Hepatitis C virus RNA: Dinucleotide frequencies and cleavage by RNase L

Washenberger, Christopher L.; Han, Jian; Kechris, Katerina; Jha, Babal K.; Silverman, Robert H.; Barton, David J.

doi:10.1016/j.virusres.2007.05.020

Cited by 64 publications

(61 citation statements)

References 69 publications

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“…The antiviral function of IFN-␣ depends on direct antiviral actions through transcriptional activation of many ISGs. Two ISGs, encoding OAS and PKR, have been shown to inhibit HCV infection in several studies (26,41,63,66,69,71), and we confirmed their anti-HCV function as described above. We then studied the impact of the Ras/Raf/MEK pathway on these two ISGs.…”

Section: Knockdown Of Raf1 Inhibits Hcv Replicationsupporting

confidence: 87%

Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Zhang

Gong

et al. 2012

J Virol

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Hepatitis C virus (HCV) is a major cause of chronic liver diseases worldwide, often leading to the development of hepatocellular carcinoma (HCC). Constitutive activation of the Ras/Raf/MEK pathway is responsible for approximately 30% of cancers. Here we attempted to address the correlation between activation of this pathway and HCV replication. We showed that knockdown of Raf1 inhibits HCV replication, while activation of the Ras/Raf/MEK pathway by V12, a constitutively active form of Ras, stimulates HCV replication. We further demonstrated that this effect is regulated through attenuation of the interferon (IFN)-JAK-STAT pathway. Activation of the Ras/Raf/MEK pathway downregulates the expression of IFN-stimulated genes (ISGs), attenuates the phosphorylation of STAT1/2, and inhibits the expression of interferon (alpha, beta, and omega) receptors 1 and 2 (IFNAR1/2). Furthermore, we observed that HCV infection activates the Ras/Raf/MEK pathway. Thus, we propose that during HCV infection, the Ras/Raf/MEK pathway is activated, which in turn attenuates the IFN-JAK-STAT pathway, resulting in stimulation of HCV replication.

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Section: Knockdown Of Raf1 Inhibits Hcv Replicationsupporting

confidence: 87%

Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Zhang

Gong

et al. 2012

J Virol

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“…UpA dinucleotides, in contrast, are direct substrates for cleavage of single-stranded RNA by endoribonucleases (4, 17, 46), including the antiviral RNase L (22,66). Rates of RNA degradation may increase in templates rich in UpA and decrease in homologous templates rich in CpG (17).…”

Section: Discussionmentioning

confidence: 99%

Genetic Inactivation of Poliovirus Infectivity by Increasing the Frequencies of CpG and UpA Dinucleotides within and across Synonymous Capsid Region Codons

Burns

Campagnoli

Shaw

et al. 2009

J Virol

156

169

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Replicative fitness of poliovirus can be modulated systematically by replacement of preferred capsid region codons with synonymous unpreferred codons. To determine the key genetic contributors to fitness reduction, we introduced different sets of synonymous codons into the capsid coding region of an infectious clone derived from the type 2 prototype strain MEF-1. Replicative fitness in HeLa cells, measured by plaque areas and virus yields in single-step growth experiments, decreased sharply with increased frequencies of the dinucleotides CpG (suppressed in higher eukaryotes and most RNA viruses) and UpA (suppressed nearly universally). Replacement of MEF-1 capsid codons with the corresponding codons from another type 2 prototype strain (Lansing), a randomization of MEF-1 synonymous codons, increased the %G؉C without increasing CpG, and reductions in the effective number of codons used had much smaller individual effects on fitness. Poliovirus fitness was reduced to the threshold of viability when CpG and UpA dinucleotides were saturated within and across synonymous codons of a capsid region interval representing only ϳ9% of the total genome. Codon replacements were associated with moderate decreases in total virion production but large decreases in the specific infectivities of intact poliovirions and viral RNAs. Replication of codon replacement viruses, but not MEF-1, was temperature sensitive at 39.5°C. Synthesis and processing of viral intracellular proteins were largely unaltered in most codon replacement constructs. Replacement of natural codons with synonymous codons with increased frequencies of CpG and UpA dinucleotides may offer a general approach to the development of attenuated vaccines with well-defined antigenicities and very high genetic stabilities.Diversification of genomic sequences is constrained in all biological systems. At the level of primary sequences, the range of variability in coding regions is restricted by the codon usage bias (CUB), whereby a subset of synonymous codons are preferentially used in translation (24,53,69). The intensity of the CUB and the specific set of preferred codons vary widely across biological systems (39). Intertwined with the CUB is the suppression of the dinucleotides CpG and TpA (or UpA in RNA viruses) in the genomes of higher eukaryotes (4,7,26,61) and many of their RNA viruses and small DNA viruses (28,49). Variation in the primary sequences of RNA virus genomes is further constrained by requirements to maintain essential secondary and higher-order structures (42, 54, 68).We previously described the modulation of the replicative fitness of the Sabin type 2 oral poliovirus vaccine (OPV) strain (Sabin 2) by systematically changing the CUB in the capsid region, replacing the naturally occurring preferred codons with an unpreferred synonymous codon (isocodon) for each of nine amino acids (8). We called our approach "codon deoptimization" to contrast with the process of codon optimization, which is frequently used to maximize expression of foreign proteins in he...

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“…It remains to be determined how the RNase L ciRNA contributes to group C enterovirus replication and pathogenesis ). If RNase L were to cleave viral RNA, one would expect to see reduced frequencies of UA and UU dinucleotides within the viral RNAs due to the selective pressure of RNase L cleavage at such sites (Washenberger et al 2007). Group C enteroviruses do not have reduced frequencies of UA and UU dinucleotides characteristic of RNase L selective pressure (data not shown), suggesting that these viruses avoid cleavage of their RNAs by RNase L. The ciRNA described in this report may be important in this regard.…”

Section: Discussionmentioning

confidence: 99%

A viral RNA competitively inhibits the antiviral endoribonuclease domain of RNase L

Townsend

Jha

Han

et al. 2008

RNA

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Ribonuclease L (RNase L) is a latent endoribonuclease in an evolutionarily ancient interferon-regulated dsRNA-activated antiviral pathway. 29-59 oligoadenylate (2-5A), the product of dsRNA-activated oligoadenylate synthetases (OASes), binds to ankyrin repeats near the amino terminus of RNase L, initiating a series of conformational changes that result in the activation of the endoribonuclease. A phylogenetically conserved RNA structure within group C enteroviruses inhibits the endoribonuclease activity of RNase L. In this study we report the mechanism by which group C enterovirus RNA inhibits RNase L. Viral RNA did not affect 2-5A binding to RNase L. Rather, the viral RNA inhibited the endoribonuclease domain. We used purified RNase L, purified 2-5A, and an RNA substrate with a 59 fluorophore and 39 quencher in FRET assays to measure inhibition of RNase L activity by the viral RNA. The group C enterovirus RNA was a competitive inhibitor of the endoribonuclease with a K i of 34 nM. Consistent with the kinetic profile of a competitive inhibitor, the viral RNA inhibited the constitutively active endoribonuclease domain of RNase L. We call this viral RNA the RNase L competitive inhibitor RNA (RNase L ciRNA).

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Hepatitis C virus RNA: Dinucleotide frequencies and cleavage by RNase L

Cited by 64 publications

References 69 publications

Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway

Genetic Inactivation of Poliovirus Infectivity by Increasing the Frequencies of CpG and UpA Dinucleotides within and across Synonymous Capsid Region Codons

A viral RNA competitively inhibits the antiviral endoribonuclease domain of RNase L

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