The evolution and clinical impact of hepatitis B virus genome diversity

Revill, Peter; Tu, Thomas; Netter, Hans Jürgen; Yuen, Lilly; Locarnini, Stephen; Littlejohn, Margaret

doi:10.1038/s41575-020-0296-6

Cited by 106 publications

(91 citation statements)

References 242 publications

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“…Patients with genotype A have more favourable response to interferon-α compared to patients with genotype D [11]. These differences suggest distinct genotypes may influence the severity of liver disease and treatment effectiveness [12]. However, it remains unclear whether there is an association between HBV genotypes and drug-resistant mutations.…”

Section: Introductionmentioning

confidence: 99%

Biological characteristics of rt181T/sW172* HBV are similar among distinct genotypes

Huaqiang

Jiajuan

et al. 2020

Preprint

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Background: The influence of genotypes on disease progression and clinical outcome of HBV infection is noted. The impact of HBV genotypes on rtA181T/sW172* mutation remains unclear. Patients and Methods: Clinical characteristics of 69 patients with rtA181T/sW172* mutation and 39 patients with rtA181V mutation were analyzed in this study. Fifteen serum specimens with rtA181T/sW172* mutation from different genotypes were collected for cloning and sequence analysis. HBV markers in HepG2 cells encoding different proportions of rtA181T/sW172* mutation and wild type strains were detected in genotype A, B, C and D, respectively.Results: No statistically difference was detected between rtA181T and rtA181V group regarding mean age, sex ratio, liver functions, HBV DNA load and HBeAg positive rate, except for HBsAg level (rtA181T group = 3.07±0.54 lg IU/ml vs rtA181V group = 3.29±0.43 lg IU/ml, P=0.037). Among 69 patients with rtA181T/sW172* mutation, HBV genotypes B and C accounted for 17.0% and 83.0%, respectively. The rate of genotype B was lower in rtA181T group (10.1%) than that in rtA181V group (29.7%), whereas genotype C was higher in rtA181T group (89.9%) than that in rtA181V group (70.3%). HBV rtA181T/sW172* mutant coexisted with wild type strains, accounted for 25% to 90% in all HBV strains. The distribution proportion showed no statistical difference between genotype B and C (59.2%±24.3% vs. 61.2%±19.1% , P=0.86). In transfection experiments, the level of HBV DNA was the highest for genotype B, while HBsAg was expressed in the highest level for genotype A. HBsAg and virus particle were barely detected in the supernatants of rtA181T/sW172* HBV clones in all genotypes. As the proportion of wild type HBV plasmid increased, deficiency of rt181T/sW172* mutation was complemented in all genotypes. No significant difference of the relative expression was found among distinct genotypes (P >0.05).Conclusions: HBV rtA181T/sW172* mutational pattern may be influenced by genotypes, but biological characteristics of this mutation is similar among distinct genotypes.

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Section: Introductionmentioning

confidence: 99%

Biological characteristics of rt181T/sW172* HBV are similar among distinct genotypes

Huaqiang

Jiajuan

et al. 2020

Preprint

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“…Many strains of HBV have arisen from distinct geographical distributions of the world. This is partly due to the long history of virus-host coevolution (over 50,000 years) and the lack of proofreading function of the viral reverse transcriptase (2)(3)(4) . These strains were grouped into 9 major genotypes (A to I) and putative J, and about 30 sub-genotypes (4,5) .…”

Section: Introductionmentioning

confidence: 99%

“…This is partly due to the long history of virus-host coevolution (over 50,000 years) and the lack of proofreading function of the viral reverse transcriptase (2)(3)(4) . These strains were grouped into 9 major genotypes (A to I) and putative J, and about 30 sub-genotypes (4,5) . There are marked differences in replication phenotype and disease natural history across HBV genotypes (6,7) , yet the pathogenicity of different HBV genotypes and their implications for treatment are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, different HBV genotypes may produce distinct spliced transcript isoforms whose precise roles are largely unknown (11)(12)(13)(14) . At least 17 spliced transcripts of pgRNA (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) and 4 spliced transcripts of preS2/S (27,28) were identified in various sources including liver, serum, and transfected cells. Interestingly, a recent study showed that HBV RNA splicing is more efficient in human hepatoma cells than other tested cell-types (14) .…”

Section: Introductionmentioning

confidence: 99%

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Quantitative analysis of the splice variants expressed by the major hepatitis B virus genotypes

Lim

Sozzi

Revill

et al. 2020

Preprint

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Hepatitis B virus (HBV) is a major human pathogen that causes liver diseases. The main HBV RNAs are unspliced transcripts that encode the key viral proteins. Recent studies show that some of the HBV spliced transcript isoforms are predictive of liver cancer, yet the roles of these spliced transcripts remain elusive. Furthermore, a total of 9 major HBV genotypes were isolated from discrete geographical regions of the world, it is likely that these genotypes may express a broad variety of spliced transcript isoforms. To systematically study the HBV splice variants, we transfected the human hepatoma cells Huh7 with 4 HBV genotypes (A2, B2, C2, and D3), followed by deep RNA-sequencing. We found that 12-25% of HBV RNAs were splice variants, which were reproducibly detected across independent biological replicates. This accounted for a total of 6 novel and 6 previously identified splice variants. In particular, two highly abundant novel splice variants, in which we called the putative splice variants 1 and 5 (pSP1 and pSP5), were specifically expressed at high levels in genotypes D3 and B2, respectively. In general, the HBV splicing profiles varied across the genotypes except for the known spliced pgRNAs SP1 and SP9, which were present in all 4 major genotypes. Counterintuitively, these singly spliced SP1 and SP9 had a suboptimal 5′ splice site, suggesting that splicing of HBV RNAs is tightly controlled by the viral post-transcriptional regulatory RNA element.

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“…Previous studies indicated that Chronic HBV infection is associated with the emergence of mutations throughout the viral genome that result in the generation of diverse viral populations or quasispecies[3]. Point mutations unable to produce e antigen often become the dominant viral quasispecies in viral population present in the infected individual.…”

Section: Introductionmentioning

confidence: 99%

The effect of basal core promoter and pre-core mutations on HBV replication and persistence in mice

Chen

Zeng

et al. 2020

Preprint

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The appearance of the BCP or Pre-C mutations, which reduce or abolish HBeAg production, could increase HBV replication. The remove of the HBeAg often lead to a vigorous immune response, which has an important role in HBV related fulminant outcome. In this study, BCP mutations and Pre-C mutations were separately introduced by site-directed mutagenesis in the same genetic background of an HBV infectious clone, to determine the effect of these mutations per se on replication. BCP and Pre-C mutations increased HBV replication both in vitro and in vivo . HBV could persist in mice injected with wild type HBV infectious clone for about 7 weeks. However, HBV could persist about 5 weeks in mice injected with BCP HBV infectious clone, and 3 weeks only in mice injected with Pre-C HBV infectious clone. HBV related CD8+ CTL response in BCP HBV infectious clone injected mice only slightly increased, but significantly increased in Pre-C HBV infectious clone injected mice compared with that in wild type HBV infectious clone injected mice. The population of Tregs significantly increased in liver but not in spleen of mice injected with Pre-C HBV infectious clone. In summary, we demonstrate that HBeAg plays an important role in suppressing the CTL response, which is related with increasing the frequency of Tregs in mouse. Lack of HBeAg expression leads to the partial loss of immune tolerance.

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The evolution and clinical impact of hepatitis B virus genome diversity

Cited by 106 publications

References 242 publications

Biological characteristics of rt181T/sW172* HBV are similar among distinct genotypes

Biological characteristics of rt181T/sW172* HBV are similar among distinct genotypes

Quantitative analysis of the splice variants expressed by the major hepatitis B virus genotypes

The effect of basal core promoter and pre-core mutations on HBV replication and persistence in mice

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