16 results on '"HBsAg mutations"'
Search Results
2. Detection of in vivo hepatitis B virus surface antigen mutations—A comparison of four routine screening assays.
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Gencay, M., Seffner, A., Pabinger, S., Gautier, J., Gohl, P., Weizenegger, M., Neofytos, D., Batrla, R., Woeste, A., Kim, H. S., Westergaard, G., Reinsch, C., Brill, E., Thuy, P. T. T., Hoang, B. H., Sonderup, M., Spearman, C. W., Brancaccio, G., Fasano, M., and Gaeta, G. B. more...
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HEPATITIS associated antigen , *GENETIC mutation , *HEPATITIS B virus , *MEDICAL screening , *DISEASE prevalence - Abstract
Summary: An important requirement for a state‐of‐the‐art hepatitis B surface antigen (HBsAg) screening assay is reliable detection of mutated HBsAg. Currently, there is a striking shortage of data regarding the detection rates of in vivo HBsAg mutations for these clinically important assays. Therefore, we compared the detection rates of four commercial HBsAg screening assays using a global cohort of 1553 patients from four continents with known HBV genotypes. These samples, which represent the broadest spectrum of known and novel HBsAg major hydrophilic region (MHR) mutations to date, were analyzed for the presence of HBsAg using the Roche Elecsys®HBsAg II Qualitative, Siemens ADVIA Centaur XP HBsAg II, Abbott Architect HBsAg Qualitative II and DiaSorin Liaison®HBsAg Qualitative assays, respectively. Of the 1553 samples, 1391 samples could be sequenced; of these, 1013 (72.8%) carried at least one of the 345 currently known amino acid substitutions (distinct HBsAg mutation) in the HBsAg MHR. All 1553 patient samples were positive for HBsAg using the Elecsys®HBsAg II Qual assay, with a sensitivity (95% confidence interval) of 99.94% (99.64%‐100%), followed by the Abbott Architect 99.81% (99.44%‐99.96%), Siemens ADVIA 99.81% (99.44%‐99.96%) and DiaSorin Liaison® 99.36% (98.82%‐99.69%) assays, respectively. Our results indicate that the Elecsys®HBsAg II Qual assay exhibits the highest sensitivity among the commercial HBsAg screening assays, and demonstrate that its capacity to detect HBV infection is not compromised by HBsAg MHR mutants. [ABSTRACT FROM AUTHOR] more...
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- 2018
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Catalog
3. Frequency of hepatitis B surface antigen variants (HBsAg) in hepatitis B virus genotype B and C infected East- and Southeast Asian patients: Detection by the Elecsys® HBsAg II assay.
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Kim, Hyon Suk, Chen, Xinyue, Xu, Min, Yan, Cunling, Liu, Yali, Deng, Haohui, Hoang, Bui Huu, Thuy, Pham Thi Thu, Wang, Terry, Yan, Yiwen, Zeng, Zhen, Gencay, Mikael, Westergaard, Gaston, Pabinger, Stephan, Kriegner, Albert, Nauck, Markus, Seffner, Anja, Gohl, Peter, Hübner, Kirsten, and Kaminski, Wolfgang E. more...
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HEPATITIS associated antigen , *VIRAL genetics , *SOUTHEAST Asians , *HEPATITIS B , *BIOLOGICAL assay , *NUCLEOTIDE sequencing , *DISEASES , *DIAGNOSIS - Abstract
Background To avoid false negative results, hepatitis B surface antigen (HBsAg) assays need to detect samples with mutations in the immunodominant ‘a’ determinant region, which vary by ethnographic region. Objective We evaluated the prevalence and type of HBsAg mutations in a hepatitis B virus (HBV)-infected East- and Southeast Asian population, and the diagnostic performance of the Elecsys ® HBsAg II Qualitative assay. Study design We analyzed 898 samples from patients with HBV infection from four sites (China [Beijing and Guangzhou], Korea and Vietnam). HBsAg mutations were detected and sequenced using highly sensitive ultra-deep sequencing and compared between the first (amino acids 124–137) and second (amino acids 139–147) loops of the ‘a’ determinant region using the Elecsys ® HBsAg II Qualitative assay. Results Overall, 237 distinct amino acid mutations in the major hydrophilic region were identified; mutations were present in 660 of 898 HBV-infected patient samples (73.5%). Within the pool of 237 distinct mutations, the majority of the amino acid mutations were found in HBV genotype C (64.8%). We identified 25 previously unknown distinct mutations, mostly prevalent in genotype C-infected Korean patients (n = 18) followed by Chinese (n = 12) patients. All 898 samples were correctly identified by the Elecsys ® HBsAg II Qualitative assay. Conclusions We observed 237 distinct (including 25 novel) mutations, demonstrating the complexity of HBsAg variants in HBV-infected East- and Southeast Asian patients. The Elecsys ® HBsAg II Qualitative assay can reliably detect HBV-positive samples and is suitable for routine diagnostic use in East and Southeast Asia. [ABSTRACT FROM AUTHOR] more...
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- 2018
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4. Substantial variation in the hepatitis B surface antigen (HBsAg) in hepatitis B virus (HBV)-positive patients from South Africa: Reliable detection of HBV by the Elecsys HBsAg II assay.
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Gencay, Mikael, Vermeulen, Marion, Neofytos, Dionysis, Westergaard, Gaston, Pabinger, Stephan, Kriegner, Albert, Seffner, Anja, Gohl, Peter, Huebner, Kirsten, Nauck, Markus, and Kaminski, Wolfgang E.
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HEPATITIS B , *HEPATITIS associated antigen , *GENETIC polymorphisms , *GENETIC mutation , *VIRAL genomes , *DIAGNOSIS - Abstract
Background It is essential that hepatitis B surface antigen (HBsAg) diagnostic assays reliably detect genetic diversity in the major hydrophilic region (MHR) of HBsAg to avoid false-negative results. Mutations in this domain display marked ethno-geographic variation and may lead to failure to diagnose hepatitis B virus (HBV) infection. Objectives Evaluate diagnostic performance of the Elecsys ® HBsAg II Qualitative assay in a cohort of South African HBV-positive blood donors. Study design A total of 179 South African HBsAg- and HBV DNA > 100 IU/mL-positive blood donor samples were included. Samples were sequenced for genetic variation in HBsAg MHR using next-generation ultra-deep sequencing. HBsAg seropositivity was determined using the Roche Elecsys HBsAg II Qualitative assay. Mutation rates were compared between the first (amino acids 124–137) and second (amino acids 139–147) loops of the immunodominant MHR ‘a’ determinant region. Frequency of occult HBV infection-associated Y100C mutations was also determined. Results We observed a total of 279 MHR mutations (117 variants) in 102 (57%) samples, of which 91 were located in the ‘a’ determinant region. The major vaccine-induced escape mutation G145R was observed in two samples. All occult HBV infection-associated Y100C and common diagnostic and vaccine-escape-associated P120T, G145R, K122R, M133L, M133T, Q129H, G130N, and T126S mutations were reliably detected by the assay, which consistently detected the presence of HBsAg in all 179 samples including samples with 11 novel mutations. Conclusions Despite substantial variation in HBsAg MHR, the Elecsys HBsAg II Qualitative assay robustly detects HBV infection in this South African cohort. [ABSTRACT FROM AUTHOR] more...
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- 2018
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5. HBsAg mutations related to occult hepatitis B virus infection in HIV-positive patients result in a reduced secretion and conformational changes of HBsAg.
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Sadeghi, Ahmadreza, Shirvani‐Dastgerdi, Elham, Tacke, Frank, Yagmur, Eray, Poortahmasebi, Vahdat, Poorebrahim, Mansour, Mohraz, Minoo, Hajabdolbaghi, Mahboobeh, Rasoolinejad, Mehrnaz, Abbasian, Ladan, Jafari, Rezvaneh, Fakhari, Zahra, Norouzi, Mehdi, Ebrahimian, Arefeh, Geravand, Babak, Alavian, Seyed Moayed, and Jazayeri, Seyed Mohammad more...
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Background: Occult hepatitis B infection (OBI) is a frequent finding in human immunodeficiency virus (HIV)-infected patients. While several related mutations in the hepatitis B virus (HBV) genome have been reported, their distinct impact on HBsAg synthesis is largely obscure. Methods: Thirty-one (18%) out of 172 HIV-infected patients, who were selected from HBsAg-negative patients, were positive for HBV-DNA assigned as being OBI-positive. We generated a series of expression constructs of variant HBsAg with 'a' determinant amino acid substitutions including P127L, P127T, S136Y, and P127T + S136Y using site-directed mutagenesis. The expression of variant HBsAg was examined by transient transfection in hepatoma cells, followed by HBsAg immunoassay and immunofluorescence stained with specific anti-HBs antibodies. The potential impact of amino acid substitutions at different positions for conformational changes in the HBsAg was investigated using bioinformatics. Results: All variants comprising either single or combined mutations resulted in significantly reduced HBsAg detection in supernatants and in cell lysates of hepatoma cells transfected with the constructs. Moreover, intracellular immunofluorescence staining of cytoblocks showed perinuclear and cytoplasmic fluorescence of HBsAg constructs with significantly diminished fluorescent intensity in comparison to the wild type. Altered protein conformations by predictive models, indicating an impaired detection by the host's immune response as well as by commercial antibody-based test assays. Conclusion: Mutations in the 'a' determinant region of HBV as often found in OBI remarkably impair the detection of HBsAg from serum and infected cells, emphasizing the relevance of alternative methods such as HBV-DNA quantification for high-risk groups like HIV-infected individuals. J. Med. Virol. 89:246-256, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR] more...
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- 2017
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6. Impacts of the G145R Mutation on the Structure and Immunogenic Activity of the Hepatitis B Surface Antigen: A Computational Analysis.
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Rezaee, Reza, Poorebrahim, Mansour, Najafi, Saeideh, Sadeghi, Solmaz, Pourdast, Alieh, Alavian, Seyed Moayed, Alavian, Seyed Ehsan, and Poortahmasebi, Vahdat
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COMPUTER simulation , *COMPUTER software , *HEPATITIS B , *HEPATITIS B vaccines , *HEPATITIS viruses , *MOLECULAR structure , *MONOCLONAL antibodies , *GENETIC mutation , *STRUCTURAL models , *VIRAL antigens - Abstract
Background: Vaccine-escaped hepatitis B virus (HBV) mutations occur within the "a" determinant area, which is located in the major hydrophilic region(MHR)of the hepatitis B surface antigen (HBsAg) protein. It is now well established that thecommonG145R mutation is highly capable of escaping from HBsAg immune recognition. However, the impacts of this mutation on the structure and immunogenic activity of HBsAg have been poorly investigated. Objectives: The present study analyzed the effects of the G145R mutation on the structure and immunogenic activity of the HBsAg. Materials and Methods: Three-dimensional (3D) structure of HBsAg for both the wild-type and G145R mutant were predicted and refined using several web tools. After quantitative evaluations, the effects of the G145R mutation on the secondary and 3D structures of the HBsAg were investigated. In parallel, the immunogenic activity of the wild-type and mutant HBsAg was also analyzed using a ClusPro docking server as well as the IEDB web tool. Further analyses were performed via molecular dynamics (MD) simulations using the GROMACS v5.0.2 simulation package. Results: The G145R mutation causes a considerable reduction in the immunogenic activity of the HBsAg through a conformational change in the HBsAg antigenic loops. This mutation inserts a new β-strand in the "a" determinant region of the HBsAg, leading to a reduced binding affinity to its monoclonal antibody, MAb12. The G145R mutation also increased the compactness and stability of the HBsAg by enhancing the rigidity of the "a" determinant. Conclusions: These data will be beneficial for designing more advanced antibodies for the recognition of the HBsAg in diagnostics. In addition, the results of this study may assist in the design or development of more effective hepatitis B vaccines. [ABSTRACT FROM AUTHOR] more...
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- 2016
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7. The Pigeonhole of Occult Hepatitis B
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Payam Dindoost, Narges Chimeh, Blain F Hollinger, Esmaeil Saberfar, Mehdi Norouzi, and Seyed Mohammad Jazayeri
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Occult Hepatitis B infection ,HBV diagnosis ,HBsAg mutations ,Medicine (General) ,R5-920 - Abstract
Occult hepatitis B (OHB), or persistent hepatitis B virus (HBV) viremia in surface-antigen-HBsAg-negative patients, has been recognized as a medical concern during the last decade. The exact magnitude, pathogenesis and clinical relevance of OHB are unclear. This review organizes the published data on OHB and presents an overview of the current hypotheses on OHB's pathogenesis and clinical relevance.Many explanations have been offered for the pathogenesis of OHB, ranging from the inability of standard immunoassays to diagnose OHB to the involvement of the versatile virus-host factors. Also, special care should be taken regarding the diagnosis of OBH. It seems that both shared viral-host factors are involved in the pathogenesis of OBH. Further molecular studies on cohort patients group need to explore such association. more...
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- 2014
8. Key mutations in the C-terminus of the HBV surface glycoprotein correlate with lower HBsAg levels in vivo, hinder HBsAg secretion in vitro and reduce HBsAg structural stability in the setting of HBeAg-negative chronic HBV genotype-D infection
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Domenico Di Carlo, M. Paoloni, Carlo Federico Perno, Giuseppe Maria De Sanctis, Ada Bertoli, Jens Verheyen, Massimo Marignani, U.S. Gill, Francesca Ceccherini Silberstein, A. Iuvara, Leonardo Duca, Miriam Lichtner, Caterina Pasquazzi, Patrick T F Kennedy, A. Battisti, Vincenzo Malagnino, Olympia E. Anastasiou, Romina Salpini, Valentina Svicher, Carlotta Cerva, Claudio Maria Mastroianni, Loredana Sarmati, Giustino Parruti, Katia Yu La Rosa, N. Iapadre, L. Carioti, Jacopo Vecchiet, L. Piermatteo, Lavinia Fabeni, Stefano Aquaro, Luna Colagrossi, Sandro Grelli, Massimo Andreoni, and Mario Angelico more...
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0301 basic medicine ,Adult ,Male ,HBsAg ,Hepatitis B virus ,Genotype ,Epidemiology ,030106 microbiology ,Immunology ,Medizin ,HBeAg-negative infection ,Biology ,Microbiology ,Settore MED/07 ,03 medical and health sciences ,Hepatitis B, Chronic ,In vivo ,Virology ,Drug Discovery ,HBsAg mutations ,Hbv genotype ,Humans ,Secretion ,Chronic ,chemistry.chemical_classification ,Hepatitis B Surface Antigens ,C-terminus ,virus diseases ,General Medicine ,Middle Aged ,Hepatitis B ,In vitro ,digestive system diseases ,030104 developmental biology ,Infectious Diseases ,chemistry ,Hbeag negative ,HBV genotypes ,HBsAg levels ,Mutation ,HBsAg C-terminus ,Parasitology ,Female ,Glycoprotein - Abstract
Increasing evidences suggest that HBsAg-production varies across HBV-genotypes. HBsAg C-terminus plays a crucial role for HBsAg-secretion. Here, we evaluate HBsAg-levels in different HBV-genotypes in HBeAg-negative chronic infection, the correlation of specific mutations in HBsAg C-terminus with HBsAg-levels in-vivo, their impact on HBsAg-secretion in-vitro and on structural stability in-silico. HBsAg-levels were investigated in 323 drug-naïve HBeAg-negative patients chronically infected with HBV genotype-D(N = 228), -A(N = 65) and -E(N = 30). Genotype-D was characterized by HBsAg-levels lower than genotype-A and -E (3.3[2.7–3.8]IU/ml; 3.8[3.5–4.2]IU/ml and 3.9[3.7–4.2]IU/ml, P < 0.001). Results confirmed by multivariable analysis correcting for patients’demographics, HBV-DNA, ALT and infection-status. In genotype-D, specific C-terminus mutations (V190A-S204N-Y206C-Y206F-S210N) significantly correlate with HBsAgP-value from P = 0.003), S204N + L205P (Phi = 0.36, P = 0.005), Y206F + S210R (Phi = 0.47, P < 0.001) and S210N + F220L (Phi = 0.40, P = 0.006). Notably, patients with these mutational pairs present HBsAg-levels 1log lower than patients without them(P-value from 0.003 to 0.02). In-vitro, the above-mentioned mutational pairs determined a significant decrease in HBsAg secretion-efficiency compared to wt(P-value from in-vivo, hamper HBsAg-release in-vitro and affect its structural stability, supporting their detrimental role on HBsAg-secretion. In this light, genotypic-testing can be a valuable tool to optimize the clinical interpretation of HBsAg in genotype-D and to provide information on HBV-pathogenicity and disease-progression. more...
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- 2020
9. The Pigeonhole of Occult Hepatitis B.
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Dindoost, Payam, Chimeh, Narges, Hollinger, Blain F., Saberfar, Esmaeil, Norouzi, Mehdi, and Mohammad Jazayeri, Seyed
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HEPATITIS B , *HEPATITIS B virus , *VIREMIA , *CELL surface antigens , *IMMUNOASSAY , *MEDICAL publishing , *PATIENTS - Abstract
Occult Hepatitis B (OHB), or persistent hepatitis B virus (HBV) viremia in surface-antigen- HBsAg-negative patients, has been recognized as a medical concern during the last decade. The exact magnitude, pathogenesis and clinical relevance of OHB are unclear. This review organizes the published data on OHB and presents an overview of the current hypotheses on OHB's pathogenesis and clinical relevance. Many explanations have been offered for the pathogenesis of OHB, ranging from the inability of standard immunoassays to diagnose OHB to the involvement of the versatile virus-host factorsAlso, special care should be taken regarding the diagnosis of OBH. It seems that both shared viral-host factors are involved in the pathogenesis of OBH. Further molecular studies on cohort patients group need to explore such association. [ABSTRACT FROM AUTHOR] more...
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- 2014
10. High frequency of complex mutational patterns in lamivudine resistant hepatitis B virus isolates.
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Neumann‐Fraune, Maria, Beggel, Bastian, Pfister, Herbert, Kaiser, Rolf, and Verheyen, Jens
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The evolution of hepatitis-B virus (HBV) drug resistance is characterized by the emergence of resistance conferring mutations and compensatory mutations. Therefore HBV drug-resistant isolates often harbor multiple mutations in the reverse transcriptase (RT) and corresponding mutations in the hepatitis B surface antigen (HBsAg). In this study mutational patterns of 60 HBV isolates harboring drug resistance mutations rtM204V or rtM204I were retrospectively analyzed. Both mutations, especially mutation rtM204V, were most often accompanied by compensatory mutations rtV173L and rtL180M but also by mutations conferring entecavir (n = 5) or adefovir resistance (n = 4). In addition, 22 (36.7%) drug resistant HBV isolates carried mutations related to immune escape in the HBsAg. In seven cases premature stop codons in HBsAg were detected resulting in the expression of truncated HBsAg. Clonal analysis of these seven quasispecies even disclosed the presence of HBV isolates carrying further stop codons and in one case the occurrence of resistance mutation rtA181T without the stop codon mutation sW172*. Interestingly, only one HBV clone carried the resistance mutations rtM204V and rtA181T. HBV drug resistant isolates frequently harbored HBsAg mutations associated with immune escape or disease progression pointing to a complex interaction of both proteins. HBV genotypic resistance tests based on population sequencing methods seemed to be inappropriate for determining the clinical relevance of stop codons in the HBsAg. J. Med. Virol. 85:775-779, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR] more...
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- 2013
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11. Performance of HBsAg point-of-care tests for detection of diagnostic escape-variants in clinical samples.
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Hirzel, Cédric, Pfister, Stefan, Gorgievski-Hrisoho, Meri, Wandeler, Gilles, and Zuercher, Samuel
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HEPATITIS associated antigen , *POINT-of-care testing , *HEPATITIS B virus , *VIRAL mutation , *BLOOD sampling , *MICROBIAL sensitivity tests - Abstract
Background Hepatitis B viruses (HBV) harboring mutations in the a-determinant of the Hepatitis B surface antigen (HBsAg) are associated with reduced reactivity of HBsAg assays. Objectives To evaluate the sensitivity and specificity of three HBsAg point-of-care tests for the detection of HBsAg of viruses harboring HBsAg mutations. Study design A selection of 50 clinical plasma samples containing HBV with HBsAg mutations was used to evaluate the performance of three HBsAg point-of-care tests (Vikia ® , bioMérieux, Marcy-L’Étoile, France. Alere Determine HBsAg™, Iverness Biomedical Innovations, Köln, Germany. Quick Profile™, LumiQuick Diagnostics, California, USA) and compared to the ARCHITECT HBsAg Qualitative ® assay (Abbott Laboratories, Sligo, Ireland). Results The sensitivity of the point-of-care tests ranged from 98% to 100%. The only false-negative result occurred using the Quick Profile™ assay with a virus harboring a D144A mutation. Conclusions The evaluated point-of-care tests revealed an excellent sensitivity in detecting HBV samples harboring HBsAg mutations. [ABSTRACT FROM AUTHOR] more...
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- 2015
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12. Detection of in vivo hepatitis B virus surface antigen mutations-A comparison of four routine screening assays
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Giuseppina Brancaccio, Teresa Santantonio, Jérémie Gautier, Peter Gohl, G.B. Gaeta, P. T. T. Thuy, C. Reinsch, B. H. Hoang, Massimo Fasano, Stephan Pabinger, C. W. Spearman, E. Brill, Gaston Westergaard, Mark W. Sonderup, A. Woeste, Anja Seffner, Mikael Gencay, Hyun-Seok Kim, Wolfgang E. Kaminski, Richard Batrla, Dionissios Neofytos, M. Weizenegger, Gencay, M, Seffner, A, Pabinger, S, Gautier, J, Gohl, P, Weizenegger, M, Neofytos, D, Batrla, R, Woeste, A, Kim, H S, Westergaard, G, Reinsch, C, Brill, E, Thuy, P T T, Hoang, B H, Sonderup, M, Spearman, C W, Brancaccio, G, Fasano, M, and Gaeta, Giovanni Battista more...
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0301 basic medicine ,HBsAg ,Hepatitis B virus ,Genotype ,Economic shortage ,“a” determinant region ,Hepatitis b surface antigen ,Sensitivity and Specificity ,Cohort Studies ,03 medical and health sciences ,Hepatitis B, Chronic ,In vivo ,Virology ,Siemens ADVIA Centaur ,HBsAg mutations ,Hbv genotype ,Medicine ,Humans ,Mass Screening ,HBV mutations ,Immunoassay ,Hepatitis B virus surface Antigen ,Routine screening ,Hepatitis B Surface Antigens ,Hepatology ,business.industry ,Diagnostic Tests, Routine ,HBV mutation ,virus diseases ,Hepatitis B ,digestive system diseases ,030104 developmental biology ,Infectious Diseases ,mutation spectrum ,Mutation ,business ,HBsAg mutation - Abstract
An important requirement for a state-of-the-art hepatitis B surface antigen (HBsAg) screening assay is reliable detection of mutated HBsAg. Currently, there is a striking shortage of data regarding the detection rates of in vivo HBsAg mutations for these clinically important assays. Therefore, we compared the detection rates of four commercial HBsAg screening assays using a global cohort of 1553 patients from four continents with known HBV genotypes. These samples, which represent the broadest spectrum of known and novel HBsAg major hydrophilic region (MHR) mutations to date, were analyzed for the presence of HBsAg using the Roche Elecsys® HBsAg II Qualitative, Siemens ADVIA Centaur XP HBsAg II, Abbott Architect HBsAg Qualitative II and DiaSorin Liaison® HBsAg Qualitative assays, respectively. Of the 1553 samples, 1391 samples could be sequenced; of these, 1013 (72.8%) carried at least one of the 345 currently known amino acid substitutions (distinct HBsAg mutation) in the HBsAg MHR. All 1553 patient samples were positive for HBsAg using the Elecsys® HBsAg II Qual assay, with a sensitivity (95% confidence interval) of 99.94% (99.64%-100%), followed by the Abbott Architect 99.81% (99.44%-99.96%), Siemens ADVIA 99.81% (99.44%-99.96%) and DiaSorin Liaison® 99.36% (98.82%-99.69%) assays, respectively. Our results indicate that the Elecsys® HBsAg II Qual assay exhibits the highest sensitivity among the commercial HBsAg screening assays, and demonstrate that its capacity to detect HBV infection is not compromised by HBsAg MHR mutants. more...
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- 2018
13. Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro
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Michela Pollicita, Alberto Spanò, Jens Verheyen, Romina Salpini, Caterina Pasquazzi, Ada Bertoli, Carmen Mirabelli, Francesca Ceccherini-Silberstein, T. Mari, Cesare Sarrecchia, Giuseppina Cappiello, Nadia Warner, Simona Francioso, Danny Colledge, Alessandro Michienzi, Carlo Federico Perno, Maria Francesca Cortese, Daniele Armenia, Elisa Orecchini, Pascale Trimoulet, Sally Soppe, Patrizia Saccomandi, Maria Concetta Bellocchi, Hervé Fleury, N. Iapadre, A. Barlattani, Valentina Svicher, Stephen Locarnini, Massimo Andreoni, Mario Angelico, Domenico Di Carlo, Jacopo Vecchiet, R. Longo, L. Carioti, Fabio Continenza, Matteo Surdo, Gabriele Missale, and S. Romano more...
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0301 basic medicine ,Male ,HBsAg ,Medizin ,HBsAg mutations ,cell proliferation ,hepatitis B ,hepatitis B surface antigen ,hepatocellular carcinoma ,0302 clinical medicine ,Gene Frequency ,Risk Factors ,Cell Cycle ,Liver Neoplasms ,virus diseases ,Hepatitis B ,Middle Aged ,University hospital ,Settore MED/07 - Microbiologia e Microbiologia Clinica ,Oncology ,Hepatocellular carcinoma ,Host-Pathogen Interactions ,030211 gastroenterology & hepatology ,Female ,Research Paper ,Adult ,medicine.medical_specialty ,Hepatitis B virus ,Carcinoma, Hepatocellular ,Genotype ,Cell proliferation ,adult ,aged ,carcinoma, hepatocellular ,cell cycle ,female ,gene frequency ,genotype ,hepatitis B surface antigens ,hepatitis B virus ,hepatitis B, chronic ,host-pathogen Interactions ,humans ,liver neoplasms ,male ,middle ,multivariate analysis ,risk factors ,mutation ,Reference laboratory ,Hepatitis b surface antigen ,03 medical and health sciences ,Hepatitis B, Chronic ,Internal medicine ,medicine ,Humans ,Aged ,Gynecology ,Hepatitis B Surface Antigens ,business.industry ,Hepatology ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Immunology ,Multivariate Analysis ,Mutation ,business - Abstract
// Romina Salpini 1, * , Matteo Surdo 1, * , Nadia Warner 2 , Maria Francesca Cortese 1 , Danny Colledge 2 , Sally Soppe 2 , Maria Concetta Bellocchi 1 , Daniele Armenia 1 , Luca Carioti 1 , Fabio Continenza 3 , Domenico Di Carlo 1 , Patrizia Saccomandi 1 , Carmen Mirabelli 1, 4 , Michela Pollicita 1 , Roberta Longo 5 , Sara Romano 5 , Giuseppina Cappiello 5 , Alberto Spano 5 , Pascale Trimoulet 6 , Herve Fleury 6 , Jacopo Vecchiet 7 , Nerio Iapadre 8 , Angelo Barlattani 9 , Ada Bertoli 1 , Terenzio Mari 10 , Caterina Pasquazzi 11 , Gabriele Missale 12 , Cesare Sarrecchia 13 , Elisa Orecchini 14 , Alessandro Michienzi 14 , Massimo Andreoni 13 , Simona Francioso 15 , Mario Angelico 15 , Jens Verheyen 16 , Francesca Ceccherini-Silberstein 1 , Stephen Locarnini 2 , Carlo Federico Perno 1 , Valentina Svicher 1 1 Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata” Rome, Italy 2 Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia 3 Laboratory of Monitoring Antiviral Drugs, National Institute for Infectious Diseases (INMI) “Lazzaro Spallanzani” Rome, Italy 4 Institut Pasteur, Unite de Biologie des Virus Enteriques, Paris, France 5 Unit of Microbiology, “S. Pertini Hospital”, Rome, Italy 6 Laboratoire de Microbiologie Fondamentale et Pathogenicite, Hopital Pellegrin Tripode, Bordeaux, France 7 Department of Medicine and Aging Sciences, “SS Annunziata” Hospital, Chieti, Italy 8 Infectious Diseases Unit, “S Salvatore” Hospital, L'Aquila, Italy 9 Hepatology Unit, “S Giacomo” Hospital, Rome, Italy 10 Hepatology Unit, “Regina Margherita” Hospital, Rome, Italy 11 Hepato-Infectivology Unit, “S Andrea” Hospital, Rome, Italy 12 Hospital of Parma, Parma, Italy 13 Tor Vergata University Hospital, Infectious Diseases Unit, Rome, Italy 14 Department of Biomedicine and Prevention, University of Rome “Tor Vergata” Rome, Italy 15 Tor Vergata University Hospital, Hepatology Unit, Rome, Italy 16 Institute of Virology, University Hospital, University of Duisburg-Essen, Essen, Germany * These authors have contributed equally to this work Correspondence to: Carlo Federico Perno, email: cf.perno@uniroma2.it Valentina Svicher, email: valentina.svicher@uniroma2.it Keywords: hepatitis B, hepatocellular carcinoma, hepatitis B surface antigen, HBsAg mutations, cell proliferation Received: November 25, 2016 Accepted: December 27, 2016 Published: February 01, 2017 ABSTRACT Background: An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation. Methods: This study included 128 chronically HBV-infected patients: 23 with HCC (73.9% D; 26.1% A HBV-genotype), and 105 without cirrhosis/HCC (72.4% D, 27.6% A) as reference-group. The impact of mutations on HBsAg-secretion was assessed by measuring the ratio [secreted/intracellular HBsAg] until day 5 post-transfection. The impact of mutations on cell-cycle advancement was assessed by flow-cytometry. Results: Two HBsAg mutations significantly correlated with HCC: P203Q (17.4% [4/23] in HCC vs 1.0% [1/105] in non-HCC, P=0.004); S210R (34.8% [8/23] in HCC vs 3.8% [4/105] in non-HCC, P more...
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- 2017
14. Impacts of the G145R Mutation on the Structure and Immunogenic Activity of the Hepatitis B Surface Antigen: A Computational Analysis
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Alieh Pourdast, Vahdat Poortahmasebi, Saeideh Najafi, Reza Rezaee, Mansour Poorebrahim, Seyed Ehsan Alavian, Solmaz Sadeghi, and Seyed Moayed Alavian
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0301 basic medicine ,HBsAg ,medicine.drug_class ,Mutant ,medicine.disease_cause ,Monoclonal antibody ,03 medical and health sciences ,0302 clinical medicine ,Vaccine Escape Mutations ,Antigen ,Medicine ,Hepatitis B virus ,Hepatology ,biology ,business.industry ,virus diseases ,HBsAg Mutations ,Hepatitis B ,medicine.disease ,Virology ,digestive system diseases ,030104 developmental biology ,Infectious Diseases ,Docking (molecular) ,G145R Mutation ,biology.protein ,030211 gastroenterology & hepatology ,Antibody ,business ,Research Article - Abstract
Background Vaccine-escaped hepatitis B virus (HBV) mutations occur within the "a" determinant area, which is located in the major hydrophilic region (MHR) of the hepatitis B surface antigen (HBsAg) protein. It is now well established that the common G145R mutation is highly capable of escaping from HBsAg immune recognition. However, the impacts of this mutation on the structure and immunogenic activity of HBsAg have been poorly investigated. Objectives The present study analyzed the effects of the G145R mutation on the structure and immunogenic activity of the HBsAg. Materials and methods Three-dimensional (3D) structure of HBsAg for both the wild-type and G145R mutant were predicted and refined using several web tools. After quantitative evaluations, the effects of the G145R mutation on the secondary and 3D structures of the HBsAg were investigated. In parallel, the immunogenic activity of the wild-type and mutant HBsAg was also analyzed using a ClusPro docking server as well as the IEDB web tool. Further analyses were performed via molecular dynamics (MD) simulations using the GROMACS v5.0.2 simulation package. Results The G145R mutation causes a considerable reduction in the immunogenic activity of the HBsAg through a conformational change in the HBsAg antigenic loops. This mutation inserts a new β-strand in the "a" determinant region of the HBsAg, leading to a reduced binding affinity to its monoclonal antibody, MAb12. The G145R mutation also increased the compactness and stability of the HBsAg by enhancing the rigidity of the "a" determinant. Conclusions These data will be beneficial for designing more advanced antibodies for the recognition of the HBsAg in diagnostics. In addition, the results of this study may assist in the design or development of more effective hepatitis B vaccines. more...
- Published
- 2016
15. Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro.
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Salpini R, Surdo M, Warner N, Cortese MF, Colledge D, Soppe S, Bellocchi MC, Armenia D, Carioti L, Continenza F, Di Carlo D, Saccomandi P, Mirabelli C, Pollicita M, Longo R, Romano S, Cappiello G, Spanò A, Trimoulet P, Fleury H, Vecchiet J, Iapadre N, Barlattani A, Bertoli A, Mari T, Pasquazzi C, Missale G, Sarrecchia C, Orecchini E, Michienzi A, Andreoni M, Francioso S, Angelico M, Verheyen J, Ceccherini-Silberstein F, Locarnini S, Perno CF, and Svicher V more...
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- Adult, Aged, Carcinoma, Hepatocellular virology, Cell Cycle, Cell Proliferation, Female, Gene Frequency, Genotype, Hepatitis B Surface Antigens metabolism, Hepatitis B virus metabolism, Hepatitis B virus physiology, Hepatitis B, Chronic virology, Host-Pathogen Interactions, Humans, Liver Neoplasms virology, Male, Middle Aged, Multivariate Analysis, Risk Factors, Carcinoma, Hepatocellular pathology, Hepatitis B Surface Antigens genetics, Hepatitis B virus genetics, Hepatitis B, Chronic pathology, Liver Neoplasms pathology, Mutation
- Abstract
Background: An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation., Methods: This study included 128 chronically HBV-infected patients: 23 with HCC (73.9% D; 26.1% A HBV-genotype), and 105 without cirrhosis/HCC (72.4% D, 27.6% A) as reference-group. The impact of mutations on HBsAg-secretion was assessed by measuring the ratio [secreted/intracellular HBsAg] until day 5 post-transfection. The impact of mutations on cell-cycle advancement was assessed by flow-cytometry., Results: Two HBsAg mutations significantly correlated with HCC: P203Q (17.4% [4/23] in HCC vs 1.0% [1/105] in non-HCC, P=0.004); S210R (34.8% [8/23] in HCC vs 3.8% [4/105] in non-HCC, P <0.001); P203Q+S210R (17.4% [4/23] in HCC vs 0% [0/110] in non-HCC, P=0.001). Both mutations reside in trans-membrane C-terminal domain critical for HBsAg-secretion. In in-vitro experiments, P203Q, S210R and P203Q+S210R significantly reduced the ratio [secreted/intracellular HBsAg] compared to wt at each time-point analysed (P <0.05), supporting an impaired HBsAg-secretion. Furthermore, P203Q and P203Q+S210R increased the percentage of cells in S-phase compared to wt, indicating cell-cycle progression (P203Q:26±13%; P203Q+S210R:29±14%; wt:18%±9, P <0.01. Additionally, S210R increased the percentage of cells in G2/M-phase (26±8% for wt versus 33±6% for S210R, P <0.001)., Conclusions: Specific mutations in HBsAg C-terminus significantly correlate with HBV-induced HCC. They hamper HBsAg-secretion and are associated with increased cellular proliferation, supporting their involvement in HCC-development. The identification of viral genetic markers associated with HCC is critical to identify patients at higher HCC-risk that may deserve intensive liver monitoring, and/or early anti-HBV therapy. more...
- Published
- 2017
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16. The pigeonhole of occult hepatitis B
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Dindoost, P., Chimeh, N., Hollinger, B. F., Esmaeil Saberfar, Norouzi, M., and Jazayeri, S. M.
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Occult Hepatitis B infection ,lcsh:R5-920 ,Hepatitis B virus ,Hepatitis B Surface Antigens ,HBsAg mutations ,Animals ,Humans ,HBV diagnosis ,lcsh:Medicine (General) ,Hepatitis B - Abstract
Occult hepatitis B (OHB), or persistent hepatitis B virus (HBV) viremia in surface-antigen-HBsAg-negative patients, has been recognized as a medical concern during the last decade. The exact magnitude, pathogenesis and clinical relevance of OHB are unclear. This review organizes the published data on OHB and presents an overview of the current hypotheses on OHB's pathogenesis and clinical relevance.Many explanations have been offered for the pathogenesis of OHB, ranging from the inability of standard immunoassays to diagnose OHB to the involvement of the versatile virus-host factors. Also, special care should be taken regarding the diagnosis of OBH. It seems that both shared viral-host factors are involved in the pathogenesis of OBH. Further molecular studies on cohort patients group need to explore such association. more...
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