Correlation Between Hepatitis B G1896A Precore Mutations and HBeAg in Chronic HBV Patients

Zhand, Sareh; Karami, Chiman; Adli, Ahmad Hosseinzadeh; Tabarraei, Alijan; Khodabakhshi, Behnaz; Moradi, Abdolvahab

doi:10.5812/jjm.17126

Cited by 9 publications

(12 citation statements)

References 29 publications

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“…When G1986A mutation is paired with C1858T, the ε structure is more stabilized, thus enhancing viral replication. Therefore, development of G1896A mutation relies on the presence or absence of C or T at position 1858, which is genotype dependent ( 1 , 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…HBeAg is a viral protein secreted by HBV infected cells. HBeAg is thought to be an indicator of viral replication and to predict patient's degree of infectiousness, whereas presence of anti-HBe antibodies often indicates a low level of viral replication ( 1 ). The presence of HBeAg is pivotal in deciding treatment whereby oral antiviral medication is continued until HBeAg seroconversion is achieved ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

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G1896A Precore Mutation and Association With HBeAg Status, Genotype and Clinical Status in Patients With Chronic Hepatitis B

et al. 2015

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Background:Precore stop codon (G1896A) mutation is one of the commonest mutations found in patients with chronic hepatitis B. However, over the years, this mutation was not reported much in Malaysia.Objectives:We therefore investigated the presence of G1896A mutation in Malaysian population and its association with HBeAg status, clinical stage, hepatitis B virus (HBV) genotype and e-seroconversion rate.Patients and Methods:Serum samples from 93 patients confirmed as hepatitis B carriers were collected for molecular assay. The whole genome of HBV was amplified by polymerase chain reaction and directly sequenced. The precore and basal core promoter regions were analyzed for presence of mutations.Results:The most commonly observed mutation in the precore region was C1858T with 64.5% prevalence. The precore mutation of interest (G1896A) was identified in 25.8% of isolates. The basal core promoter mutations detected were A1762T-G1764A (26.9%), C1653T (8.6%), A1752G (10.8%) and C1766T (2.2%). No significant association was observed between G1896A mutation and HBeAg-negativity. Nonetheless, G1896A was highly prevalent among HBV genotype B. Clinical association revealed that subjects with G1896A mutations were mainly detected in asymptomatic chronic hepatitis B (58.3%) and liver cirrhosis (41.7%). One subject was diagnosed with fulminant hepatitis (4.2%) and 8.3% had hepatocellular carcinoma (HCC).Conclusions:Our data suggested an intermediate prevalence of G1896A mutation among Malaysian hepatitis B carriers. The stop codon mutation has a significant association with genotype B and patients with chronic hepatitis B and liver cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

G1896A Precore Mutation and Association With HBeAg Status, Genotype and Clinical Status in Patients With Chronic Hepatitis B

et al. 2015

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“…Enhanced NF-B activity in HBV G1896A bioptic liver tumor tissues from HBV-infected patients. In HBV infections, the mutation of G to A at genomic position 1896 (G1896A) gives rise to a precore/HBeAg-null variant of HBV (35,36). We selected bioptic liver samples infected with either the G1896A mutant (precore/HBeAg-null) or G1896 wt (precore/HBeAg positive) by excluding mixed genotypes (Fig.…”

Section: Figmentioning

confidence: 99%

Hepatitis B e Antigen Inhibits NF-κB Activity by Interrupting K63-Linked Ubiquitination of NEMO

Wang

Cui

Yang

et al. 2019

J Virol

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Viruses have adopted diverse strategies to suppress antiviral responses. Hepatitis B virus (HBV), a virus that is prevalent worldwide, manipulates the host's innate immune system to evade scavenging. It is reported that the hepatitis B e antigen (HBeAg) can interfere with NF-B activity, which then leads to high viral loads, while HBV with the G1896A mutation remains infectious without the production of HBeAg but can induce more severe proinflammatory response and liver damage. The aim of current work was to study the molecular mechanism by which HBeAg suppresses interleukin-1␤ (IL-1␤)-stimulated NF-B activity, which leads to the suppression of the innate immune responses to HBV infection. Our study revealed that HBeAg could interact with NEMO, a regulatory subunit associated with IB kinase, which regulates the activation of NF-B. HBeAg suppressed the IL-1␤-induced tumor necrosis factor (TNF)-associated factor 6 (TRAF6)-dependent K63-linked ubiquitination of NEMO, thereby downregulating NF-B activity and promoting virus replication. We further demonstrated the inhibitory effect of HBeAg on the NF-B signaling pathway using primary human hepatocytes, HBV-infected HepG2-NTCP cells, and clinical liver samples. Our study reveals a molecular mechanism whereby HBeAg suppresses IL-1␤-induced NF-B activation by decreasing the TRAF6dependent K63-linked ubiquitination of NEMO, which may thereby enhance HBV replication and promote a persistent infection. IMPORTANCE The role of HBeAg in inflammatory responses during the infection of hepatitis B virus (HBV) is not fully understood, and several previous reports with regard to the NF-B pathway are controversial. In this study, we showed that HBeAg could suppress both Toll-like receptor 2 (TLR2)-and IL-1␤-induced activation of NF-B in cells and clinical samples, and we further revealed novel molecular mechanisms. We found that HBeAg can associate with NEMO, the regulatory subunit for IB kinase (IKK) that controls the NF-B signaling pathway, and thereby inhibits TRAF6-mediated K63-linked ubiquitination of NEMO, resulting in downregulation of NF-B activity and promotion of virus replication. In contrast, the HBeAg-negative HBV mutant can induce higher levels of NF-B activity. These results are important for understanding the HBV-induced pathogenesis of chronic hepatitis and indicate that different clinical measures should be considered to treat HBeAg-positive and HBeAg-negative infections. Our findings represent a conceptual advance in HBV-related suppression of NF-B signaling.

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“…In natural infections, mutations in the precore region take place around the time of HBeAg seroconversion, and the most common one is a G to A substitution at nucleotide 1896 (G1896A), which prevents the production of precore and HBeAg, resulting in a natural HBeAg/precore-null HBV mutant. (22,23) We made use of such a natural mutation and selected two groups of bioptic liver tumor tissues infected with either HBV G1896 wt (HBeAg/precore-expressing) or the G1896A mutant (HBeAg/precore-null), with exclusion of mixed genotypes (Supporting Fig. S8A).…”

Section: Hbeag/precore Inhibits P53 Activity In Bioptic Liver Tumor Tmentioning

confidence: 99%

Hepatitis B e antigen and its precursors promote the progress of hepatocellular carcinoma by interacting with NUMB and decreasing p53 activity

et al. 2016

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Hepatitis B viral infection is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. Although several viral factors have been identified that may increase the risk for HCC development, the molecular mechanisms leading to the transformation of normal hepatocytes into cancer cells remain elusive. In this study, we demonstrated that the intracellular hepatitis B e antigen (HBeAg) and its precore precursors, but not their homologous core protein, could associate with NUMB and thereby impair the stability and transcriptional activity of tumor suppressor p53. HBeAg and its precursors could disrupt p53-NUMB and HDM2-NUMB interactions and tricomplex p53-HDM2-NUMB formation, inhibit the acetylation and translocation of p53 from cytosol to the nucleus, promote HDM2-mediated ubiquitination and degradation of p53, and suppress p53-dependent apoptosis. A xenograft tumorigenicity assay showed that expression of HBeAg and its precursors promoted carcinogenesis in a mouse model. Immunohistochemical analysis of the bioptic liver samples of HCC patients revealed that HBeAg positivity was associated with reduced transcriptional activity of p53. Taken together, the results suggest a role of intracellular HBeAg and its precursors in HCC development. Conclusion: HBeAg and its precursors promote HDM2-mediated degradation and impair transcriptional activity of p53 by interacting with NUMB, consequently contributing to HCC development. (HEPATOLOGY 2016;64:390-404) H epatitis B viral (HBV) infection represents a major public health problem, with more than 350 million humans chronically infected worldwide at risk of developing chronic liver diseases and hepatocellular carcinoma (HCC).(1) HBV is a small, enveloped DNA virus with four open reading frames (C, P, S, and X) in the genome, which results in expression of the seven different HBV proteins through use of varying in-frame start codons. For example, open reading frame preC-C encodes both hepatitis B core antigen (HBcAg) and the precore protein (p25), the latter being processed in the endoplasmic reticulum to produce hepatitis B e antigen (HBeAg or p17) and its intermediate (p22).It has been proposed that HBeAg may contribute to the development of liver cancer, and its role as a marker of active viral replication is most likely associated with increased risk of HCC.(2) Mutations in the precore region, which were the first major common variants of HBV discovered, (3) are first detectable around the time of HBeAg seroconversion and include mutations that prevent HBeAg synthesis without interfering with the production of infectious virions. The most common of these mutations is a G to A substitution at nucleotide 1896Abbreviations: EGFP, enhanced green fluorescent protein; HA, hemagglutinin; HBcAg, hepatitis B core antigen; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma; mRNA, messenger RNA; wt, wild type.

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Correlation Between Hepatitis B G1896A Precore Mutations and HBeAg in Chronic HBV Patients

Cited by 9 publications

References 29 publications

G1896A Precore Mutation and Association With HBeAg Status, Genotype and Clinical Status in Patients With Chronic Hepatitis B

G1896A Precore Mutation and Association With HBeAg Status, Genotype and Clinical Status in Patients With Chronic Hepatitis B

Hepatitis B e Antigen Inhibits NF-κB Activity by Interrupting K63-Linked Ubiquitination of NEMO

Hepatitis B e antigen and its precursors promote the progress of hepatocellular carcinoma by interacting with NUMB and decreasing p53 activity

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