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. 2018 Nov 1;10(11):603.
doi: 10.3390/v10110603.

Comprehensive Analysis of Hepatitis B Virus Promoter Region Mutations

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Free PMC article

Comprehensive Analysis of Hepatitis B Virus Promoter Region Mutations

Vanessa Meier-Stephenson et al. Viruses. .
Free PMC article

Abstract

Over 250 million people are infected chronically with hepatitis B virus (HBV), the leading cause of liver cancer worldwide. HBV persists, due, in part, to its compact, stable minichromosome, the covalently-closed, circular DNA (cccDNA), which resides in the hepatocytes' nuclei. Current therapies target downstream replication products, however, a true virological cure will require targeting the cccDNA. Finding targets on such a small, compact genome is challenging. For HBV, to remain replication-competent, it needs to maintain nucleotide fidelity in key regions, such as the promoter regions, to ensure that it can continue to utilize the necessary host proteins. HBVdb (HBV database) is a repository of HBV sequences spanning all genotypes (A⁻H) amplified from clinical samples, and hence implying an extensive collection of replication-competent viruses. Here, we analyzed the HBV sequences from HBVdb using bioinformatics tools to comprehensively assess the HBV core and X promoter regions amongst the nearly 70,000 HBV sequences for highly-conserved nucleotides and variant frequencies. Notably, there is a high degree of nucleotide conservation within specific segments of these promoter regions highlighting their importance in potential host protein-viral interactions and thus the virus' viability. Such findings may have key implications for designing antivirals to target these areas.

Keywords: Hepatitis B virus (HBV); X promoter; basal core promoter; cccDNA; genotype alignments; logo analyses; single nucleotide polymorphisms.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Schematic of the HBV genome. (A) From the (−)-strand DNA, overlapping reading frames code for gene segments C, P, S, and X. Transcripts are depicted by the outer thin lines and ending in the poly-A adenylation sequence. The X and Core promoter regions are highlighted by green rectangles preceding the corresponding gene. (B) Core promoter schematic.
Figure 2
Figure 2
HBV X and Core promoter regions. Upper bar represents the consensus sequence across all genotypes. Highlighted segments refer to previously identified binding sites for various host proteins. Stacked LOGO sequences are displayed per genotype to give a pictorial representation of conserved nucleotides and variants. The complete consensus for the core promoter (nts 1613–1849) is included in the Supplementary Figure S1.
Figure 2
Figure 2
HBV X and Core promoter regions. Upper bar represents the consensus sequence across all genotypes. Highlighted segments refer to previously identified binding sites for various host proteins. Stacked LOGO sequences are displayed per genotype to give a pictorial representation of conserved nucleotides and variants. The complete consensus for the core promoter (nts 1613–1849) is included in the Supplementary Figure S1.
Figure 3
Figure 3
High-risk HCC mutations by genotype. The average of each mutation across all genotypes is outlined by a dashed box. Asterixis refer to significance based on average value.

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