Amino Acid Substitutions at Positions 122 and 145 of Hepatitis B Virus Surface Antigen (HBsAg) Determine the Antigenicity and Immunogenicity of HBsAg and Influence<i>In Vivo</i>HBsAg Clearance

Wu, Chunchen; Deng, Wanyu; Deng, Lei; Cao, Liang; Qin, Bo; Li, Songxia; Wang, Yun; Pei, Rongjuan; Yang, Dongliang; Lu, Mengji; Chen, Xinwen

doi:10.1128/jvi.06353-11

Cited by 78 publications

(73 citation statements)

References 31 publications

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“…Oon et al (32) reported that HBV carriers, including HCC patients who were negative for HBsAg but positive for anti-HBc and anti-HBs, had the T126S, Q129D, M133L, T140I, and G145R mutations within the S region. Wu et al (31) reported that amino acid residues at positions 122 and 145 of HBsAg had a major effect on antigenicity and immunogenicity. HBsAg mutants can escape current detection and persist in HBV-infected individuals after the loss of HBsAg (32).…”

Section: Discussionmentioning

confidence: 99%

Application of a Newly Developed High-Sensitivity HBsAg Chemiluminescent Enzyme Immunoassay for Hepatitis B Patients with HBsAg Seroclearance

et al. 2013

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We modified and automated a highly sensitive chemiluminescent enzyme immunoassay (CLEIA) for surface antigen (HBsAg) detection using a combination of monoclonal antibodies, each for a specific epitope of HBsAg, and by improving an earlier conjugation technique. Of 471 hepatitis B virus (HBV) carriers seen in our hospital between 2009 and 2012, 26 were HBsAg seronegative as determined by the Abbott Architect assay. The Lumipulse HBsAg-HQ assay was used to recheck those 26 patients who demonstrated seroclearance by the Abbott Architect assay. The performance of the Lumipulse HBsAg-HQ assay was compared with that of a quantitative HBsAg detection system (Abbott Architect) and the Roche Cobas TaqMan HBV DNA assay (CTM) (lower limit of detection, 2.1 log copies/ml) using blood serum samples from patients who were determined to be HBsAg seronegative by the Abbott Architect assay. Ten patients had spontaneous HBsAg loss. Of 8 patients treated with nucleotide analogues (NAs), two were HBsAg seronegative after stopping lamivudine therapy and 6 were HBsAg seronegative during entecavir therapy. Eight acute hepatitis B (AH) patients became HBsAg seronegative. Of the 26 patients, 16 were HBsAg positive by the Lumipulse HBsAg-HQ assay but negative by the Abbott Architect assay. The differences between the two assays in terms of detectable HBsAg persisted over the long term in the spontaneous loss group (median, 10 months), the NA-treated group (2.5 months), and the AH group (0.5 months). In 9 patients, the Lumipulse HBsAg-HQ assay detected HBsAg when HBV DNA was negative by the CTM assay. HBsAg was also detected by the Lumipulse HBsAg-HQ assay in 4 patients with an anti-HBs concentration of >10 mIU/ml, 3 of whom had no HBsAg escape mutations. The automatic, highly sensitive HBsAg CLEIA Lumipulse HBsAg-HQ is a convenient and precise assay for HBV monitoring.T oday, Ͼ400 million people worldwide are hepatitis B virus (HBV) carriers (1). We have monitored HBV markers, such as HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HB core-related antigen (HBcrAg), in chronic hepatitis B patients. The measurement of HBV DNA levels by a PCR-based method is the state-of-the-art technique for monitoring HBV replication in clinical practice (2). However, it is suboptimal for chronic hepatitis B patients who are medicated with nucleotide analogues (NAs), as those, in many cases, can decrease HBV DNA to below the limit of detection.HBsAg is a secreted envelope protein that is continuously shed into the blood as long as HBV infection persists, irrespective of viral replication. Recent advances in HBsAg quantification (qHBsAg) have opened up new perspectives in the study of HBV; qHBsAg levels are correlated with intrahepatic covalently closed circular (ccc) DNA, which is used as a template for viral transcription and maintains the chronic HBV infection state (3-5). Additionally, a correlation between qHBsAg and HBV DNA has been suggested, with the possibility of a role for qHBsAg as a surrogate marker for viral r...

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Section: Discussionmentioning

confidence: 99%

Application of a Newly Developed High-Sensitivity HBsAg Chemiluminescent Enzyme Immunoassay for Hepatitis B Patients with HBsAg Seroclearance

et al. 2013

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“…HBsAg, HBeAg, antibodies to HBsAg in mouse sera, culture supernatants, and cell lysates of transfected cells were detected as described previously (23)(24)(25).…”

Section: ͼ10mentioning

confidence: 99%

“…Indirect immunofluorescence (IF) staining of transfected cells was performed as described previously (21,23,24). Anti-HBc (Dako, Carpinteria, CA) and anti-HBs (S1; kindly provided by Yan Bin) were used as primary antibodies, and Alexa Fluor 488-conjugated and Alexa Fluor 568-conjugated antibodies (Life Technologies, Carlsbad, CA) were used for secondary detection.…”

Section: ͼ10mentioning

confidence: 99%

“…Purification of core-associated HBV DNA in liver tissue and quantification of HBV DNA were performed as described previously (23,26). The real-time PCR primers P5/P6 and the TaqMan probe were used: P5, 5=-AAATCTCCAGTCACTCACCAACC-3= (nt 321 to 343); P6, 5=-C ATAGCAGCAGGATGCAGAGG-3= (nt 423 to 403); TaqMan probe, 5=-6-carboxyfluorescein (FAM)-TCCTCCAATTTGTCCTGGTTATCGCT-MGB-3= (nt 349 to 374).…”

Section: ͼ10mentioning

confidence: 99%

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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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“…The plasmid pHBV1.3 contains a 1.3-mer, over-length HBV genotype A2 genome (adw2 subtype; GenBank accession number: X02763.1) [9] and was kindly provided by Prof Dr Dong-liang YANG (Tongji Hospital of Tongji Medical College, Wuhan, China). The HBV genome region that encoded the full-length Cp185 protein was amplified by PCR using pHBV1.3 as a template [10,11] .…”

Section: Plasmidsmentioning

confidence: 99%

Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation

Shi

Chen

et al. 2014

Acta Pharmacol Sin

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Aim: To investigate the action of isothiafludine (NZ-4), a derivative of bis-heterocycle tandem pairs from the natural product leucamide A, on the replication cycle of hepatitis B virus (HBV) in vitro and in vivo. Methods: HBV replication cycle was monitored in HepG2.2.15 cells using qPCR, qRT-PCR, and Southern and Northern blotting. HBV protein expression and capsid assembly were detected using Western blotting and native agarose gel electrophoresis analysis. The interaction of pregenomic RNA (pgRNA) and the core protein was investigated by RNA immunoprecipitation. To evaluate the anti-HBV effect of NZ-4 in vivo, DHBV-infected ducks were orally administered NZ-4 (25, 50 or 100 mg· kg -1 ·d -1 ) for 15 d. Results: NZ-4 suppressed intracellular HBV replication in HepG2.2.15 cells with an IC 50 value of 1.33 μmol/L, whereas the compound inhibited the cell viability with an IC 50 value of 50.4 μmol/L. Furthermore, NZ-4 was active against the replication of various drugresistant HBV mutants, including 3TC/ETV-dual-resistant and ADV-resistant HBV mutants. NZ-4 (5, 10, and 20 μmol/L) concentrationdependently reduced the encapsidated HBV pgRNA, resulting in the assembly of replication-deficient capsids in HepG2.2.15 cells. Oral administration of NZ-4 dose-dependently inhibited DHBV DNA replication in the DHBV-infected ducks. Conclusion: NZ-4 inhibits HBV replication by interfering with the interaction between pgRNA and HBcAg in the capsid assembly process, thus increasing the replication-deficient HBV capsids. Such mechanism of action might provide a new therapeutic strategy to combat HBV infection.

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Amino Acid Substitutions at Positions 122 and 145 of Hepatitis B Virus Surface Antigen (HBsAg) Determine the Antigenicity and Immunogenicity of HBsAg and InfluenceIn VivoHBsAg Clearance

Cited by 78 publications

References 31 publications

Application of a Newly Developed High-Sensitivity HBsAg Chemiluminescent Enzyme Immunoassay for Hepatitis B Patients with HBsAg Seroclearance

Application of a Newly Developed High-Sensitivity HBsAg Chemiluminescent Enzyme Immunoassay for Hepatitis B Patients with HBsAg Seroclearance

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

Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation

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