Effects of HBV Genetic Variability on RNAi Strategies

Panjaworayan, Nattanan; Brown, C. M.

doi:10.1155/2011/367908

Cited by 5 publications

(3 citation statements)

References 65 publications

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“…Viral RNA elements have been identified as antiviral targets due to conservation of sequence and functions that are distinguishable from the host (Panjaworayan and Brown, 2011 ; Chen et al, 2014 ; Cardno et al, 2015 ; Le Grice, 2015 ; Hermann, 2016 ; Hilimire et al, 2017 ). For example, the internal ribosome entry sites (IRES) of hepatitis C virus (HCV) is targeted by benzimidazole (Dibrov et al, 2012 ).…”

Section: Know Your Enemymentioning

confidence: 99%

Know Your Enemy: Successful Bioinformatic Approaches to Predict Functional RNA Structures in Viral RNAs

Lim

Brown

2018

Front. Microbiol.

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Structured RNA elements may control virus replication, transcription and translation, and their distinct features are being exploited by novel antiviral strategies. Viral RNA elements continue to be discovered using combinations of experimental and computational analyses. However, the wealth of sequence data, notably from deep viral RNA sequencing, viromes, and metagenomes, necessitates computational approaches being used as an essential discovery tool. In this review, we describe practical approaches being used to discover functional RNA elements in viral genomes. In addition to success stories in new and emerging viruses, these approaches have revealed some surprising new features of well-studied viruses e.g., human immunodeficiency virus, hepatitis C virus, influenza, and dengue viruses. Some notable discoveries were facilitated by new comparative analyses of diverse viral genome alignments. Importantly, comparative approaches for finding RNA elements embedded in coding and non-coding regions differ. With the exponential growth of computer power we have progressed from stem-loop prediction on single sequences to cutting edge 3D prediction, and from command line to user friendly web interfaces. Despite these advances, many powerful, user friendly prediction tools and resources are underutilized by the virology community.

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Section: Know Your Enemymentioning

confidence: 99%

Know Your Enemy: Successful Bioinformatic Approaches to Predict Functional RNA Structures in Viral RNAs

Lim

Brown

2018

Front. Microbiol.

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“…Understanding the sequence variations of the RNA stem-loops is also important for antiviral siRNA (small interfering RNA) design, as siRNA targeting the SLa region has been effective in vitro. [23][24][25]…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus nuclear export elements: RNA stem-loop α and β, key parts of the HBV post-transcriptional regulatory element

Lim

Brown

2016

RNA Biology

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Many viruses contain RNA elements that modulate splicing and/or promote nuclear export of their RNAs. The RNAs of the major human pathogen, hepatitis B virus (HBV) contain a large (~600 bases) composite cis-acting 'post-transcriptional regulatory element' (PRE). This element promotes expression from these naturally intronless transcripts. Indeed, the related woodchuck hepadnavirus PRE (WPRE) is used to enhance expression in gene therapy and other expression vectors. These PRE are likely to act through a combination of mechanisms, including promotion of RNA nuclear export. Functional components of both the HBV PRE and WPRE are 2 conserved RNA cis-acting stem-loop (SL) structures, SLα and SLβ. They are within the coding regions of polymerase (P) gene, and both P and X genes, respectively. Based on previous studies using mutagenesis and/or nuclear magnetic resonance (NMR), here we propose 2 covariance models for SLα and SLβ. The model for the 30-nucleotide SLα contains a G-bulge and a CNGG(U) apical loop of which the first and the fourth loop residues form a CG pair and the fifth loop residue is bulged out, as observed in the NMR structure. The model for the 23-nucleotide SLβ contains a 7-base-pair stem and a 9-nucleotide loop. Comparison of the models with other RNA structural elements, as well as similarity searches of human transcriptome and viral genomes demonstrate that SLα and SLβ are specific to HBV transcripts. However, they are well conserved among the hepadnaviruses of non-human primates, the woodchuck and ground squirrel.

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“…Indeed RNAi strategies against the conserved HBV ε region have been effective despite its secondary structure. This structure was expected to reduce the ability of siRNAs or synthetic miRNAs to target this region 36 . In addition, the protein/RNA interaction in replication and the initiation of replication has been a target of anti-HBV drugs 37 …”

Section: Discussionmentioning

confidence: 99%

Distinct families ofcis-acting RNA replication elements epsilon from hepatitis B viruses

Chen

Brown²

2012

RNA Biology

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The hepadnavirus encapsidation signal, epsilon (ε), is an RNA structure located at the 5′ end of the viral pregenomic RNA. It is essential for viral replication and functions in polymerase protein binding and priming. This structure could also have potential regulatory roles in controlling the expression of viral replicative proteins. In addition to its structure, the primary sequence of this RNA element has crucial functional roles in the viral lifecycle. Although the ε elements in hepadnaviruses share common critical functions, there are some significant differences in mammalian and avian hepadnaviruses, which include both sequence and structural variations. Here we present several covariance models for ε elements from the Hepadnaviridae. The model building included experimentally determined data from previous studies using chemical probing and NMR analysis. These models have sufficient similarity to comprise a clan. The clan has in common a highly conserved overall structure consisting of a lower-stem, bulge, upper-stem and apical-loop. The models differ in functionally critical regions—notably the two types of avian ε elements have a tetra-loop (UGUU) including a non-canonical UU base pair, while the hepatitis B virus (HBV) epsilon has a tri-loop (UGU). The avian epsilon elements have a less stable dynamic structure in the upper stem. Comparisons between these models and all other Rfam models, and searches of genomes, showed these structures are specific to the Hepadnaviridae. Two family models and the clan are available from the Rfam database.

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Effects of HBV Genetic Variability on RNAi Strategies

Cited by 5 publications

References 65 publications

Know Your Enemy: Successful Bioinformatic Approaches to Predict Functional RNA Structures in Viral RNAs

Know Your Enemy: Successful Bioinformatic Approaches to Predict Functional RNA Structures in Viral RNAs

Hepatitis B virus nuclear export elements: RNA stem-loop α and β, key parts of the HBV post-transcriptional regulatory element

Distinct families ofcis-acting RNA replication elements epsilon from hepatitis B viruses

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