Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein.
Hangfei Qi,Virginia Chu,Nicholas C. Wu,Zugen Chen,Shawna Truong,Gurpreet Brar,Sheng Yao Su,Sheng Yao Su,Yushen Du,Yushen Du,Vaithilingaraja Arumugaswami,C. Anders Olson,Shu Hua Chen,Chung Yen Lin,Ting-Ting Wu,Ren Sun,Ren Sun +16 more
TLDR
In this paper, a high-throughput profiling platform was developed to enable mapping of hepatitis C virus (HCV) sequences critical for anti-IFN function at high resolution, and it was found that p7 is a critical immune evasion protein that suppresses the antiviral IFN function by counteracting the function of IFI6-16.Abstract:
Hepatitis C virus (HCV) encodes mechanisms to evade the multilayered antiviral actions of the host immune system. Great progress has been made in elucidating the strategies HCV employs to down-regulate interferon (IFN) production, impede IFN signaling transduction, and impair IFN-stimulated gene (ISG) expression. However, there is a limited understanding of the mechanisms governing how viral proteins counteract the antiviral functions of downstream IFN effectors due to the lack of an efficient approach to identify such interactions systematically. To study the mechanisms by which HCV antagonizes the IFN responses, we have developed a high-throughput profiling platform that enables mapping of HCV sequences critical for anti-IFN function at high resolution. Genome-wide profiling performed with a 15-nt insertion mutant library of HCV showed that mutations in the p7 region conferred high levels of IFN sensitivity, which could be alleviated by the expression of WT p7 protein. This finding suggests that p7 protein of HCV has an immune evasion function. By screening a liver-specific ISG library, we identified that IFI6-16 significantly inhibits the replication of p7 mutant viruses without affecting WT virus replication. In contrast, knockout of IFI6-16 reversed the IFN hypersensitivity of p7 mutant virus. In addition, p7 was found to be coimmunoprecipitated with IFI6-16 and to counteract the function of IFI6-16 by depolarizing the mitochondria potential. Our data suggest that p7 is a critical immune evasion protein that suppresses the antiviral IFN function by counteracting the function of IFI6-16.read more
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A CRISPR screen identifies IFI6 as an ER-resident interferon effector that blocks flavivirus replication.
R. Blake Richardson,Maikke B. Ohlson,Jennifer L. Eitson,Ashwani Kumar,Matthew B. McDougal,Ian N. Boys,Katrina B. Mar,Pamela C. De La Cruz-Rivera,Connor Douglas,Genevieve Konopka,Chao Xing,John W. Schoggins +11 more
TL;DR: Findings support a model in which the IFN response is armed with a membrane-targeted effector that discriminately blocks the establishment of virus-specific ER microenvironments that are required for replication.
Journal ArticleDOI
Virus control of cell metabolism for replication and evasion of host immune responses
TL;DR: This review explores how viruses mimic, exploit or interfere with host cell metabolic pathways and how, in doing so, they may evade immune responses.
Journal ArticleDOI
Recent advances in antiviral interferon-stimulated gene biology.
TL;DR: This review highlights selected recent findings of ISG effectors that contribute to the understanding of the interferon antiviral response.
Journal ArticleDOI
High-Throughput Fitness Profiling of Zika Virus E Protein Reveals Different Roles for Glycosylation during Infection of Mammalian and Mosquito Cells
Danyang Gong,Tian-hao Zhang,Dawei Zhao,Yushen Du,Travis J. Chapa,Yuan Shi,Laurie Wang,Deisy Contreras,Gang Zeng,Pei Yong Shi,Ting-Ting Wu,Vaithilingaraja Arumugaswami,Ren Sun +12 more
TL;DR: A gene-wide mapping of functional residues of ZIKV E protein using a mutant library, with changes covering every nucleotide position is reported, showing that ablation of glycosylation selectively benefits ZikV infection of mosquito cells by enhancing cell entry, whereas it either has little impact on Zika virus infection on certain human cells or leads to decreased infection through the entry factor DC-SIGN.
Journal ArticleDOI
Acute Infection of Viral Pathogens and Their Innate Immune Escape.
Kul Raj Rai,Prasha Shrestha,Bincai Yang,Yuhai Chen,Shasha Liu,Mohamed Maarouf,Ji-Long Chen,Ji-Long Chen +7 more
TL;DR: In this article, the authors discuss the pathogenesis of acute infections caused by viral pathogens and highlight broad immune escape strategies exhibited by viruses, including physical barriers, various phagocytic cells, group of cytokines, interferons, and IFN-stimulated genes.
References
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TL;DR: The institution of blood-screening measures in developed countries has decreased the risk of transfusion-associated hepatitis to a negligible level, but new cases continue to occur mainly as a result of injection-drug use and, to a lesser degree, through other means of percutaneous or mucous-membrane exposure.
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TL;DR: Cardif is described, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKα, IKKβ and IKKɛ kinases by means of its C-terminal region, leading to the activation of NF-κB and IRF3.
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TL;DR: This Review discusses four main effector pathways of the IFN-mediated antiviral response: the Mx GTPase pathway, the 2′,5′-oligoadenylate-synthetase-directed ribonuclease L pathways, the protein kinase R pathway and the ISG15 ubiquitin-like pathway.
Journal ArticleDOI
A diverse range of gene products are effectors of the type I interferon antiviral response
John W. Schoggins,Sam J. Wilson,Maryline Panis,Mary Murphy,Christopher T. Jones,Paul D. Bieniasz,Charles M. Rice +6 more
TL;DR: It is shown that different viruses are targeted by unique sets of ISGs, and that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities.
Journal ArticleDOI
Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection
Nezam H. Afdhal,Stefan Zeuzem,Paul Y. Kwo,Mario Chojkier,Norman Gitlin,Massimo Puoti,Manuel Romero-Gómez,Jean-Pierre Zarski,Kosh Agarwal,Peter Buggisch,Graham R. Foster,Norbert Bräu,Maria Buti,Ira M. Jacobson,G. Mani Subramanian,Xiao Ding,Hongmei Mo,Jenny C. Yang,Phillip S. Pang,William T. Symonds,John G. McHutchison,Andrew J. Muir,Alessandra Mangia,Patrick Marcellin +23 more
TL;DR: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection.