Pathogen-Associated Molecular Pattern Recognition of Hepatitis C Virus Transmitted/Founder Variants by RIG-I Is Dependent on U-Core Length
Pathogen-Associated Molecular Pattern Recognition of Hepatitis C Virus Transmitted/Founder Variants by RIG-I Is Dependent on U-Core Length
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DOI：
10.1128/jvi.01964-15
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发表时间：
2015-11-01
影响因子：
5.4
通讯作者：
Gale, Michael, Jr.
中科院分区：
文献类型：
--
作者：
Kell, Alison;Stoddard, Mark;Gale, Michael, Jr.
尽管针对丙型肝炎病毒 (HCV) 引入了直接作用抗病毒 (DAA) 药物，但感染仍然是一个主要的公共卫生问题，因为 DAA 疗法不能预防再感染，而且患者仍可能发展为慢性肝病。慢性 HCV 感染受到多种病毒免疫逃避策略的支持，但值得注意的是，20% 至 30% 的急性感染在出现适应性免疫反应之前会自发清除，因此暗示先天免疫可以解决急性 HCV 感染。然而，调节急性感染的病毒-宿主相互作用尚不清楚。 HCV 的传播涉及一种或几种传播/创始人 (T/F) 变异。在受感染的肝细胞中，视黄酸诱导基因 I (RIG-I) 蛋白识别 HCV RNA 的 5' 三磷酸 (5' ppp) 和位于由聚 U/UC 组成的 3' 非翻译区内的病原体相关分子模式 (PAMP) 基序。 PAMP 结合激活 RIG-I 诱导先天免疫信号传导和 1 型干扰素抗病毒防御。 HCV Poly-U/UC 序列的长度和复杂性可能不同，这表明 T/F 基因组中的 PAMP 多样性可以调节急性 HCV 感染的先天免疫控制。使用从急性感染患者身上回收的 HCV T/F 基因组中的 14 个独特的 Poly-U/UC 序列，我们测试了 RIG-I 识别和先天免疫激活是否与 PAMP 序列特征相关。我们表明，T/F 变体以依赖于聚 U/UC PAMP 的 U 核心基序长度的方式被 RIG-I 识别，并被 RIG-I 识别以诱导限制急性感染的先天免疫反应。因此，RIG-I 对 T/F HCV 变体的 PAMP 识别可能会赋予先天免疫信号传导和 HCV 限制，从而影响急性期到慢性期的转变。重要性识别非自身分子模式（例如病毒核酸中所见的分子模式）是触发对病毒感染的免疫反应的重要步骤。先天免疫是由丙型肝炎病毒感染通过细胞 RIG-I 蛋白识别病毒 RNA 诱导的，其中 RIG-I 识别病毒基因组中的多聚尿苷/胞嘧啶基序。该基序内的变异可能为急性感染期间传播/创始人病毒提供免疫逃避策略。使用从急性感染的 HCV 患者中回收的 HCV T/F 基因组中的 14 个独特的 Poly-U/UC 序列，我们证明 RIG-I 结合和先天免疫的激活主要取决于该基序内尿苷核心的长度。在急性感染中发现的 T/F 变体在基序内包含更长的 U 核心，可以激活 RIG-I 并诱导足以限制病毒感染的先天免疫信号。因此，RIG-I 对 T/F 变异的识别可能会显着影响从急性感染到慢性感染的转变。
Despite the introduction of direct-acting antiviral (DAA) drugs against hepatitis C virus (HCV), infection remains a major public health concern because DAA therapeutics do not prevent reinfection and patients can still progress to chronic liver disease. Chronic HCV infection is supported by a variety of viral immune evasion strategies, but, remarkably, 20% to 30% of acute infections spontaneously clear prior to development of adaptive immune responses, thus implicating innate immunity in resolving acute HCV infection. However, the virus-host interactions regulating acute infection are unknown. Transmission of HCV involves one or a few transmitted/founder (T/F) variants. In infected hepatocytes, the retinoic acid-inducible gene I (RIG-I) protein recognizes 5' triphosphate (5' ppp) of the HCV RNA and a pathogen-associated molecular pattern (PAMP) motif located within the 3' untranslated region consisting of poly-U/UC. PAMP binding activates RIG-I to induce innate immune signaling and type 1 interferon antiviral defenses. HCV poly-U/UC sequences can differ in length and complexity, suggesting that PAMP diversity in T/F genomes could regulate innate immune control of acute HCV infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acute-infection patients, we tested whether RIG-I recognition and innate immune activation correlate with PAMP sequence characteristics. We show that T/F variants are recognized by RIG-I in a manner dependent on length of the U-core motif of the poly-U/UC PAMP and are recognized by RIG-I to induce innate immune responses that restrict acute infection. PAMP recognition of T/F HCV variants by RIG-I may therefore impart innate immune signaling and HCV restriction to impact acute-phase-to-chronic-phase transition.IMPORTANCERecognition of nonself molecular patterns such as those seen with viral nucleic acids is an essential step in triggering the immune response to virus infection. Innate immunity is induced by hepatitis C virus infection through the recognition of viral RNA by the cellular RIG-I protein, where RIG-I recognizes a poly-uridine/cytosine motif in the viral genome. Variation within this motif may provide an immune evasion strategy for transmitted/founder viruses during acute infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acutely infected HCV patients, we demonstrate that RIG-I binding and activation of innate immunity depend primarily on the length of the uridine core within this motif. T/F variants found in acute infection contained longer U cores within the motif and could activate RIG-I and induce innate immune signaling sufficient to restrict viral infection. Thus, recognition of T/F variants by RIG-I could significantly impact the transition from acute to chronic infection.