先天免疫反应，通过一种未知的机制恢复复制，开始向HAD发展。在这里，我们表明，抑制细胞因子信号（SOCS）3，IFN信号的分子抑制剂，可能会让HIV-1逃避中枢神经系统内的先天免疫。我们发现SOCS 3在HAD的体内SIV/猕猴模型中升高，并且表达模式与病毒复制的复发和CNS疾病的发作相关。在体外，HIV-1调节蛋白转录反式激活因子（达特）以NF-κ B依赖性方式诱导人和鼠巨噬细胞中的SOCS 3。SOCS 3表达在通路激活和下游抗病毒基因表达的近端水平上减弱巨噬细胞对IFN-β的应答，从而克服IFN-β对HIV-1复制的抑制作用。这些研究表明，由HIV-1感染的脑中存在的刺激物如达特诱导的SOCS 3表达抑制抗病毒IFN-β信号传导以增强HIV-1在巨噬细胞中的复制。SOCS 3在体外表达的这一结果得到了体内病毒载量增加和CNS疾病发作相关性的支持，表明SOCS 3可能允许HIV-1逃避CNS内的保护性先天免疫应答，允许病毒复制复发，并最终促进向HAD的进展。
HIV-1 replication within macrophages of the CNS often results in cognitive and motor impairment, which is known as HIV-associated dementia (HAD) in its most severe form. IFN-β suppresses viral replication within these cells during early CNS infection, but the effect is transient. HIV-1 eventually overcomes this protective innate immune response to resume replication through an unknown mechanism, initiating the progression toward HAD. Here, we show that Suppressor Of Cytokine Signaling (SOCS) 3, a molecular inhibitor of IFN signaling, may allow HIV-1 to evade innate immunity within the CNS. We find that SOCS3 is elevated in an in vivo SIV/macaque model of HAD, and that the pattern of expression correlates with recurrence of viral replication and onset of CNS disease. In vitro, the HIV-1 regulatory protein transactivator of transcription (Tat) induces SOCS3 in both human and murine macrophages in a NF-κB-dependent manner. SOCS3 expression attenuates the response of macrophages to IFN-β at both proximal levels of pathway activation and downstream antiviral gene expression, and consequently overcomes the inhibitory effect of IFN-β on HIV-1 replication. These studies indicate that SOCS3 expression, induced by stimuli present in the HIV-1-infected brain such as Tat, inhibits antiviral IFN-β signaling to enhance HIV-1 replication in macrophages. This consequence of SOCS3 expression in vitro, supported by a correlation with increased viral load and onset of CNS disease in vivo, suggests that SOCS3 may allow HIV-1 to evade the protective innate immune response within the CNS, allowing the recurrence of viral replication, and ultimately promoting progression toward HAD.
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影响因子：
20.3
作者：
Cheng, Sherman M.;Li, James C. B.;Lau, Allan S. Y.
通讯作者：
Lau, Allan S. Y.
影响因子：
4.8
作者：
Gatto, L;Berlato, C;Bazzoni, F
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Bazzoni, F
影响因子：
20.3
作者：
Cassatella, MA;Gasperini, S;Yoshimura, A
通讯作者：
Yoshimura, A
影响因子：
56.9
作者：
COCCHI, F;DEVICO, AL;LUSSO, P
通讯作者：
LUSSO, P
影响因子：
4.4
作者：
Ehlting, Christian;Lai, Wi S.;Bode, Johannes G.
通讯作者：
Bode, Johannes G.