A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus
Ludmila Prokunina-Olsson,Brian Muchmore,Wei Tang,Ruth M. Pfeiffer,Heiyoung Park,Harold Dickensheets,Dianna Hergott,Patricia Porter-Gill,Adam Mumy,Indu Kohaar,Sabrina Chen,Nathan Brand,McAnthony Tarway,Luyang Liu,Faruk Sheikh,Jacquie Astemborski,Herbert L. Bonkovsky,Brian R. Edlin,Brian R. Edlin,Charles D. Howell,Timothy R. Morgan,Timothy R. Morgan,David L. Thomas,Barbara Rehermann,Raymond P. Donnelly,Thomas R. O'Brien +25 more
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TLDR
RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection provides new insights into the genetic regulation of HCV clearance and its clinical management.Abstract:
Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.read more
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Interferon-Stimulated Genes: A Complex Web of Host Defenses
TL;DR: This review begins by introducing interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production and describes ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the Jak-STAT pathway.
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Type I interferons in infectious disease.
TL;DR: Experimental models of tuberculosis have demonstrated that prostaglandin E2 and interleukin-1 inhibit type I IFN expression and its downstream effects, demonstrating that a cross-regulatory network of cytokines operates during infectious diseases to provide protection with minimum damage to the host.
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All-Oral 12-Week Treatment With Daclatasvir Plus Sofosbuvir in Patients With Hepatitis C Virus Genotype 3 Infection: ALLY-3 Phase III Study
David R. Nelson,James N. Cooper,Jacob Lalezari,Eric Lawitz,Paul J. Pockros,Norman Gitlin,B. Freilich,Ziad Younes,William Harlan,Reem Ghalib,Godson Oguchi,Paul J. Thuluvath,Grisell Ortiz-Lasanta,Mordechai Rabinovitz,David E. Bernstein,Michael J. Bennett,Trevor Hawkins,Natarajan Ravendhran,Aasim Sheikh,Peter Varunok,Kris V. Kowdley,Delphine Hennicken,Fiona McPhee,Khurram Rana,Eric Hughes +24 more
TL;DR: A 12‐week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated; there were no adverse events leading to discontinuation and only 1 serious AE on‐treatment, which was unrelated to study medications.
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Shared and Distinct Functions of Type I and Type III Interferons.
TL;DR: A model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient is discussed.
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Journal ArticleDOI
Table S2: Trans-factors and trinucleotide repeat instability Trans-factor
Journal ArticleDOI
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.
Dongliang Ge,Jacques Fellay,Alexander J. Thompson,Jason Simon,Kevin V. Shianna,Thomas J. Urban,Erin L. Heinzen,Ping Qiu,Arthur H. Bertelsen,Andrew J. Muir,Mark S. Sulkowski,John G. McHutchison,David Goldstein +12 more
TL;DR: It is reported that a genetic polymorphism near the IL28B gene, encoding interferon-λ-3 (IFN-α-2a) is associated with an approximately twofold change in response to treatment, both among patients of European ancestry and African-Americans.
Journal ArticleDOI
Production of infectious hepatitis C virus in tissue culture from a cloned viral genome
Takaji Wakita,Thomas Pietschmann,Takanobu Kato,Takanobu Kato,Tomoko Date,Michiko Miyamoto,Zijiang Zhao,Krishna K. Murthy,Anja Habermann,Hans-Georg Kräusslich,Masashi Mizokami,Ralf Bartenschlager,T. Jake Liang +12 more
TL;DR: It is shown that the JFH1 genome replicates efficiently and supports secretion of viral particles after transfection into a human hepatoma cell line (Huh7) and provides a powerful tool for studying the viral life cycle and developing antiviral strategies.
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