3′ RNA Elements in Hepatitis C Virus Replication: Kissing Partners and Long Poly(U)

You, Shihyun; Rice, Charles M.

doi:10.1128/jvi.01796-07

Cited by 119 publications

(166 citation statements)

References 54 publications

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“…3). It has been reported that the length and composition of the poly(U/UC) tract is important for the replication of HCV replicons (Friebe & Bartenschlager, 2002;Yi & Lemon, 2003;You & Rice, 2008). However, no replication advantage of a poly(U/UC) tract longer than 86 bp was revealed in this study.…”

Section: Discussioncontrasting

confidence: 41%

“…Each segment of HCV was cloned into this vector to generate the full-length clones. The HCV-KT9 clone was established using the 39-terminal fragment with the longest poly(U/UC) tract length (115 nt), which should have a high replication ability (Friebe & Bartenschlager, 2002;Yi & Lemon, 2003;You & Rice, 2008). A clone with a shorter poly(U/UC) tract length (86 nt), HCV-KT1, was also generated.…”

Section: Methodsmentioning

confidence: 99%

“…We obtained 24 39-extremity clones with different poly(U/UC) tract lengths. We selected the clone with the longest (U/UC) tract because a previous study indicated that the length of poly(U/UC) tract correlates with HCV replication in an HCV replicon system (Friebe & Bartenschlager, 2002;Yi & Lemon, 2003;You & Rice, 2008). The length of the poly(U/UC) tract in the longest 39 clone was 115 nt.…”

Section: Characteristics Of Genotype 1b Clones Hcv-kt9 and Hcv-kt1mentioning

confidence: 99%

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Establishment of an infectious genotype 1b hepatitis C virus clone in human hepatocyte chimeric mice

Kimura

Imamura

Hiraga

et al. 2008

Journal of General Virology

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The establishment of clonal infection of hepatitis C virus (HCV) in a small-animal model is important for the analysis of HCV virology. A previous study developed models of molecularly cloned genotype 1a and 2a HCV infection using human hepatocyte-transplanted chimeric mice. This study developed a new model of molecularly cloned genotype 1b HCV infection. A full-length genotype 1b HCV genome, HCV-KT9, was cloned from a serum sample from a patient with severe acute hepatitis. The chimeric mice were inoculated intrahepatically with in vitro-transcribed HCV-KT9 RNA. Inoculated mice developed viraemia at 2 weeks post-infection, and this persisted for more than 6 weeks. Passage experiments indicated that the sera of these mice contained infectious HCV. Interestingly, a similar clone, HCV-KT1, in which the poly(U/UC) tract was 29 nt shorter than in HCV-KT9, showed poorer in vivo infectivity and replication ability. An in vitro study showed that no virus was produced in the culture medium from HCV-KT9-transfected cells. In conclusion, this study developed a genetically engineered genotype 1b HCV-infected mouse. This mouse model will be useful for the study of HCV virology, particularly the mechanism underlying the variable resistance of HCV genotypes to interferon therapy.

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Section: Discussioncontrasting

confidence: 41%

Section: Methodsmentioning

confidence: 99%

Section: Characteristics Of Genotype 1b Clones Hcv-kt9 and Hcv-kt1mentioning

confidence: 99%

See 1 more Smart Citation

Establishment of an infectious genotype 1b hepatitis C virus clone in human hepatocyte chimeric mice

Kimura

Imamura

Hiraga

et al. 2008

Journal of General Virology

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“…5'ppp was necessary but not sufficient for stable binding of HCV PAMP RNA by RIG-I. In terms of the HCV genome, well-defined internal RNA interactions of the 5' and 3' ends 21,22 could provide 5'ppp and PAMP motif proximity for stable RIG-I binding. The poly-U/UC motif is an essential determinant of HCV replication fitness 21 .…”

mentioning

confidence: 96%

“…In terms of the HCV genome, well-defined internal RNA interactions of the 5' and 3' ends 21,22 could provide 5'ppp and PAMP motif proximity for stable RIG-I binding. The poly-U/UC motif is an essential determinant of HCV replication fitness 21 . Thus, while the virus must maintain this motif for its viability, the host takes advantage of this requirement and targets the poly-U/UC region as a discriminator of PAMP RNA through RIG-I interaction.…”

mentioning

confidence: 99%

Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

Saito

Owen

Jiang

et al. 2008

Nature

672

735

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Innate immune defenses are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs) 1. Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people 2. Infection is governed by hepatic immune defenses triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals IRF-3 activation to induce the expression of α/β interferon (IFN) and antiviral/interferon-stimulated genes (ISGs) that limit infection 3 -10. Here we identified the poly-uridine motif of the HCV genome 3' nontranslated region (NTR) as the PAMP substrate of RIG-I, and show that this and similar homopoly-uridine motifs present in the genome of RNA viruses is the chief feature of RIG-I recognition and immune triggering 8. 5' terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent upon homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signaling to induce a hepatic innate immune response in vivo, and triggered IFN and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by identifying homopoly-uridine motfis present in the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and define immunogenic features of the PAMP/RIG-I interaction that could be utilized as an immune adjuvant for vaccine and immunotherapy approaches.To determine the nature of the HCV PAMP RNA we conducted a functional screen to identify possible HCV PAMP RNA motifs. We assessed the ability of full length HCV genome RNA or contiguous HCV RNA segments to trigger the IFN-β promoter in transfected Huh7 cells. The full-length HCV genome RNA triggered innate immune signaling to induce the IFN-β promoter (Fig. 1a). Two regions of the HCV RNA, encoding nt 2406-3256 and nt 8872-9616, stimulated significant induction of the IFN-β promoter (Fig. 1b) with signaling activity respectively localized to nt 2406-2696 of the open reading frame and nt 9389-9619 encoding the 3' NTR (Fig.1c). Deletion of nt 9389-9619 but not nt 2408-2663 from the HCV genome significantly attenuated signaling to the IFN-β promoter (Fig 1d). PAMP motifs are typically conserved among strains of a pathogen 1 , and sequence comparison of multiple HCV genomes revealed global variability within nt 2406-3696 among virus strains but nt 9389-9616 encoded motifs of high conservation (Fig. S1) Thus, the viral 3' NTR might encode HCV PAMP motifs that trigger innate immune signaling in the host cell.The HCV 3' NTR is comprised of three regions: a variable region (VR) with potential secondary structure, a nonstructured poly-U/UC region containing polyuridine with interspersed ribocytidine, and the terminal X region containing three conserved stem-loop structures (Fig. 1e) 12 . We evaluated the ability of RNA encoding the HCV 3' NTR or each of its regions to trigger intracellular si...

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Core‐Lations Between Intrinsic Disorder and Multifaceted Activities in Hepatitis C Virus and Related Viruses

2011

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3′ RNA Elements in Hepatitis C Virus Replication: Kissing Partners and Long Poly(U)

Cited by 119 publications

References 54 publications

Establishment of an infectious genotype 1b hepatitis C virus clone in human hepatocyte chimeric mice

Establishment of an infectious genotype 1b hepatitis C virus clone in human hepatocyte chimeric mice

Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

Core‐Lations Between Intrinsic Disorder and Multifaceted Activities in Hepatitis C Virus and Related Viruses

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