Human Immunodeficiency Virus Type 1 Mediates Global Disruption of Innate Antiviral Signaling and Immune Defenses within Infected Cells
Human Immunodeficiency Virus Type 1 Mediates Global Disruption of Innate Antiviral Signaling and Immune Defenses within Infected Cells
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DOI：
10.1128/jvi.00849-09
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发表时间：
2009-10-15
影响因子：
5.4
通讯作者：
Gale, Michael, Jr.
中科院分区：
文献类型：
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作者：
Doehle, Brian P.;Hladik, Florian;Gale, Michael, Jr.
干扰素调节因子3（IRF-3）是限制病毒复制的先天性细胞内免疫防御所必需的，但这些防御无法抑制人类免疫缺陷病毒（HIV）感染，最终可能与机会性合并感染和进展为AIDS相关。在这里，我们检查了病毒感染和合并感染期间CD 4（+）细胞中的抗病毒防御，揭示了HIV-1（HIV-1）通过抑制IRF-3指导先天免疫信号传导的全面破坏并支持合并感染模型。T细胞对副粘病毒感染作出反应，激活IRF-3和干扰素刺激的基因表达，但它们未能对HIV-1作出反应。反应的缺乏与HIV-1感染细胞中IRF-3而不是IRF-7的显著消耗相关，这支持了强大的病毒复制，而活性IRF-3的异位表达抑制了HIV-1感染。IRF-3消耗依赖于生产性HIV-1复制周期，并导致Toll样受体和RIG-I样受体先天免疫信号传导的特异性破坏，使细胞允许继发性病毒感染。在体内，急性HIV-1感染患者的CD 4（+）T细胞中IRF-3水平降低，但长期无进展者的IRF-3水平未降低。我们的研究结果表明，IRF-3的病毒抑制通过破坏IRF-3依赖的信号通路和宿主细胞的先天抗病毒防御来促进HIV-1感染。IRF-3可能指导先天性抗病毒反应，调节HIV-1复制和病毒设定点，同时控制对机会性病毒合并感染的易感性。
Interferon regulatory factor 3 (IRF-3) is essential for innate intracellular immune defenses that limit virus replication, but these defenses fail to suppress human immunodeficiency virus (HIV) infection, which can ultimately associate with opportunistic coinfections and the progression to AIDS. Here, we examined antiviral defenses in CD4(+) cells during virus infection and coinfection, revealing that HIV type 1 (HIV-1) directs a global disruption of innate immune signaling and supports a coinfection model through suppression of IRF-3. T cells responded to paramyxovirus infection to activate IRF-3 and interferon-stimulated gene expression, but they failed to mount a response against HIV-1. The lack of response associated with a marked depletion of IRF-3 but not IRF-7 in HIV-1-infected cells, which supported robust viral replication, whereas ectopic expression of active IRF-3 suppressed HIV-1 infection. IRF-3 depletion was dependent on a productive HIV-1 replication cycle and caused the specific disruption of Toll-like receptor and RIG-I-like receptor innate immune signaling that rendered cells permissive to secondary virus infection. IRF-3 levels were reduced in vivo within CD4(+) T cells from patients with acute HIV-1 infection but not from long-term nonprogressors. Our results indicate that viral suppression of IRF-3 promotes HIV-1 infection by disrupting IRF-3-dependent signaling pathways and innate antiviral defenses of the host cell. IRF-3 may direct an innate antiviral response that regulates HIV-1 replication and viral set point while governing susceptibility to opportunistic virus coinfections.