The Coding Region of the HCV Genome Contains a Network of Regulatory RNA Structures

Pirakitikulr, Nathan; Kohlway, Andrew; Lindenbach, Brett D.; Pyle, Anna Marie

doi:10.1016/j.molcel.2016.01.024

Cited by 108 publications

(161 citation statements)

References 37 publications

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“…Discrete RNA structures have been suggested to participate in innate immune evasion and contribute to overall viral fitness [18–20]. Similar secondary structures were predicted within our sequence set.…”

Section: Resultssupporting

confidence: 75%

“…Similar secondary structures were predicted within our sequence set. SL1412 as described by Pirakitikulr and colleagues (2016), spans codons 357–371 of the amplicon (Fig 7) [18]. This region is implicated in significant synonymous-synonymous interactions, specifically codons 166 and 167 (Fig 3).…”

Section: Resultsmentioning

confidence: 99%

“…For HIV-1 it is well established that gene junctions are enriched in RNA secondary structures and that such structures facilitate recombination-mediated gene swapping [29]. Conserved secondary RNA structures have also been mapped along the entire length of the HCV genome including elements of the E1/E2 gene junction [18–20]. We have previously documented recombinants within our data set and identified the recombination breakpoints at the E1/E2 gene junction [7, 17].…”

Section: Discussionmentioning

confidence: 99%

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Synonymous Co-Variation across the E1/E2 Gene Junction of Hepatitis C Virus Defines Virion Fitness

Palmer

Fanning

2016

PLoS ONE

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Hepatitis C virus is a positive-sense single-stranded RNA virus. The gene junction partitioning the viral glycoproteins E1 and E2 displays concurrent sequence evolution with the 3′-end of E1 highly conserved and the 5′-end of E2 highly heterogeneous. This gene junction is also believed to contain structured RNA elements, with a growing body of evidence suggesting that such structures can act as an additional level of viral replication and transcriptional control. We have previously used ultradeep pyrosequencing to analyze an amplicon library spanning the E1/E2 gene junction from a treatment naïve patient where samples were collected over 10 years of chronic HCV infection. During this timeframe maintenance of an in-frame insertion, recombination and humoral immune targeting of discrete virus sub-populations was reported. In the current study, we present evidence of epistatic evolution across the E1/E2 gene junction and observe the development of co-varying networks of codons set against a background of a complex virome with periodic shifts in population dominance. Overtime, the number of codons actively mutating decreases for all virus groupings. We identify strong synonymous co-variation between codon sites in a group of sequences harbouring a 3 bp in-frame insertion and propose that synonymous mutation acts to stabilize the RNA structural backbone.

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Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Synonymous Co-Variation across the E1/E2 Gene Junction of Hepatitis C Virus Defines Virion Fitness

Palmer

Fanning

2016

PLoS ONE

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“…These results were reproducible across multiple RNAs and multiple target cell types. Importantly, recent work from numerous laboratories has used various SHAPE reagents in vitro, with results validated by a number of orthogonal techniques (Somarowthu et al 2015;Guo and Bartel 2016;Hawkes et al 2016;Pirakitikulr et al 2016). These published examples and our head-to-head comparison of SHAPE electrophiles provide clear and direct evidence that in vitro the reagents are largely equivalent.…”

Section: Resultsmentioning

confidence: 61%

Comparison of SHAPE reagents for mapping RNA structures inside living cells

Lee

Flynn

Kadina

et al. 2016

RNA

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Recent advances in SHAPE technology have converted the classic primer extension method to next-generation sequencing platforms, allowing transcriptome-level analysis of RNA secondary structure. In particular, icSHAPE and SHAPE-MaP, using NAI-N 3 and 1M7 reagents, respectively, are methods that claim to measure in vivo structure with high-throughput sequencing. However, these compounds have not been compared on an unbiased, raw-signal level. Here, we directly compare several in vivo SHAPE acylation reagents using the simple primer extension assay. We conclude that while multiple SHAPE technologies are effective at measuring purified RNAs in vitro, acylimidazole reagents NAI and NAI-N 3 give markedly greater signals with lower background than 1M7 for in vivo measurement of the RNA structurome.

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“…The latter observation has led to clinical proof-of-concept studies of an antagomir as an antiviral agent against hepatitis C [35,36]. Exciting discoveries continue to be generated, including the identification of additional layers of information within the genomic RNA (''codes within the code") [37], mechanisms regulating the turnover of viral RNA and its interactions with host proteins and microRNAs [38], and the discovery of HCV RNA as a 'microRNA sponge', with potential implications for the pathogenesis of hepatitis C and of HCV-related hepatocellular carcinoma (HCC) [39].…”

Section: Hcv Rnamentioning

confidence: 99%

Future landscape of hepatitis C research – Basic, translational and clinical perspectives

Moradpour

Grakoui

Manns

2016

Journal of Hepatology

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With the latest all-oral interferon- and ribavirin-free regimens based on direct acting antivirals against the hepatitis C virus (HCV), sustained virological response rates of >90% are achieved, which is equivalent to cure. This has become possible for all genotypes and all subgroups of patients, including many of the most difficult-to-treat populations so far. Since a prophylactic HCV vaccine is not yet available, control of HCV infection will for the time being have to rely on the use of effective and safe antiviral treatments as well as their accessibility and affordability. Different approaches may apply to different parts of the world, eradication of HCV representing a major long-term goal. Whether hepatitis C becomes the first chronic viral infection to be eradicated without a prophylactic vaccine remains to be shown. Here, we briefly summarize advances in the molecular virology of hepatitis C, highlight lessons of biological relevance that were learned through the study of HCV, and its translational and clinical implications. We have also listed selected unsolved challenges, emphasizing that HCV is a unique model and that advances in this direction may yield knowledge of broad biological significance, novel technologies and insights into related important human pathogens.

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The Coding Region of the HCV Genome Contains a Network of Regulatory RNA Structures

Cited by 108 publications

References 37 publications

Synonymous Co-Variation across the E1/E2 Gene Junction of Hepatitis C Virus Defines Virion Fitness

Synonymous Co-Variation across the E1/E2 Gene Junction of Hepatitis C Virus Defines Virion Fitness

Comparison of SHAPE reagents for mapping RNA structures inside living cells

Future landscape of hepatitis C research – Basic, translational and clinical perspectives

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