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在接受直接抗病毒药物（DAA）治疗后，丙型肝炎病毒（HCV）感染患者血液和人源化小鼠肝脏中固有免疫失调的快速逆转。

Rapid reversal of innate immune dysregulation in blood of patients and livers of humanized mice with HCV following DAA therapy.

作者信息

Burchill Matthew A, Roby Justin A, Crochet Nanette, Wind-Rotolo Megan, Stone Amy E, Edwards Michael G, Dran Rachael J, Kriss Michael S, Gale Michael, Rosen Hugo R

机构信息

Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver (UCD), Aurora, Colorado, United States of America.

Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, United States of America.

出版信息

PLoS One. 2017 Oct 17;12(10):e0186213. doi: 10.1371/journal.pone.0186213. eCollection 2017.

DOI:10.1371/journal.pone.0186213
PMID:29040318
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5645093/
Abstract

RESULTS

First, in patients receiving two different combinations of DAAs, we found that DAAs induced not only rapid viral clearance, but also a re-setting of antiviral immune responses in the peripheral blood. Specifically, we see a rapid decline in the expression of genes associated with chronic IFN stimulation (IFIT3, USP18, IFIT1) as well as a rapid decline in genes associated with inflammation (IL1β, CXCL10, CXCL11) in the peripheral blood that precedes the complete removal of virus from the blood. Interestingly, this rapid reversal of innate immune activation was not seen in patients who successfully clear chronic HCV infection using IFN-based therapy. Next, using a novel humanized mouse model (Fah-/-RAG2-/-IL2rgnull-FRG), we assessed the changes that occur in the hepatic tissue following DAA treatment. DAA-mediated rapid HCV clearance resulted in blunting of the expression of proinflammatory responses while functionally restoring the RIG-I/MAVS axis in the liver of humanized mice.

CONCLUSIONS

Collectively, our data demonstrate that the rapid viral clearance following treatment with DAAs results in the rebalancing of innate antiviral response in both the peripheral blood and the liver as well as enhanced antiviral signaling within previously infected hepatocytes.

摘要

结果

首先，在接受两种不同直接抗病毒药物（DAA）组合治疗的患者中，我们发现DAA不仅能诱导病毒快速清除，还能在外周血中重新设定抗病毒免疫反应。具体而言，我们观察到与慢性干扰素刺激相关的基因（IFIT3、USP18、IFIT1）表达迅速下降，以及在外周血中与炎症相关的基因（IL1β、CXCL10、CXCL11）表达迅速下降，这一现象发生在血液中病毒被完全清除之前。有趣的是，在使用基于干扰素的疗法成功清除慢性丙型肝炎病毒感染的患者中，未观察到这种先天免疫激活的快速逆转。接下来，我们使用一种新型人源化小鼠模型（Fah-/-RAG2-/-IL2rgnull-FRG），评估了DAA治疗后肝组织中发生的变化。DAA介导的丙型肝炎病毒快速清除导致促炎反应表达减弱，同时在人源化小鼠肝脏中功能性恢复RIG-I/MAVS轴。

结论

总体而言，我们的数据表明，DAA治疗后病毒的快速清除导致外周血和肝脏中先天抗病毒反应的重新平衡，以及先前感染的肝细胞内抗病毒信号增强。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b45d/5645093/5694140a6fa9/pone.0186213.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b45d/5645093/ffb61e0a71f0/pone.0186213.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b45d/5645093/56cef35ee707/pone.0186213.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b45d/5645093/5a164aab51ea/pone.0186213.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b45d/5645093/5694140a6fa9/pone.0186213.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b45d/5645093/ffb61e0a71f0/pone.0186213.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b45d/5645093/56cef35ee707/pone.0186213.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b45d/5645093/5a164aab51ea/pone.0186213.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b45d/5645093/5694140a6fa9/pone.0186213.g004.jpg

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