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1.  Differential, Type I Interferon-Mediated Autophagic Trafficking of Hepatitis C Virus Proteins in Mouse Liver 
Gastroenterology  2011;141(2):674-685.e6.
BACKGROUND & AIMS
The hepatitis C virus (HCV) serine protease NS3/4A can cleave mitochondria-associated, anti-viral signaling protein (MAVS) and block retinoic acid-inducible gene I–mediated interferon (IFN) responses. Although this mechanism is thought to have an important role in HCV-mediated innate immunosuppression, its significance in viral persistence is not clear.
METHODS
We generated transgenic mice that express the HCV NS3/4A proteins specifically in the liver and challenged the animals with a recombinant vesicular stomatitis virus (VSV), a synthetic HCV genome, IFN-α, or IFN-β. We evaluated the effects of HCV serine protease on the innate immune responses and their interactions.
RESULTS
Expression of HCV NS3/4A resulted in cleavage of intrahepatic MAVS; challenge of transgenic mice with VSV or a synthetic HCV genome induced strong, type I IFN-mediated responses that were not significantly lower than those of control mice. Different challenge agents induced production of different ratios of IFN-α and -β, resulting in different autophagic responses and vesicular trafficking patterns of endoplasmic reticulum- and mitochondria-associated viral proteins. IFN-β promoted degradation of the viral proteins by the autolysosome. Variant isoforms of MAVS were associated with distinct, type I IFN-mediated autophagic responses; these responses have a role in trafficking of viral components to endosomal compartments that contain toll-like receptor -3.
CONCLUSIONS
IFN-β-mediates a distinct autophagic mechanism of anti-viral host defense. MAVS have an important role in type I IFN-induced autophagic trafficking of viral proteins.
doi:10.1053/j.gastro.2011.04.060
PMCID: PMC3152629  PMID: 21683701
Autophagy; TLR3; liver disease; RIG-I
2.  IFNα/β and autophagy 
Autophagy  2011;7(11):1394-1396.
Hepatitis C virus (HCV) infects approximately 130 million people worldwide. The clinical sequelae of this chronic disease include cirrhosis, functional failure and carcinoma of the liver. HCV induces autophagy, a fundamental cellular process for maintaining homeostasis and mediating innate immune response, and also inhibits autophagic protein degradation and suppresses antiviral immunity. In addition to this ploy, the HCV serine protease composed of the viral nonstructural proteins 3/4A (NS3/4A) can enzymatically digest two cellular proteins, mitochondria-associated antiviral signaling protein (MAVS) and toll/interleukin-1 receptor domain containing adaptor inducing IFNβ (TRIF). Since these two proteins are the adaptor molecules in the retinoic acid-inducible gene I (RIG-I) and TLR3 pathways, respectively, their cleavage has been suggested as a pivotal mechanism by which HCV blunts the IFNα/β signaling and antiviral responses. Thus far, how HCV perturbs autophagy and copes with IFNα/β in the liver remains unclear.
doi:10.4161/auto.7.11.17514
PMCID: PMC3359484  PMID: 21997372
autophagy; hepatitis C virus; liver disease; NS3/4A protease; RIG-I; Type I interferon; TLR3; transgenic mouse
3.  Aberrant transcription and post-transcriptional processing of hepatitis C virus non-structural genes in transgenic mice 
Transgenic research  2011;20(6):1273-1284.
Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease worldwide. Since several aspects of the infection remain unresolved, there is a pressing need for a convenient animal model that can mimic the clinical disease and aid the evaluation of treatment strategies. Although some success has been achieved in transgenic approaches for development of rodent models of HCV, transgenic expression of the complete HCV polyprotein or an entire set of the viral non-structural (NS) proteins continues to be a serious challenge. Using northern blot and 5′ rapid amplification of cDNA ends (RACE), we unraveled two possible mechanisms that can impede HCV NS transgene expression in the mouse liver. Several truncated transcripts are produced from alternate transcription start sites along the HCV NS sequence within the murine environment, in vivo. Translation of these shorter transcripts is blocked either by the positioning of a contextual stop codon or through a shift in the reading frame. In addition, the complete NS transcript undergoes trans-splicing through 5′ recombination with a non-transgene-derived, spliced leader sequence that appends a potential stop codon upstream of the translation start. These findings thus demonstrate that HCV NS-derived transgenes are subject to aberrant transcriptional initiation and post-transcriptional processing in the nucleus of a mouse host. Strategies to prevent such aberrant transcription start/RNA processing might be key to the development of a successful HCV transgenic mouse model.
doi:10.1007/s11248-011-9494-x
PMCID: PMC3188684  PMID: 21347690
Hepatitis C virus; Non-structural proteins; Transgenic mouse; Aberrant transcription; Trans-splicing

Results 1-3 (3)