Hepatitis B Virus Basal Core Promoter Mutation and DNA Load Correlate with Expression of Hepatitis B Core Antigen in Patients with Chronic Hepatitis B

Liu, Chun‐Jen; Jeng, Yung‐Ming; Chen, Chi-Lin; Cheng, Huei‐Ru; Chen, Pei‐Jer; Chen, Ting-Chi; Liu, Chen–Hua; Lai, Ming-Yang; Chen, Ding‐Shinn; Kao, Jia‐Horng

doi:10.1086/596655

Cited by 30 publications

(23 citation statements)

References 47 publications

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“…Our observation of a predominantly cytoplasmic core phenotype in hepatoma cells after expression in the context of other viral proteins corresponds to histological data derived from HBV infected patients with low viral loads (Liu et al, 2009). The similarity between hepatoma cell lines and in vivo infection indicates that the level of cell differentiation has no major impact on core localization, and we conclude that viral factors are decisive.…”

Section: Discussionsupporting

confidence: 84%

“…An excess of pol would further interfere with capsid formation as each mature capsid/virion contains just one pol molecule (Bartenschlager & Schaller, 1992). Even if this assumption is still controversial (Zhang & Tavis, 2006), it is consistent with the observation that transfected cell lines produce fewer viruses than infected hepatocytes in vivo, and is in agreement with data from patient biopsies showing that cytoplasmic capsids are correlated with low viraemia (Liu et al, 2009). …”

Section: Discussionsupporting

confidence: 81%

“…The localization of core in humans is also variable: Akiba et al (1987) and Sharma et al (2002) observed more frequent nuclear localization while others observed a mainly cytoplasmic core and/or capsid localization (Liu et al, 2009;Michalak & Nowosławski, 1982;Park et al, 1999;Petit & Pillot, 1985). In terms of disease and viral load, the majority of studies associate cytoplasmic capsids with high hepatocellular injury (Chu et al, 1995Kim et al, 2006;Naoumov et al, 1990) and a low level viraemia (Liu et al, 2009) while nuclear dominance is associated with high viral load and minor hepatitis activity .…”

Section: Introductionmentioning

confidence: 99%

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Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Deroubaix

Osseman

Cassany

et al. 2015

Journal of General Virology

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Biopsies from patients show that hepadnaviral core proteins and capsids -collectively called core -are found in the nucleus and cytoplasm of infected hepatocytes. In the majority of studies, cytoplasmic core localization is related to low viraemia while nuclear core localization is associated with high viral loads. In order to better understand the molecular interactions leading to core localization, we analysed transfected hepatoma cells using immune fluorescence microscopy. We observed that expression of core protein in the absence of other viral proteins led to nuclear localization of core protein and capsids, while expression of core in the context of the other viral proteins resulted in a predominantly cytoplasmic localization. Analysis of which viral partner was responsible for cytoplasmic retention indicated that the HBx, surface proteins and HBeAg had no impact but that the viral polymerase was the major determinant. Further analysis revealed that e, an RNA structure to which the viral polymerase binds, was essential for cytoplasmic retention. Furthermore, we showed that core protein phosphorylation at Ser 164 was essential for the cytoplasmic core localization phenotype, which is likely to explain differences observed between individual cells.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Deroubaix

Osseman

Cassany

et al. 2015

Journal of General Virology

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“…Mutations in core regulatory elements involved in viral replication were described previously (8,13). Compared to HBsAg ϩ strains, deletions, insertions, and substitutions at single or multiple sites were observed in the CURS and BCP (15/21) regions of OBI strains (Table 4).…”

Section: Discussionmentioning

confidence: 83%

Characterization of Occult Hepatitis B Virus Infection from Blood Donors in China

Zheng

Wang

et al. 2011

J Clin Microbiol

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Prevalence and characteristics of occult hepatitis B virus (HBV) infection (OBI) of genotypes B and C prevalent inChina have not been extensively explored. Characterization of OBI strains obtained from Chinese blood donors was based on clinical and serological analyses, follow-up testing, and sequence analyses. Twentyeight samples from 165,371 HBV surface antigen (HBsAg)-negative plasmas were confirmed HBsAg negative and DNA positive(HBsAg ؊ /DNA ؉ ), of which 22 were classified as OBIs and 6 as window period infections. The OBI incidence was 1:7,517 in blood donors, whose ages ranged between 20 and 45 years (median, 28 years). OBI donors had normal alanine aminotransferase (ALT) levels and low viral loads ranging between unquantifiable amounts and 178 IU/ml (median, 14 IU/ml). Sequences from 21 basic core promoter/precore (BCP/PC) regions, five whole genomes, and two additional pre-S/S regions from OBI strains were compared to genotypes B and C HBsAg ؉ reference strains. Eighty-six percent (6/7) of OBI strains were genotype C. Deletions, insertions, stop codons, and substitutions were detected in 15/21 (71%) core regulatory elements of OBI strains. Critical mutations were found in the core proteins of 5/5 OBI strains in parallel with random substitutions in pre-S/S proteins from 6/7 (86%) OBI strains. Critical mutations in core regulatory elements and core proteins might affect OBI genotype B and C strain replication. That there were few S protein substitutions suggests a minor role of the host immune defenses in OBI occurrence.Hepatitis B virus (HBV) infection is a major threat to human health worldwide, especially to people living in developing countries. The number of HBV carriers with detectable surface antigen (HBsAg) is estimated to be over 300 million globally, while there are around 100 million HBVinfected individuals in mainland China (12). HBV serological testing is widely used in controlling the risk of HBV transmission among people who donate blood or have health examinations in China. However, some studies recently showed HBV DNA at low levels detected in HBsAgnegative individuals, some of whom transmitted HBV infections to recipients of blood transfusions (10). Occult hepatitis B virus infection (OBI) is defined as the detection of HBV DNA in the serum or liver tissue of patients who test negative for HBsAg (15). Currently, testing for HBsAg is performed for screening of HBV infection in blood donors in China, but nucleic acid testing (NAT) is not used.A characterization of OBI strains of genotypes A1, A2, D, and E in comparison with wild-type HBV in samples obtained from European and African blood donors was recently published. The mechanisms for generating OBI strains were mainly related to either imperfect immune control or to genetic viral defects and appeared largely genotype dependent (1, 4). However, analysis of OBI strains of genotypes B and C prevalent in Southeast Asia and China has not been extensively explored, particularly in terms of molecular characterization (14,20).This study prov...

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“…HBcAg tended to localize in the cytoplasm in the presence of the A1762T/G1764A double mutation (35,36). However, the localization of HBcAg from a fulminant HBV strain was changed to the nucleus when both G1862T and G1896A were also present (3).…”

Section: Discussionmentioning

confidence: 99%

Coexistence of Hepatitis B Virus Quasispecies Enhances Viral Replication and the Ability To Induce Host Antibody and Cellular Immune Responses

Cao

Shi

et al. 2014

J Virol

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Hepatitis IMPORTANCE Hepatitis B virus (HBV)is an important human pathogen. HBV quasispecies with genetically heterogenous variants are thought to play a role in the progression of HBV-associated liver diseases. So far, direct evidence is available in only a few cases to confirm the proposed role of HBV variants in the pathogenesis. We report here that the coexistence of two naturally occurring HBV variants at a ratio of 1 to 4 increased HBV replication and induced significantly stronger intrahepatic cytotoxic T lymphocyte responses and antibody responses specific to HBV surface antigen (HBsAg) in mice. Our discovery uncovered an unexpected aspect of HBV quasispecies: the coexistence of different variants can significantly modulate specific host immune responses and may enhance immune-mediated liver damage under some circumstances, representing a novel mechanism for the immunopathogenesis of HBV infection.

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Hepatitis B Virus Basal Core Promoter Mutation and DNA Load Correlate with Expression of Hepatitis B Core Antigen in Patients with Chronic Hepatitis B

Abstract: HBV BCP mutation and HBV load, but not genotype, contribute to the expression of intrahepatic HBcAg.

Cited by 30 publications

References 47 publications

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Characterization of Occult Hepatitis B Virus Infection from Blood Donors in China

Coexistence of Hepatitis B Virus Quasispecies Enhances Viral Replication and the Ability To Induce Host Antibody and Cellular Immune Responses

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