Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression

Choi, Yu Min; Lee, So Young; Kim, Bum Joon

doi:10.3748/wjg.v24.i16.1708

Cited by 43 publications

(61 citation statements)

References 127 publications

(234 reference statements)

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“…Some RT mutations, such as rtI91L, have been positively associated with HCC; however, this has not been experimentally confirmed in vitro and is considered a putative nucleotide analogues-resistant mutation. These mutations have been reported in Bangladesh as well [25,48].…”

Section: Discussionmentioning

confidence: 74%

PreS1 Mutations Alter the Large HBsAg Antigenicity of a Hepatitis B Virus Strain Isolated in Bangladesh

Hossain

Mahmud

Nazir

et al. 2020

IJMS

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Mutations in the hepatitis B virus (HBV) genome can potentially lead to vaccination failure, diagnostic escape, and disease progression. However, there are no reports on viral gene expression and large hepatitis B surface antigen (HBsAg) antigenicity alterations due to mutations in HBV isolated from a Bangladeshi population. Here, we sequenced the full genome of the HBV isolated from a clinically infected patient in Bangladesh. The open reading frames (ORFs) (P, S, C, and X) of the isolated HBV strain were successfully amplified and cloned into a mammalian expression vector. The HBV isolate was identified as genotype C (sub-genotype C2), serotype adr, and evolutionarily related to strains isolated in Indonesia, Malaysia, and China. Clinically significant mutations, such as preS1 C2964A, reverse transcriptase domain I91L, and small HBsAg N3S, were identified. The viral P, S, C, and X genes were expressed in HEK-293T and HepG2 cells by transient transfection with a native subcellular distribution pattern analyzed by immunofluorescence assay. Western blotting of large HBsAg using preS1 antibody showed no staining, and preS1 ELISA showed a significant reduction in reactivity due to amino acid mutations. This mutated preS1 sequence has been identified in several Asian countries. To our knowledge, this is the first report investigating changes in large HBsAg antigenicity due to preS1 mutations.

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Section: Discussionmentioning

confidence: 74%

PreS1 Mutations Alter the Large HBsAg Antigenicity of a Hepatitis B Virus Strain Isolated in Bangladesh

Hossain

Mahmud

Nazir

et al. 2020

IJMS

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“…Studies have shown that HBV gene resistance mutations are associated with infected HBV genotypes [8,10]. Some scholars believe that HBV C genotype is more prevalent resistant than B genotype [11,12], but some scholars have found that A181T/V mutation, ETV resistance mutation and multidrug resistance mutation is more predominant in C genotype than B genotype, The incidence of M204I and N236T mutation in B genotypes was higher than that of in C genotype [13]. Some scholars believe that the treatment responses of NAs are similar in each genotype, but there are differences among the primary resistance mutations [14].…”

Section: Discussionmentioning

confidence: 99%

Retrospective Analysis of HBV Pre-Existing Mutations and Drug-induced Resistance Mutations in Patients with Hepatitis B Virus-Related Cirrhosis

Wang

Dai

et al. 2019

IGH

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Background: The reported prevalence and necessity of detection of HBV reverse transcriptase (RT) mutation prior to treatment is varied and remains controversial. This study aimed to identify the prevalence of HBV pre-existing gene resistance mutations and compare the difference between pre-existing mutations and drug-induced resistance mutations in patients with hepatitis B virus-related cirrhosis.Methods: 180 patients with hepatitis B virus-related cirrhosis which included 68 patients with virological breakthrough and 112 treatment-naive cirrhosis patients were retrospectively enrolled. The drug-resistant mutations of HBV reverse transcriptase domain were screened by direct gene sequencing. One-way ANOVA analysis was performed in the comparison among different groups. Ratios difference was compared with the chi-square test.Results: There were 48 patients (48/112, 42.86%) with drug resistance mutations in nucleoside/nucleotide analogues (NAs) treatment-naive group, 59 patients (59/68, 86.76%) showed drug-resistant mutations in the NAs treatment group. The gene resistance mutation patterns in treatment-naive group were mainly rtS213T, rtV214A, 191V/I and rtN/H238T/D, and the types of resistance mutations in the treated group were different. The adefovir (ADV) group: mainly rtA181T/V and rtS213T; lamivudine/ telbivudine (LAM/LDT) group: rtL180M+ rtM204I/V/S and rtM204I/V/S or a complex mutation pattern containing 204 site; entecavir (ETV) group: The drug resistance pattern is the simultaneous presence of multiple site mutations. LAM/LDT sequential ADV group: The variant type was multi-site and resistant to both ADV and LAM.Conclusion: There was a prevalence of pre-existing mutations in RT region of HBV polymerase in patients with hepatitis B virus-related cirrhosis, The mutation pattern is mainly related to LAM and ADV-related compensatory mutations, while the drug-induced mutation pattern is more complicated, mainly related to the antiviral drugs used and there are mainly primary mutations. Patients with cirrhosis should be tested genetic resistance mutation before using antiviral drugs.

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“…BN constructed using these sites was shown to detect RR or SR with high accuracy (CA = 98.8%), while achieving the expected accuracy (CA = 53.4%) on randomlabeled data. It is interesting that among the selected 22 sites, 6 located at the RT positions 82, 139, 153, 191, 223 and 233 have been reported as related to drug resistance [31][32][33] . Thus, the findings of groups rather than individual Protein 3D-structure mapping.…”

Section: Sr/rr-associated Mutationsmentioning

confidence: 99%

Complex genetic encoding of the hepatitis B virus on-drug persistence

Thai

Lara

et al. 2020

Sci Rep

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Tenofovir disoproxil fumarate (TDF) is one of the nucleotide analogs capable of inhibiting the reverse transcriptase (RT) activity of HIV and hepatitis B virus (HBV). There is no known HBV resistance to TDF. However, detectable variation in duration of HBV persistence in patients on TDF therapy suggests the existence of genetic mechanisms of on-drug persistence that reduce TDF efficacy for some HBV strains without affording actual resistance. Here, the whole genome of intra-host HBV variants (N = 1,288) was sequenced from patients with rapid (RR, N = 5) and slow response (SR, N = 5) to TDF. Association of HBV genomic and protein polymorphic sites to RR and SR was assessed using phylogenetic analysis and Bayesian network methods. We show that, in difference to resistance to nucleotide analogs, which is mainly associated with few specific mutations in RT, the HBV on-TDF persistence is defined by genetic variations across the entire HBV genome. Analysis of the inferred 3D-structures indicates no difference in affinity of TDF binding by RT encoded by intra-host HBV variants that rapidly decline or persist in presence of TDF. This finding suggests that effectiveness of TDF recognition and binding does not contribute significantly to on-drug persistence. Differences in patterns of genetic associations to TDF response between HBV genotypes B and C and lack of a single pattern of mutations among intra-host variants sensitive to TDF indicate a complex genetic encoding of the trait. We hypothesize that there are many genetic mechanisms of on-drug persistence, which are differentially available to HBV strains. These pervasive mechanisms are insufficient to prevent viral inhibition completely but may contribute significantly to robustness of actual resistance. On-drug persistence may reduce the overall effectiveness of therapy and should be considered for development of more potent drugs.

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Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression

Cited by 43 publications

References 127 publications

PreS1 Mutations Alter the Large HBsAg Antigenicity of a Hepatitis B Virus Strain Isolated in Bangladesh

PreS1 Mutations Alter the Large HBsAg Antigenicity of a Hepatitis B Virus Strain Isolated in Bangladesh

Retrospective Analysis of HBV Pre-Existing Mutations and Drug-induced Resistance Mutations in Patients with Hepatitis B Virus-Related Cirrhosis

Complex genetic encoding of the hepatitis B virus on-drug persistence

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