Vpu Mediates Depletion of Interferon Regulatory Factor 3 during HIV Infection by a Lysosome-Dependent Mechanism
Vpu Mediates Depletion of Interferon Regulatory Factor 3 during HIV Infection by a Lysosome-Dependent Mechanism
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DOI：
10.1128/jvi.00423-12
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发表时间：
2012-08-01
影响因子：
5.4
通讯作者：
Gale, Michael, Jr.
中科院分区：
文献类型：
--
作者：
Doehle, Brian P.;Chang, Kristina;Gale, Michael, Jr.
艾滋病毒已经进化出复杂的机制，通过细胞内的天然免疫防御来避免限制，否则就可以控制急性病毒感染和病毒传播。当宿主细胞的模式识别受体(PRR)蛋白与病毒产物中存在的病原体相关分子模式(PAMP)相结合时，固有防御被触发。干扰素调节因子3(IRF3)在先天免疫的PRR信号转导中起核心作用，可驱动I型干扰素(IFN)和干扰素刺激基因(ISGs)的表达，包括多种HIV限制性因子，这些因子可直接限制病毒复制和/或编程适应性免疫。艾滋病毒对T细胞的有效感染依赖于IRF3的靶向蛋白降解，这种降解是通过病毒引导的机制发生的，这种机制导致了天然免疫防御的抑制。然而，HIV控制先天免疫信号和IRF3功能的机制还没有确定。在这里，我们研究了通过对PRR信号的差异控制而识别的HIV毒株诱导的先天免疫反应。我们发现了不同于典型的流行的HIV毒株的病毒，它们缺乏降解IRF3的能力。我们的研究表明，IRF3调控特异性地映射到HIV辅助蛋白VPU。我们定义了VPU和IRF3之间的分子相互作用，将IRF3重定向到内溶酶体内进行蛋白质降解，从而使HIV能够避免先天的抗病毒免疫反应。我们的研究表明，VPU是一个重要的IRF3调节因子，通过先天免疫抑制支持急性HIV感染。这些观察结果将VPU-IRF3接口定义为旨在增强对艾滋病毒免疫反应的治疗策略的新靶点。
HIV has evolved sophisticated mechanisms to avoid restriction by intracellular innate immune defenses that otherwise serve to control acute viral infection and virus dissemination. Innate defenses are triggered when pattern recognition receptor (PRR) proteins of the host cell engage pathogen-associated molecule patterns (PAMPs) present in viral products. Interferon regulatory factor 3 (IRF3) plays a central role in PRR signaling of innate immunity to drive the expression of type I interferon (IFN) and interferon-stimulated genes (ISGs), including a variety of HIV restriction factors, that serve to limit viral replication directly and/or program adaptive immunity. Productive infection of T cells by HIV is dependent upon the targeted proteolysis of IRF3 that occurs through a virus-directed mechanism that results in suppression of innate immune defenses. However, the mechanisms by which HIV controls innate immune signaling and IRF3 function are not defined. Here, we examined the innate immune response induced by HIV strains identified through their differential control of PRR signaling. We identified viruses that, unlike typical circulating HIV strains, lack the ability to degrade IRF3. Our studies show that IRF3 regulation maps specifically to the HIV accessory protein Vpu. We define a molecular interaction between Vpu and IRF3 that redirects IRF3 to the endolysosome for proteolytic degradation, thus allowing HIV to avoid the innate antiviral immune response. Our studies reveal that Vpu is an important IRF3 regulator that supports acute HIV infection through innate immune suppression. These observations define the Vpu-IRF3 interface as a novel target for therapeutic strategies aimed at enhancing the immune response to HIV.