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1
Shrestha, Umid Kumar, and Bhup Dev Bhatta. "Seroprevalence of hepatitis B virus, hepatitis C virus and human immunodeficiency virus in the western region of Nepal." Journal of Advances in Internal Medicine 5, no. 1 (March 30, 2017): 6–10. http://dx.doi.org/10.3126/jaim.v5i1.17064.
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Background and aims: The hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are associated with major public health concerns. The aim of the study was to determine the seroprevalence of HBV, HCV and HIV in the western region of Nepal.Methods: This was a cross-sectional observational study, in which 15,791 patients, attending to Manipal Teaching Hospital, Pokhara, Nepal, were investigated for HBV, HCV and HIV from June 2013 to March 2016; demographic and biochemical profile were studied among the patients with positive test results.Results: Among 15,791 patients [male 6614 (41.9%) and female 9177 (58.1%)], HBV was found in 180 (1.1%), HCV in 52 (0.3%) and HIV in 77 (0.5%). The HBV was found in 63.9% of males and 36.1% of females, HCV in 67.3% of males and 32.7% of females, and HIV in 61% of males and 39% of females which showed that males had more positivity of HBV (P<0.001), HCV (P<0.001) and HIV (P 0.001) than that of female. The HBV was found more in 20-29 years age group (27.2%), HCV in 30-39 years (32.7%), and HIV in 40-49 years (28.6%), with all having p<0.001. Among the patients of HBV, HCV and HIV, the mean values of total bilirubin were 1.4 mg/dl, 0.8 mg/dl and 2.6 mg/dl, Aspartate Transaminase 75.9 U/L, 54.3 U/L and 92.7 U/L, Alanine Transaminase 54.6 U/L, 55.5 U/L and 56.1 U/L, and Alkaline Phosphatase 124.2 U/L, 109.2 U/L and 107.2 U/L, respectively. The majority of patients with HCV had a history of intravenous drug abuse and HIV had concomitant alcoholic liver disease.Conclusion: The HBV was more prevalent followed by HIV and HCV in the western region of Nepal with more prevalence seen in males than in females. Regular screening of HBV, HCV and HIV among the selected patients can help detecting many new cases in Nepal.Journal of Advances in Internal Medicine 2016;05(01):6-10
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Bryant, Martin L., Edward G. Bridges, Laurent Placidi, Abdesslem Faraj, Anna-Giulia Loi, Claire Pierra, David Dukhan, et al. "Antiviral l-Nucleosides Specific for Hepatitis B Virus Infection." Antimicrobial Agents and Chemotherapy 45, no. 1 (January 1, 2001): 229–35. http://dx.doi.org/10.1128/aac.45.1.229-235.2001.
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ABSTRACT A unique series of simple “unnatural” nucleosides has been discovered to inhibit hepatitis B virus (HBV) replication. Through structure-activity analysis it was found that the 3′-OH group of the β-l-2′-deoxyribose of the β-l-2′-deoxynucleoside confers specific antihepadnavirus activity. The unsubstituted nucleosides β-l-2′-deoxycytidine, β-l-thymidine, and β-l-2′-deoxyadenosine had the most potent, selective, and specific antiviral activity against HBV replication. Human DNA polymerases (α, β, and γ) and mitochondrial function were not affected. In the woodchuck model of chronic HBV infection, viral load was reduced by as much as 108 genome equivalents/ml of serum and there was no drug-related toxicity. In addition, the decline in woodchuck hepatitis virus surface antigen paralleled the decrease in viral load. These investigational drugs, used alone or in combination, are expected to offer new therapeutic options for patients with chronic HBV infection.
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Yum, Jung Sun, Byung Cheol Ahn, Hyun Jin Jo, Dong Yeon Kim, Ki Hyun Kim, Hyo Sun Kim, Young Chul Sung, Jaeseung Yoon, John Morrey, and Hong Mo Moon. "Use of Pre-S Protein-Containing Hepatitis B Virus Surface Antigens and a Powerful Adjuvant To Develop an Immune Therapy for Chronic Hepatitis B Virus Infection." Clinical and Vaccine Immunology 19, no. 2 (December 7, 2011): 120–27. http://dx.doi.org/10.1128/cvi.05355-11.
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ABSTRACTA hepatitis B virus (HBV) vaccine has been developed using a new adjuvant and HBV surface antigens produced from a CHO cell line. The purified HBV surface antigens are composed of L protein, M protein, and S protein in a mixture of 20- and 40-nm-diameter particles and filamentous forms. This HBV surface antigen, formulated with L-pampo, a proprietary adjuvant, induced 10 times more antibody than the same antigen with alum and was capable of inducing strong immune responses in three different HBV transgenic mice. In spite of the presence of a large amount of HBV antigen in the blood, no antibody against HBV surface antigen was normally detected in these transgenic mice. After immunization, the HBV antigen was also cleared from the blood.
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Akar, A., B. Bournique, and R. Scholler. "Detection of Hepatitis B Virus DNA in Serum by a Nonisotopic Hybridization Technique." Clinical Chemistry 38, no. 7 (July 1, 1992): 1352–55. http://dx.doi.org/10.1093/clinchem/38.7.1352.
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Abstract We developed a nonisotopic technique, Hepagene, for measuring hepatitis B virus (HBV) DNA in human serum by using a sulfonated probe that is detected by a sandwich immunoenzymatic reaction. The detection limit, determined by serum dilution tests, was 2.5 ng/L. The precision of the Hepagene test was demonstrated by the accurate reproducibility observed for low (3 ng/L) and medium (38 ng/L) concentrations of HBV DNA assayed in 24 different series. Specificity was established by assaying HBV DNA in sera from 98 patients by the Hepagene technique or by a solution hybridization assay with an 125I-labeled probe. Results by both techniques agreed for 94 sera (96%), with 68 being concordant for HBV DNA negativity and 26 for positivity. HBV DNA titers assayed by both methods also agreed. Hepagene represents the first nonisotopic HBV DNA assay involving a sulfonated probe and with performance characteristics equivalent to those of classical radioactive hybridization techniques.
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Saha, Manujendra N., Atsushi Tanaka, Atsushi Jinno-Oue, Nobuaki Shimizu, Kazushi Tamura, Masahiko Shinagawa, Joe Chiba, and Hiroo Hoshino. "Formation of Vesicular Stomatitis Virus Pseudotypes Bearing Surface Proteins of Hepatitis B Virus." Journal of Virology 79, no. 19 (October 1, 2005): 12566–74. http://dx.doi.org/10.1128/jvi.79.19.12566-12574.2005.
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ABSTRACT It has been difficult to propagate and titrate hepatitis B virus (HBV) in tissue culture. We examined whether vesicular stomatitis virus (VSV) pseudotypes bearing HBV surface (HBs) proteins infectious for human cell lines could be prepared. For this, expression plasmids for three surface proteins, L, M, and S, of HBV were made. 293T cells were then transfected with these plasmids either individually or in different combinations. 293T cells expressing HBs proteins were infected with VSVΔG*-G, a recombinant VSV expressing green fluorescent protein (GFP), to make VSV pseudotypes. Culture supernatants together with cells were harvested and sonicated for a short time. The infectivities of freshly harvested supernatants were determined by quantifying the number of cells expressing GFP after neutralization with anti-VSV serum and mouse monoclonal antibodies (MAbs) against HBs protein. Among 14 cell lines tested for susceptibility to HBV pseudotype samples, HepG2, JHH-7, and 293T cells were judged to be the most susceptible. Namely, the infectious units (IU) of the culture supernatant samples neutralized with anti-VSV in the absence and presence of anti-HBs S MAbs and titrated on HepG2 cells ranged from 1,000 to 4,000 IU/ml and 200 to 400 IU/ml, respectively, suggesting the presence of VSVΔG*(HBV) pseudotypes. This infectivity was inhibited by treatment with lactoferrin or dextran sulfate. Pretreatment of the cells with trypsin or tunicamycin inhibited plating of the pseudotype samples. The HBV pseudotypes can be used to analyze early steps of HBV infection, including the entry mechanism of HBV.
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Guidotti, Luca G., Amber Morris, Heike Mendez, Rick Koch, Robert H. Silverman, Bryan R. G. Williams, and Francis V. Chisari. "Interferon-Regulated Pathways That Control Hepatitis B Virus Replication in Transgenic Mice." Journal of Virology 76, no. 6 (March 15, 2002): 2617–21. http://dx.doi.org/10.1128/jvi.76.6.2617-2621.2002.
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ABSTRACT We previously showed that the intrahepatic induction of cytokines such as alpha/beta interferon (IFN-α/β) and gamma interferon (IFN-γ) inhibits hepatitis B virus (HBV) replication noncytopathically in the livers of transgenic mice. The intracellular pathway(s) responsible for this effect is still poorly understood. To identify interferon (IFN)-inducible intracellular genes that could play a role in our system, we crossed HBV transgenic mice with mice deficient in IFN regulatory factor 1 (IRF-1), the double-stranded RNA-activated protein kinase (PKR), or RNase L (RNase L) (IRF-1−/−, PKR−/−, or RNase L−/− mice, respectively), three well-characterized IFN-inducible genes that mediate antiviral activity. We showed that unmanipulated IRF-1−/− or PKR−/− transgenic mice replicate HBV in the liver at slightly higher levels than the respective controls, suggesting that both IRF-1 and PKR individually appear to mediate signals that modulate HBV replication under basal conditions. These same animals were responsive to the antiviral effects of the IFN-α/β inducer poly(I-C) or recombinant murine IFN-γ, suggesting that under these conditions, either the IRF-1 or the PKR genes can mediate the antiviral activity of the IFNs or other IFN-inducible genes mediate the antiviral effects. Finally, RNase L−/− transgenic mice were undistinguishable from controls under basal conditions and after poly(I-C) or IFN-γ administration, suggesting that RNase L does not modulate HBV replication in this model.
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Chu, C. K., T. Ma, K. Shanmuganathan, C. Wang, Y. Xiang, S. B. Pai, G. Q. Yao, J. P. Sommadossi, and Y. C. Cheng. "Use of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus." Antimicrobial Agents and Chemotherapy 39, no. 4 (April 1995): 979–81. http://dx.doi.org/10.1128/aac.39.4.979.
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A novel anti-hepatitis B virus (anti-HBV) agent, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), was synthesized and found to be a potent anti-HBV and anti-Epstein-Barr virus agent. Its in vitro potency was evaluated in 2.2.15 and H1 cells for anti-HBV and anti-Epstein-Barr virus activities, respectively. In vitro cytotoxicity in MT2, CEM, 2.2.15, and H1 cells was also assessed, and the results indicated high antiviral selectivities of L-FMAU in these cells.
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Balakrishna Pai, S., S. H. Liu, Y. L. Zhu, C. K. Chu, and Y. C. Cheng. "Inhibition of hepatitis B virus by a novel L-nucleoside, 2'-fluoro-5-methyl-beta-L-arabinofuranosyl uracil." Antimicrobial Agents and Chemotherapy 40, no. 2 (February 1996): 380–86. http://dx.doi.org/10.1128/aac.40.2.380.
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2'-Fluoro-5-methyl-beta-L-arabinofuranosyl uracil (L-FMAU) was discovered to have potent antiviral activity against hepatitis B virus (HBV). L-FMAU was more potent than its D-enantiomer and produced dose-dependent inhibition of the viral DNA replication in 2.2.15 cells (human HepG2 cells with the HBV genome), with a 50% inhibitory concentration of 0.1 microM. There was no inhibitory effect on HBV transcription or protein synthesis. In the 2.2.15 cell system, L-FMAU did not show any toxicity up to 200 microM, whereas the D-enantiomer was toxic, with a 50% inhibitory concentration of 50 microM. Repeated treatments of HepG2 cells with L-FMAU at a 1 microM concentration for 9 days did not result in any decrease in the total mitochondrial DNA content, suggesting that a mode of toxicity similar to that produced by 2',3'-dideoxycytidine is unlikely. Also at concentrations as high as 200 microM, L-FMAU did not adversely affect mitochondrial function as determined by lactic acid production by L-FMAU-treated hepatoma cells. L-FMAU was metabolized in the cells to its mono-, di-, and triphosphates, A dose-dependent inhibition of HBV DNA synthesis by L-FMAU triphosphate was observed in the DNA polymerase assays with isolated HBV particles, suggesting that the mode of action of this compound could involve viral polymerase. However, L-FMAU was not incorporated into the cellular DNA. Considering the potent inhibition of the viral DNA synthesis and the nontoxicity of L-FMAU towards the host DNA synthetic machinery, this compound should be further explored for development as asn anti-HBV drug.
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Patient, Romuald, Christophe Hourioux, Pierre-Yves Sizaret, Sylvie Trassard, Camille Sureau, and Philippe Roingeard. "Hepatitis B Virus Subviral Envelope Particle Morphogenesis and Intracellular Trafficking." Journal of Virology 81, no. 8 (January 31, 2007): 3842–51. http://dx.doi.org/10.1128/jvi.02741-06.
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ABSTRACT Hepatitis B virus (HBV) is unusual in that its surface proteins (small [S], medium, and large [L]) are not only incorporated into the virion envelope but they also bud into empty subviral particles in great excess over virions. The morphogenesis of these subviral envelope particles remains unclear, but the S protein is essential and sufficient for budding. We show here that, in contrast to the presumed model, the HBV subviral particle formed by the S protein self-assembles into branched filaments in the lumen of the endoplasmic reticulum (ER). These long filaments are then folded and bridged for packing into crystal-like structures, which are then transported by ER-derived vesicles to the ER-Golgi intermediate compartment (ERGIC). Within the ERGIC, they are unpacked and relaxed, and their size and shape probably limits further progression through the secretory pathway. Such progression requires their conversion into spherical particles, which occurred spontaneously during the purification of these filaments by affinity chromatography. Small branched filaments are also formed by the L protein in the ER lumen, but these filaments are not packed into transport vesicles. They are transported less efficiently to the ERGIC, potentially accounting for the retention of the L protein within cells. These findings shed light on an important step in the HBV infectious cycle, as the intracellular accumulation of HBV subviral filaments may be directly linked to viral pathogenesis.
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Fu, Lei, and Yung-Chi Cheng. "Characterization of Novel Human Hepatoma Cell Lines with Stable Hepatitis B Virus Secretion for Evaluating New Compounds against Lamivudine- and Penciclovir-Resistant Virus." Antimicrobial Agents and Chemotherapy 44, no. 12 (December 1, 2000): 3402–7. http://dx.doi.org/10.1128/aac.44.12.3402-3407.2000.
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ABSTRACT l-Nucleoside analogs are new therapeutic agents for treatment of chronic hepatitis B. However, their clinical application was limited by the emergence of viral resistance. It is important to develop a new system to evaluate drug cross-resistance and to test new agents that may overcome resistant virus. In this report, three cell lines HepG2-WT10, HepG2-SM1, and HepG2-DM2 are presented; these cell lines were established by transfection of HepG2 cells with unique fully functional 1.1× hepatitis B virus (HBV) genomes: wild-type HBV-adr and its L526M and L526MM550V variants, respectively. We have demonstrated that these genomes have different susceptibilities to lamivudine [l(−)SddC] and penciclovir (PCV). By examining HBV RNA transcription, antigen expression, progeny DNA replication, and viral susceptibilities to l(−)SddC, PCV, and other nucleoside analogs, it is concluded that the cell lines are able to stably producel(−)SddC- and PCV-sensitive and -resistant HBV virions. In addition, the relative susceptibilities of the wild-type and mutant HBV produced from the stably transfected cell lines to several anti-HBV nucleoside analogs were also examined and found to be about the same as those found by using a transient infection system. PMEA [9-(2-phosphonylmethoxytehyl)-adenine] and QYL685 are able to suppress l(−)SddC- and PCV-resistant HBV. In conclusion, this cell culture system is a novel and useful tool for evaluating anti-HBV compounds and biologics.
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Inoue, Jun, Kosuke Sato, Masashi Ninomiya, and Atsushi Masamune. "Envelope Proteins of Hepatitis B Virus: Molecular Biology and Involvement in Carcinogenesis." Viruses 13, no. 6 (June 11, 2021): 1124. http://dx.doi.org/10.3390/v13061124.
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The envelope of hepatitis B virus (HBV), which is required for the entry to hepatocytes, consists of a lipid bilayer derived from hepatocyte and HBV envelope proteins, large/middle/small hepatitis B surface antigen (L/M/SHBs). The mechanisms and host factors for the envelope formation in the hepatocytes are being revealed. HBV-infected hepatocytes release a large amount of subviral particles (SVPs) containing L/M/SHBs that facilitate escape from the immune system. Recently, novel drugs inhibiting the functions of the viral envelope and those inhibiting the release of SVPs have been reported. LHBs that accumulate in ER is considered to promote carcinogenesis and, especially, deletion mutants in the preS1/S2 domain have been reported to be associated with the development of hepatocellular carcinoma (HCC). In this review, we summarize recent reports on the findings regarding the biological characteristics of HBV envelope proteins, their involvement in HCC development and new agents targeting the envelope.
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Barrera, Azeneth, Bernadette Guerra, Lena Notvall, and Robert E. Lanford. "Mapping of the Hepatitis B Virus Pre-S1 Domain Involved in Receptor Recognition." Journal of Virology 79, no. 15 (August 1, 2005): 9786–98. http://dx.doi.org/10.1128/jvi.79.15.9786-9798.2005.
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ABSTRACT Hepatitis B virus (HBV) and woolly monkey hepatitis B virus (WMHBV) are primate hepadnaviruses that display restricted tissue and host tropisms. Hepatitis D virus (HDV) particles pseudotyped with HBV and WMHBV envelopes (HBV-HDV and WM-HDV) preferentially infect human and spider monkey hepatocytes, respectively, thereby confirming host range bias in vitro. The analysis of chimeric HBV and WMHBV large (L) envelope proteins suggests that the pre-S1 domain may comprise two regions that affect infectivity: one within the amino-terminal 40 amino acids of pre-S1 and one downstream of this region. In the present study, we further characterized the role of the amino terminus of pre-S1 in infectivity by examining the ability of synthetic peptides to competitively block HDV infection of primary human and spider monkey hepatocytes. A synthetic peptide representing the first 45 residues of the pre-S1 domain of the HBV L protein blocked infectivity of HBV-HDV and WM-HDV, with a requirement for myristylation of the amino terminal residue. Competition studies with truncated peptides suggested that pre-S1 residues 5 to 20 represent the minimal domain for inhibition of HDV infection and, thus, presumably represent the residues involved in virus-host receptor interaction. Recombinant pre-S1 proteins expressed in insect cells blocked infection with HBV-HDV and WM-HDV at a concentration of 1 nanomolar. The ability of short pre-S1 peptides to efficiently inhibit HDV infection suggests that they represent suitable ligands for identification of the HBV receptor and that a pre-S1 mimetic may represent a rational therapy for the treatment of HBV infection.
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Alaoui, A. M. El, A. Faraj, C. Pierra, V. Boudou, R. Johnson, C. Mathé, G. Gosselin, et al. "Inhibition of Hepatitis B Virus Replication by Nucleoside Enantiomers of β-2′,3′-Dideoxypurine Analogues." Antiviral Chemistry and Chemotherapy 7, no. 5 (October 1996): 276–80. http://dx.doi.org/10.1177/095632029600700508.
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Various purine β-L-2′,3′-dideoxynucleoside analogues with both sugar and base modifications including β-L-ddG, β-L-ddl, β-L-ddA, 2′-azido-β-L-araddA, 2′-amino-β-L-araddA, 2′,5′-anhydro-β-L-araddA, 2′-azido-β-L-ddA, 2′-amino-β-L-ddA, 2′-fluoro-β-L-ddA, 3′-azido-β-L-ddA, 3′-amino-β-L-ddA, 3′-fluoro-β-L-ddA, 2,6-diamino-β-L-2′,3′-dideoxyfuranosylpurine, 6-cyclopropylamino-β-L-ddA, 2′-azido-6-N-triphenylphosphine-β-L-araddA, 2-amino-6-methylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopropylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2-amino-6-cyclopentylamino-β-L-2′,3′-dideoxyfuranosylpurine, 2′,3′-didehydro-β-L-ddA and 2′,3′-didehydro-6-N-triphenyl phosphine-β-L-ddA were synthesized and evaluated as potential inhibitors of hepatitis B virus (HBV) replication in HBV DNA-transfected human hepatoblastoma-derived Hep-G2 cells (2.2.15 cells). β-L-ddA, 2′-azido-β-L-ddA, 3′-azido-β-L-ddA, 2″,3′-didehydro-β-L-ddA (β-L-D4A) and a modified base of β-L-D4A, inhibited HBV replication in vitro. β-L-D4A was the more potent and selective antiHBV agent with a 50% effective concentration value of 0.1 μM and a selectivity index of 1800. On the basis of this finding, studies are in progress to synthesize new purine derivatives with the β-L unnatural configuration which hopefully will lead to identifying additional potent and highly selective anti-HBV agents.
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Yan, Ran, Xuesen Zhao, Dawei Cai, Yuanjie Liu, Timothy M. Block, Ju-Tao Guo, and Haitao Guo. "The Interferon-Inducible Protein Tetherin Inhibits Hepatitis B Virus Virion Secretion." Journal of Virology 89, no. 18 (June 24, 2015): 9200–9212. http://dx.doi.org/10.1128/jvi.00933-15.
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ABSTRACTInterferon alpha (IFN-α) is an approved medication for chronic hepatitis B therapy. Besides acting as an immunomodulator, IFN-α elicits a pleiotropic antiviral state in hepatitis B virus (HBV)-infected hepatocytes, but whether or not IFN-α impedes the late steps of the HBV life cycle, such as HBV secretion, remains elusive. Here we report that IFN-α treatment of HepAD38 cells with established HBV replication selectively reduced HBV virion release without altering intracellular viral replication or the secretion of HBV subviral particles and nonenveloped capsids. In search of the interferon-stimulated gene(s) that is responsible for the reduction of HBV virion release, we found that tetherin, a broad-spectrum antiviral transmembrane protein that inhibits the egress of a variety of enveloped viruses, was highly induced by IFN-α in HepAD38 cells and in primary human hepatocytes. We further demonstrated that the expression of full-length tetherin, but not the C-terminal glycosylphosphatidylinositol (GPI) anchor-truncated form, inhibited HBV virion egress from HepAD38 cells. In addition, GPI anchor-truncated tetherin exhibited a dominant-negative effect and was incorporated into the liberated virions. We also found colocalization of tetherin and HBV L protein at the intracellular multivesicular body, where the budding of HBV virions takes place. In line with this, electron microscopy demonstrated that HBV virions were tethered in the lumen of the cisterna membrane under tetherin expression. Finally, knockdown of tetherin or overexpression of dominant negative tetherin attenuated the IFN-α-mediated reduction of HBV virion release. Taken together, our study suggests that IFN-α inhibits HBV virion egress from hepatocytes through the induction of tetherin.IMPORTANCETetherin is a host restriction factor that blocks the egress of a variety of enveloped viruses through tethering the budding virions on the cell surface with its membrane anchor domains. Here we report that interferon directly and selectively inhibits the secretion of HBV virions, but not subviral particles or nonenveloped capsids, through the induction of tetherin in hepatocyte-derived cells. The antiviral function of tetherin requires the carboxyl-terminal GPI anchor, while the GPI anchor deletion mutant exhibits dominant negative activity and attaches to liberated HBV virions. Consistent with the fact that HBV is an intracellular budding virus, microscopy analyses demonstrated that the tethering of HBV virions occurs in the intracellular cisterna and that tetherin colocalizes with HBV virions on the multivesicular body, which is the HBV virion budding site. Our study not only expands the antiviral spectrum of tetherin but also sheds light on the mechanisms of interferon-elicited anti-HBV responses.
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Chai, Ning, Severin Gudima, Jinhong Chang, and John Taylor. "Immunoadhesins Containing Pre-S Domains of Hepatitis B Virus Large Envelope Protein Are Secreted and Inhibit Virus Infection." Journal of Virology 81, no. 10 (February 28, 2007): 4912–18. http://dx.doi.org/10.1128/jvi.02865-06.
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ABSTRACT Hepatitis B virus (HBV) replication produces three envelope proteins (L, M, and S) that have a common C terminus. L, the largest, contains a domain, pre-S1, not present on M. Similarly M contains a domain, pre-S2, not present on S. The pre-S1 region has important functions in the HBV life cycle. Thus, as an approach to studying these roles, the pre-S1 and/or pre-S2 sequences of HBV (serotype adw2, genotype A) were expressed as N-terminal fusions to the Fc domain of a rabbit immunoglobulin G chain. Such proteins, known as immunoadhesins (IA), were highly expressed following transfection of cultured cells and, when the pre-S1 region was present, >80% were secreted. The IA were myristoylated at a glycine penultimate to the N terminus, although mutation studies showed that this modification was not needed for secretion. As few as 30 amino acids from the N terminus of pre-S1 were both necessary and sufficient to drive secretion of IA. Even expression of pre-S1 plus pre-S2, in the absence of an immunoglobulin chain, led to efficient secretion. Overall, these studies demonstrate an unexpected ability of the N terminus of pre-S1 to promote protein secretion. In addition, some of these secreted IA, at nanomolar concentrations, inhibited infection of primary human hepatocytes either by hepatitis delta virus (HDV), a subviral agent that uses HBV envelope proteins, or HBV. These IA have potential to be part of antiviral therapies against chronic HDV and HBV, and may help understand the attachment and entry mechanisms used by these important human pathogens.
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Saeed, Umar, Yasir Waheed, Muhammad Ashraf, Usman Waheed, Sadia Anjum, and Muhammad Sohail Afzal. "Estimation of Hepatitis B Virus, Hepatitis C Virus, and Different Clinical Parameters in the Thalassemic Population of Capital Twin Cities of Pakistan." Virology: Research and Treatment 6 (January 2015): VRT.S31744. http://dx.doi.org/10.4137/vrt.s31744.
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Hepatitis B and C are serious public health problems worldwide. Thalassemia patients are dependent on blood transfusions throughout their life and are at high risk of viral infections. The aim of this study was to estimate the prevalence of hepatitis B/C infections and different clinical parameters in multitransfused thalassemia population. In this study, 262 multitransfused β-thalassemia patients were enrolled from the capital twin cities of Pakistan. The presence of hepatitis B virus (HBV)/hepatitis C virus (HCV), alanine aminotransferase (ALT) level, serum creatinine, serum ferritin, hepatomegaly, splenomegaly, and splenectomy were analyzed. The overall prevalence of HBV and HCV was 3.08% and 55.73%, respectively, with 100% of patients older than 20 years had HCV infection. The ALT levels among HBV- and HCV-positive thalassemia patients were 92.62 ± 41.57 U/L and 98 ± 63.65 U/L, respectively; creatinine values observed were 0.4 ± 0.35 mg/dL (for HBV) and 0.39 ± 0.24 mg/dL (for HCV), while serum ferritin levels were 6865.87 ± 1649.13 ng/dL (for HBV) and 5445.95 ± 3059.28 ng/dL (for HCV). A total of 74.8% and 82.20% of HBV- and HCV-positive patients had hepatomegaly with an average increase in liver size of 4.17 and 4.33 cm, respectively. Splenomegaly was observed in 64.9% and 67.12% of HBV- and HCV-positive patients with an average increase in spleen size of 4 and 4.46 cm, respectively. Splenectomy was observed among 14.50% and 15.75% of HBV- and HCV-infected thalassemia patients. There is a strong need to properly screen blood before transfusions to reduce the future load of viral hepatitis from Pakistan.
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Bronowicki, Jean-Pierre. "L’infection nosocomiale par le virus de l′hépatite B : un risque à ne pas méconnaître." Gastroentérologie Clinique et Biologique 30, no. 12 (December 2006): 1346–48. http://dx.doi.org/10.1016/s0399-8320(06)73552-7.
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Zhang, Zhensheng, Eun Sun, Jing-hsiung James Ou, and T. Jake Liang. "Inhibition of Cellular Proteasome Activities Mediates HBX-Independent Hepatitis B Virus Replication In Vivo." Journal of Virology 84, no. 18 (June 30, 2010): 9326–31. http://dx.doi.org/10.1128/jvi.00579-10.
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ABSTRACT The X protein (HBX) of the hepatitis B virus (HBV) is essential for HBV productive infection in vivo. Our previous study (Z. Hu, Z. Zhang, E. Doo, O. Coux, A. L. Goldberg, and T. J. Liang, J. Virol. 73:7231-7240, 1999) shows that interaction of HBX with the proteasome complex may underlie the pleiotropic functions of HBX. Previously, we demonstrated that HBX affects hepadnaviral replication through a proteasome-dependent pathway in cell culture models. In the present study, we studied the effect of the proteasome inhibitor MLN-273 in two HBV mouse models. We demonstrated that administration of MLN-273 to transgenic mice containing the replication-competent HBV genome with the defective HBX gene substantially enhanced HBV replication, while the compound had a minor effect on wild-type HBV transgenic mice. Similar results were obtained by using C57BL/6 mice infected with recombinant adenoviruses expressing the replicating HBV genome. Our data suggest that HBV replication is subjected to regulation by cellular proteasome and HBX functions through the inhibition of proteasome activities to enhance HBV replication in vivo.
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Zhu, Y. L., S. B. Pai, S. H. Liu, K. L. Grove, B. C. Jones, C. Simons, J. Zemlicka, and Y. C. Cheng. "Inhibition of replication of hepatitis B virus by cytallene in vitro." Antimicrobial Agents and Chemotherapy 41, no. 8 (August 1997): 1755–60. http://dx.doi.org/10.1128/aac.41.8.1755.
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The acyclic cytosine nucleoside analog cytallene [1-(4'-hydroxy-1',2'-butadienyl)cytosine], which has both (+)- and (-)-enantiomers, was evaluated for its anti-hepatitis B virus (HBV) activity in 2.2.15 cells and was found to have potent activity against HBV DNA synthesis. The R-(-)-enantiomer was found to be the more active of the cytallene enantiomers, with a 50% inhibition concentration against HBV synthesis (HBIC50) of 0.08 microM. Its antiviral activity could be reversed by deoxycytidine (dC) and less efficiently by cytidine. Upon removal of the R-(-)-enantiomer from culture medium, the synthesis of HBV DNA could reinitiate, which suggested that the antiviral action is reversible. The R-(-)-enantiomer was also found to be more cytotoxic than the S-(+)-enantiomer. The degree of cytotoxicity varied among the cell lines, with a 50% inhibition of cell growth at greater than 10 microM. The R-(-)-enantiomer had no effect on HBV RNA synthesis and mitochondrial DNA synthesis at a concentration of 10 times or more than the HBIC50. The two enantiomers cannot be deaminated by dC deaminase, and they can be phosphorylated by cytoplasmic dC kinase. The R-(-)-enantiomer of cytallene is the first acyclic cytosine analog with potent inhibitory activity against HBV similar to those of other L-(-)-ddC analogs.
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Sung, Vicky M. H., and Michael M. C. Lai. "Murine Retroviral Pseudotype Virus Containing Hepatitis B Virus Large and Small Surface Antigens Confers Specific Tropism for Primary Human Hepatocytes: a Potential Liver-Specific Targeting System." Journal of Virology 76, no. 2 (January 15, 2002): 912–17. http://dx.doi.org/10.1128/jvi.76.2.912-917.2002.
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ABSTRACT We have developed a system for producing murine leukemia virus (MLV) pseudotyped with human hepatitis B virus (HBV) large (L) and small (S) surface antigens (HBsAg) for targeting primary human hepatocytes. Using the MLV(HBV) pseudotype virus containing a β-galactosidase reporter gene, we demonstrated that this pseudotype virus exhibits strict tropism for primary human hepatocytes, similar to the natural target cell specificity of HBV. It does not infect any of the established tissue culture cell lines, including human hepatoma cell lines (HepG2 and Huh-7), or rat primary hepatocytes. The infectivity of MLV(HBV) for human hepatocytes was inhibited by anti-HBs antibody. The L form of HBsAg was both necessary and sufficient for virus infectivity, but the presence of both L and S forms enhanced the surface expression of HBsAg and thus increased virus production. The middle form of HBsAg was not necessary. This pseudotype virus bypasses the requirement for the liver-specific transcription factors for HBV replication, enabling direct study of HBV tissue tropism conferred by the viral envelope proteins. This virus also offers a potential liver-specific targeting system for gene therapy.
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Sureau, Camille, Chantal Fournier-Wirth, and Patrick Maurel. "Role of N Glycosylation of Hepatitis B Virus Envelope Proteins in Morphogenesis and Infectivity of Hepatitis Delta Virus." Journal of Virology 77, no. 9 (May 1, 2003): 5519–23. http://dx.doi.org/10.1128/jvi.77.9.5519-5523.2003.
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ABSTRACT Hepatitis delta virus (HDV) particles are coated with the large (L), middle (M), and small (S) hepatitis B virus envelope proteins. In the present study, we constructed glycosylation-defective envelope protein mutants and evaluated their capacity to assist in the maturation of infectious HDV in vitro. We observed that the removal of N-linked carbohydrates on the S, M, and L proteins was tolerated for the assembly of subviral hepatitis B virus (HBV) particles but was partially inhibitory for the formation of HDV virions. However, when assayed on primary cultures of human hepatocytes, virions coated with S, M, and L proteins lacking N-linked glycans were infectious. Furthermore, in the absence of M, HDV particles coated with nonglycosylated S and L proteins retained infectivity. These results indicate that carbohydrates on the HBV envelope proteins are not essential for the in vitro infectivity of HDV.
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Kai, Tatsuyuki, Kazuhiko Ikeda, Yutaka Shiga, Hideo Kimura, Hideyoshi Noji, Kazuei Ogawa, Kunihiko Takeyama, and Yukio Maruyama. "Imatinib Mesylate Induced Fatal Hepatitis B Virus (HBV) Reactivation in a Patient with CML." Blood 104, no. 11 (November 16, 2004): 4677. http://dx.doi.org/10.1182/blood.v104.11.4677.4677.
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Abstract Imatinib mesylate (Glivec; Novartis, Basel, Switzerland), which is a selective inhibitor of the Bcr/Abl tyrosine kinase, is now widely used for the treatment of Ph-positive leukemia based on the remarkable efficacy. Treatment with imatinib mesylate is generally well tolerated, and the risk for severe adverse effects is low. Hepatic toxicity is less common and usually resolves with interruption of imatinib therapy. On the other hand, although it is well known that HBV reactivations are observed in cancer patients with chronic HBV infection during chemotherapies, imatinib mesylate-induced HBV reactivation has not been reported yet. Here, we report the first case complicated by fatal fulminant HBV reactivation during imatinib mesylate treatment for CML. A 54-year-old man was diagnosed as CML on October 2003. At that time, HBsAg, HBeAb, and HBcAb were positive, whereas HBsAb was negative. HCV Ab and HCV RNA were also positive. However, hepatic examinations revealed normal findings, except slightly elevated levels of AST (50 IU/L). On November 2003, imatinib mesylate was started at the dose of 400mg/day p.o. and continued without any hepatic adverse effects. In contrast, the patient was suffered from neutropenia (grade 2) and lymphocytopenia (grade 2) on December 2003. Although dose of imatinib mesylate was reduced (300mg/day), lymphocytopenia continued. Since May 6, 2004, the patient complained general fatigue. On May 11, AST, ALT, and total bilirubin were 125 IU/L, 95 IU/L, and 0.7 mg/dl, respectively. At that time, bone marrow cytogenetics using a FISH of Bcr/Abl detected 2.0% fusion gene. Then, hepatic function deteriorated despite imatinib mesylate administration was stopped. On May 27, the patient had severe hepatic dysfunction with high AST, ALT, and total bilirubin (2098 IU/L, 1574 IU/L, and 5.6 mg/dl, respectively). In addition, prolonged prothrombin time (13.6%) and deterioration of consciousness were observed. HBV DNA polymerase was extremely increased (> 20000 cpm; normal range: <30). He was diagnosed as a fulminant hepatitis due to HBV reactivation and referred to the Second Department of Internal Medicine (Hepatology) of Fukushima Medical University. Although he received intensive treatments including plasma exchanges, he died from hepatic failure on June 21 2004. This is the first case of a fulminant hepatitis due to HBV reactivation during treatment of imatinib mesylate. Although it is not clear how HBV was reactivated in our case, one of the possible causes may be the lymphocytopenic status by imatinib mesylate. In fact, among the chemotherapeutic agents, the use of steroid is the most significant risk factor of HBV reactivation in cancer patients with chronic HBV infection (Yeo et al, Br J Cancer, 2004). Ph-positive leukemia patients receiving imatinib mesylate often develop transient lymphocytopenia and/or neutropenia (Druker et al, N Engl J Med, 2002). Therefore, in the patients with chronic hepatic viral infections such as HBV and HCV, we should take care of viral reactivation in use of imatinib mesylate. We should also consider prophylaxis of viral reactivation using antiviral drugs or alternative initial therapy with interferon-α for both anti-leukemic and anti-viral effects to treat CML patients with chronic hepatitic viral infection.
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Shih, Chiaho, Szu-Yao Wu, Shu-Fan Chou, and Ta-Tung Thomas Yuan. "Virion Secretion of Hepatitis B Virus Naturally Occurring Core Antigen Variants." Cells 10, no. 1 (December 30, 2020): 43. http://dx.doi.org/10.3390/cells10010043.
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In natural infection, hepatitis B virus (HBV) core protein (HBc) accumulates frequent mutations. The most frequent HBc variant in chronic hepatitis B patients is mutant 97L, changing from an isoleucine or phenylalanine to a leucine (L) at HBc amino acid 97. One dogma in the HBV research field is that wild type HBV secretes predominantly virions containing mature double-stranded DNA genomes. Immature genomes, containing single-stranded RNA or DNA, do not get efficiently secreted until reaching genome maturity. Interestingly, HBc variant 97L does not follow this dogma in virion secretion. Instead, it exhibits an immature secretion phenotype, which preferentially secretes virions containing immature genomes. Other aberrant behaviors in virion secretion were also observed in different naturally occurring HBc variants. A hydrophobic pocket around amino acid 97 was identified by bioinformatics, genetic analysis, and cryo-EM. We postulated that this hydrophobic pocket could mediate the transduction of the genome maturation signal for envelopment from the capsid interior to its surface. Virion morphogenesis must involve interactions between HBc, envelope proteins (HBsAg) and host factors, such as components of ESCRT (endosomal sorting complex required for transport). Immature secretion can be offset by compensatory mutations, occurring at other positions in HBc or HBsAg. Recently, we demonstrated in mice that the persistence of intrahepatic HBV DNA is related to virion secretion regulated by HBV genome maturity. HBV virion secretion could be an antiviral drug target.
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Chai, Ning, Ho Eun Chang, Emmanuelle Nicolas, Severin Gudima, Jinhong Chang, and John Taylor. "Assembly of Hepatitis B Virus Envelope Proteins onto a Lentivirus Pseudotype That Infects Primary Human Hepatocytes." Journal of Virology 81, no. 20 (August 1, 2007): 10897–904. http://dx.doi.org/10.1128/jvi.00959-07.
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ABSTRACT This study demonstrates that the envelope proteins of hepatitis B virus (HBV) could be incorporated into the lipid membrane of lentivirus pseudotype particles. The assembly procedure was initiated by the transfection of 293T cells with three plasmids: (i) a human immunodeficiency virus (HIV) packaging construct, (ii) a transfer plasmid expressing a reporter gene, and (iii) a plasmid expressing large (L), middle (M), and small (S) HBV envelope proteins. After 2 days, hepatitis B surface antigen and the antigenic forms of L, M, and S were detected at the cell surface by flow cytometry. Also, virus particles that were able to infect cultured primary human hepatocytes (PHH) were released. Under optimal conditions, 50% of PHH could be infected. In addition, the susceptibility of PHH and the resistance of other cell types to the pseudotype particles were similar to those observed for HBV and hepatitis delta virus (HDV), which shares the same L, M, and S. Furthermore, the infection of PHH by the pseudotype was sensitive to known inhibitors of HBV and HDV entry. These findings of specific and efficient infection of hepatocytes could be applicable to liver-specific gene therapy and may help clarify the attachment and entry mechanism used by HBV and HDV.
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Hennig, Holger, Ines Puchta, Jürgen Luhm, Peter Schlenke, Siegfried Goerg, and Holger Kirchner. "Frequency and load of hepatitis B virus DNA in first-time blood donors with antibodies to hepatitis B core antigen." Blood 100, no. 7 (October 1, 2002): 2637–41. http://dx.doi.org/10.1182/blood-2002-03-0798.
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The objective of this study was to determine the frequency and load of hepatitis B virus (HBV) DNA in anti-HBc–positive first-time blood donors; it was designed to contribute to determining whether anti-HBc screening of blood donations might reduce the residual risk of posttransfusion HBV infection. A total of 14 251 first-time blood donors were tested for anti-HBc using a microparticle enzyme immunoassay; positive results were confirmed by a second enzyme-linked immunosorbent assay (ELISA). For the detection of HBV DNA from plasma samples, we developed a novel and highly sensitive real-time polymerase chain reaction (PCR) assay. The 95% detection limit of the method amounted to 27.8 IU/mL, consistent with the World Health Organization (WHO) international standard for HBV DNA. A total of 216 blood donors (1.52%) tested anti-HBc–positive in both tests, and 205 of them (16 HBsAg+, 189 HBsAg−) were tested for HBV DNA. In 14 (87.5%) of the HBsAg-positive blood donors, HBV DNA was repeatedly detected, and in 3 (1.59%) of the HBsAg-negative donors, HBV DNA was also found repeatedly. In the 3 HBV DNA–positive, HBsAg-negative cases, anti-HBe and anti-HBs (> 100 IU/L) were also detectable. HBV DNA in HBsAg-negative as well as HBsAg-positive samples was seen at a low level. Thus, HBV DNA is sometimes found in HBsAg-negative, anti-HBc–positive, and anti-HBs–positive donors. Retrospective studies on regular blood donors and recipients are necessary to determine the infection rate due to those donations. Routine anti-HBc screening of blood donations could probably prevent some transfusion-transmitted HBV infections.
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Matthes, E., A. Funk, I. Krahn, K. Gaertner, M. von Janta-Lipinski, L. Lin, H. Will, and H. Sirma. "Strong and Selective Inhibitors of Hepatitis B Virus Replication among Novel N4-Hydroxy- and 5-Methyl-β-l-Deoxycytidine Analogues." Antimicrobial Agents and Chemotherapy 51, no. 7 (April 2, 2007): 2523–30. http://dx.doi.org/10.1128/aac.00001-07.
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ABSTRACT Novel N4-hydroxy- and 5-methyl-modified β-l-deoxycytidine analogues were synthesized and evaluated as anti-hepatitis B virus (HBV) agents. Their in vitro efficiencies were investigated in HepG2.2.15 cells stably transfected with HBV. β-l-2′,3′-Didehydro-2′,3′-dideoxy-N4-hydroxycytidine (β-l-Hyd4C) was most effective in reducing secreted HBV DNA (50% effective concentration [EC50], 0.03 μM), followed by β-l-2′,3′-dideoxy-3′-thia-N4-hydroxycytidine (EC50, 0.51 μM), β-l-2′,3′-dideoxy-N4-hydroxycytidine (EC50, 0.55 μM), and β-l-5-methyl-2′-deoxycytidine (EC50, 0.9 μM). The inhibition of the presumed target, the HBV DNA polymerase, by the triphosphates of some of the β-l-cytidine derivatives was also assessed. In accordance with the cell culture data, β-l-Hyd4C triphosphate was the most active inhibitor, with a 50% inhibitory concentration of 0.21 μM. The cytotoxicities of some of the 4-NHOH-modified β-l-nucleosides were dramatically lower than those of the corresponding cytidine analogues with the unmodified 4-NH2 group. The 50% cytotoxic concentrations for β-l-Hyd4C in HepG2 and HL-60 cells were 2,500 μM and 3,500 μM, respectively. In summary, our results demonstrate that at least β-l-Hyd4C can be recommended as a highly efficient and extremely selective inhibitor of HBV replication for further investigations.
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Jang, Jieun, Hyunsung Park, Jungyeon Lee, Yundeok Kim, Soo Jeong Kim, June-Won Cheong, Yoo Hong Min, and Jin Seok Kim. "Post-Autotransplant Hepatitis B Virus (HBV) Reactivation in Lymphoma and Multiple Myeloma Patients with Hepatitis B Surface Antigen-Positive or Resolved HBV Infection." Blood 124, no. 21 (December 6, 2014): 1196. http://dx.doi.org/10.1182/blood.v124.21.1196.1196.
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Abstract Background: Although hepatitis B virus (HBV) reactivation in patients with hepatitis B surface antigen (HBsAg)-positive or resolved HBV infection (HBsAg-negative and hepatitis B core antibody [anti-HBc]-positive) undergoing anticancer therapy with or without rituximab has been frequently reported, few studies have evaluated the risk of HBV reactivation in patients receiving autologous stem cell transplantation (ASCT). We studied the rate of hepatitis and HBV reactivation after ASCT in lymphoma and multiple myeloma (MM) patients with HBsAg-positive or resolved HBV infection. Methods & Materials: Medical records of patients who diagnosed with lymphoma or MM and received ASCT between November 2005 and April 2014 in Severance hospital were retrospectively analyzed. HBV status was screened routinely at ASCT and when viral-related hepatitis was suspected after ASCT. Hepatitis was defined as a 3-fold or greater increase in serum alanine transaminase (ALT) that exceeded the reference range (>46 IU/L) or an absolute increase of ALT to more than 100 IU/L. HBV reactivation was defined as elevation of serum HBV-DNA level more than 1 log IU/L from baseline in HBsAg(+) patients. In case of resolved HBV patients, positive conversion of HBsAg (reverse seroconversion) with or without increase of ALT was defined as HBV reactivation. Hepatitis and HBV reactivation occurred before 1 year after ASCT was considered ASCT-related in this study. Result: A total of 297 patients (196 lymphoma and 101 MM) were studied. Median age at diagnosis was 47 years (range 16-64). A male to female ratio was 1.36:1. Most common subtype of lymphoma was diffuse large B-cell lymphoma (DLBCL, n=111). The median duration from diagnosis to ASCT was 475 days (range 105-5230) and 175 days (range 39-5400) in lymphoma and MM patients, respectively. Busulfan-based (n= 161, 82.1%) conditioning regimens were commonly used in lymphoma patients and melphalan-based (n=101, 100%) conditioning regimens were used in MM patients. The patients with HBsAg(-) did not received a routine anti-HBV prophylaxis regardless of the presence of anti-HBc. Nine patients did not tested for HBV at ASCT. Among 274 patients with HBsAg(-), 110 patients were anti-HBc(+) (resolved HBV infection) and 161 patients were anti-HBc(-). Within 1 year after ASCT, 48 of anti-HBc(+) and 71 of anti-HBc(-) patients experienced hepatitis (43.6% vs. 44.1%, p>0.999). The most common cause of hepatitis was drug-related (n= 81, 66.9%). There was no HBsAg reverse seroconversion within 1 year after ASCT. After 1 year, Only one patient with anti-HBc(+) experienced HBV reactivation at days 763 after ASCT and 3 patients with anti-HBc(-) showed HBsAg reverse seroconversion at days 406, 457 and 1172 post-transplant. In the subset of 178 lymphoma patients with HBsAg(-), 90 patients had a history of previous use of anti-CD20 monoclonal antibody, of whom 37 patients were anti-HBc(+). Twelve of anti-HBc(+) and 24 of anti-HBc(-) patients experienced hepatitis (32.4% vs. 45.3%, p=0.276) but there was no HBV reactivation related hepatitis within 1 year after ASCT. Among 14 patients with HBsAg(+) at ASCT, 13 patients received rituximab-containing chemotherapy before ASCT. They had received prophylactic HBV therapy with lamivudine (n=6), telbivudine (n=4), clevudine (n=2), adefovir (n=1) and tenofovir (n=1). Among them, 3 patients with telbivudine (n=1, 25%), clevudine (n=1, 50%) and lamivudine (n=1, 16.7%) experienced HBV reactivation at days 36, 161 and 204 after ASCT. Conclusion: Our data suggest that ASCT-related HBV reactivation is rare in lymphoma and MM patients with resolved HBV infection regardless of previous anti-CD20 therapy. Routine anti-HBV prophylaxis is not necessary for patients with resolved HBV infection. In case of HBsAg(+) patients, antiviral prophylaxis with lamivudine, clevudine, or telbivudine may not be sufficient to prevent HBV reactivation after ASCT. More potent antiviral agents such as adefovir or tenofovir should be considered. Figure 1 Figure 1. Characteristics of 7 patients with HBV reactivation or HBsAg reverse seroconversion after ASCT. Disclosures No relevant conflicts of interest to declare.
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Kolassery, Sandesh. "Correlation of HBsAg quantitation by ELISA with serum hepatitis B virus DNA quantitative PCR in chronic hepatitis B patients." International Journal of Research in Medical Sciences 5, no. 6 (May 27, 2017): 2422. http://dx.doi.org/10.18203/2320-6012.ijrms20172126.
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Background: Serum HBV DNA is a useful and reliable marker to diagnose and monitor CHB on treatment. The limitation of HBV DNA is that it is expensive and that the assays lack uniformity and standardization. Hence there is a need for more economical and reliable marker. HBsAg quantitation is one such surrogate serological marker. The objective of the current study is to compare and correlate the serum hepatitis B DNA quantitative PCR with HBsAg quantitation.Methods: Patients with CHB attending to the outpatient clinic of Gastroenterology department were enrolled in the study. Patients with undetectable HBV DNA levels and those co-infected with HCV or HIV were excluded from the study. All patients were tested for serological markers like HBsAg (rapid), HBeAg, anti HBe and HBV DNA-PCR. HBsAg quantification was done using conventional ELISA immunoassay. HBV-DNA and qHBsAg levels were expressed in log10IU/ml. Pearson correlation was used to estimate correlation between HBV DNA and HBsAg quantitation. Statistical analysis was done using SPSS and P value of <0.05 was considered significant.Results: A total of 38 patients were enrolled in the study. 23.62% were females and mean age of patients in the entire study group was 35.72 years. The mean ALT level was 103.80U/L. 26.32% (n = 10) were HBeAg positive. Mean HBV DNA and qHBsAg levels for the entire cohort were 5.81 log10IU/ml and 5.83 log10IU/ml respectively with a correlation coefficient of 0.318 (P = 0.130). For HBeAg positive patients the mean HBV DNA and qHBsAg levels were 7.90 log10IU/ml and 5.91 log10IU/ml respectively with a correlation coefficient of 0.722 (P = 0.043). HBV DNA levels were significantly higher in HBeAg positive patients compared with HBeAg negative patients (7.9 versus 4.01; P = 0.002). qHBsAg levels were also marginally high in HBeAg positive patients (5.91 versus 5.8; P = 0.136). Neither HBV DNA levels nor qHBsAg levels correlated with serum ALT levels.Conclusions: There is a significant correlation between quantitative HBsAg levels and HBV-DNA levels in HBeAg positive patients with chronic hepatitis B but not in HBeAg negative patients. HBV-DNA levels are significantly higher in HBeAg positive patients.
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Pai, S. Balakrishna, Rekha B. Pai, Meng-Yu Xie, Tolunay Beker, Junxing Shi, Philip M. Tharnish, Chung K. Chu, and Raymond F. Schinazi. "Characterization of Hepatitis B Virus Inhibition by Novel 2′-Fluoro-2′,3′-Unsaturated Beta-D- and l-nucleosides." Antiviral Chemistry and Chemotherapy 16, no. 3 (June 2005): 183–92. http://dx.doi.org/10.1177/095632020501600304.
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The clinical emergence of lamivudine and adefovir resistance mutations on prolonged therapy further necessitates the development of additional drugs for the treatment of hepatitis B virus (HBV) infections. We have evaluated a number of novel 2′-fluoro-2′,3′-unsaturated d- and l-nucleosides for their anti-HBV activity in the HepG2–2.2.15 cell system. The most potent nucleosides were β-l-2′-fluoro-2′,3′-dideoxy-2′,3′-didehydrocytidine (l-2′-Fd4C) and β-l-2′-fluoro-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine (l-2′-Fd4FC) with median effective concentrations (EC50) of 0.002 μM and 0.004 μM, respectively. The d-enantiomers of the 2′-fluoro-substituted cytidine analogues in this series showed activity, with the 5-fluorocytidine (d-2′-Fd4FC) being the most potent (EC50=0.05 μM). The active compounds were not cytotoxic to a number of cell lines or to bone marrow progenitor cells. Furthermore, mitochondrial DNA synthesis and function were not affected by these nucleosides. l-2′-Fd4C did not affect viral transcription, implying that it does not inhibit cellular RNA polymerase II. Studies with the HBV polymerase in core particles revealed that the 5′-triphosphates of l-2′-Fd4C and d-2′-Fd4FC produced a dose-dependent inhibition of the incorporation of 32P-dCTP into the HBV DNA, indicating that the mechanism of action of these compounds is through specific inhibition of viral DNA synthesis. This class of nucleosides, which exhibit potent antiviral activity and a favourable safety profile, have potential for the treatment of HBV infections and warrant further development.
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Lepère, Charlotte, Morgane Régeard, Jacques Le Seyec, and Philippe Gripon. "The Translocation Motif of Hepatitis B Virus Envelope Proteins Is Dispensable for Infectivity." Journal of Virology 81, no. 14 (May 9, 2007): 7816–18. http://dx.doi.org/10.1128/jvi.00224-07.
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ABSTRACT The early events of hepatitis B virus (HBV) infection remain unclear. In 2006, Stoeckl et al. proposed a new entry mechanism involving a translocation motif (TLM) present in the pre-S2 domain of envelope proteins (L. Stoeckl, A. Funk, A. Kopitzki, B. Brandenburg, S. Oess, H. Will, H. Sirma, and E. Hildt, Proc. Natl. Acad. Sci. USA 103:6730-6734, 2006). After receptor binding and internalization into the endosomal compartment, this motif would allow the translocation of HBV particles through the endosomal membrane into the cytosol. In this study we have used two different mutated viruses containing a truncated TLM and showed their ability to infect human hepatocytes in primary culture, thus demonstrating the dispensability of the TLM for HBV infectivity.
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Hartmann-Stühler, Cora, and Reinhild Prange. "Hepatitis B Virus Large Envelope Protein Interacts with γ2-Adaptin, a Clathrin Adaptor-Related Protein." Journal of Virology 75, no. 11 (June 1, 2001): 5343–51. http://dx.doi.org/10.1128/jvi.75.11.5343-5351.2001.
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ABSTRACT For the outcome of a hepatitis B virus (HBV) infection, the viral L envelope protein with its pre-S domain performs pivotal functions by mediating attachment of HBV to liver cells, envelopment of viral capsids, release of (sub)viral particles, regulation of supercoiled DNA amplification, and transcriptional transactivation. To assess its multiple functions and host-protein assistance involved, we initiated a two-hybrid screen using the L-specific pre-S1 domain as bait. With this approach, we have identified γ2-adaptin, a putative member of the clathrin adaptor proteins responsible for protein sorting and trafficking, as a specific binding partner of L protein. Evidence for a physical interaction between L protein and γ2-adaptin was also demonstrated by affinity chromatography and coimmunoprecipitation, and the binding sites were mapped to the L-specific pre-S1 domain and the γ2-adaptin-specific ear domain. The specificity of the interaction was further sustained by the failure of γ1-adaptin, a closely related γ2-adaptin homologue, to associate with L protein. Analysis of an L mutant protein indicates that the L–γ2-adaptin interaction strictly depends on the pre-S1 domain of transmembrane L protein oriented to the cytosol and thus appears to occur in the cytosolic environment. Interestingly, coexpression of the two interacting partners in transfected cells resulted in recruitment of γ2-adaptin by L protein onto cis-Golgi-like structures, strongly indicating that the association is physiologically relevant. Together, the results suggest a role for γ2-adaptin in L-mediated processes of viral biogenesis and/or pathogenesis, such as facilitating and guiding HBV assembly.
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Dudanova, Olga P., M. E. Shubina, I. A. Belavina, E. A. Elpaeva, M. M. Pisareva, M. P. Grudinin, and O. I. Kiselev. "Chronic hepatitis with double B/C infection: virological, clinical, morphological characteristics." Clinical Medicine (Russian Journal) 94, no. 4 (June 1, 2016): 289–94. http://dx.doi.org/10.18821/0023-2149-2016-94-4-289-294.
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Aim. To estimate the frequency, virological and clinical characteristics of chronic viral hepatitis (CVH) with double B/C infection. Materials and methods. We examined 282 patients with CVH. Genomes of hepatitis B virus (HBV) and hepatitis C virus (HCV) were studied by PCR in blood and liver (AmpliSens HBV and Amplisens HCV, Russia), nuclear proteins (HBcorAg HBV and NS3 HCV) were determined by immunohistochemical method (Novocastra, UK), HBV genome was sequenced by the Sanger method using ABI prism BigDye Terminator v3.1 kits and ABIPRISM 3100 analyzer (AppliedBiosystems, USA). Indices of histological activity (HAI), fibrosis, and portal vein (PV) congestion index (CI) were calculated by formula CI=SBB/LBV, where S is PV cross section area in cm2 and LBV - linear blood flow velocity in cm/s (Vivid Pro-7 apparatus, USA). Results. CVH with double B/C infection was diagnosed in 85 (30.1%) patients including 44.7% with viral genomes and proteins in the liver, 42.4% with HCV viremia, and 12.9% with HBV/HCV viremia. Maximum CVH activity was documented in patients with latent HBV/HCV viremia (ALT 157.2±59.2 U/l, HAI 11.6±1.3, fibrosis 2.8±0.7, CI 0.059±0.005); it was minimal in patients without viremia (Alt 76.25±63.0 U/l, HAI 6.7+-0.6, fibrosis 1.7±0.5, CI 0.042±0.001; p <0.05). Patients with latent HBV infection had precore/ore and pres/s mutations in HBV genome and cytoplasmic localization of HBcorAg. Conclusion. Double B/C infection was diagnosed in 30.1% of the patients with CVH dominated by HCV. Patients with latent HBV had precore/ore and pres/s mutations. The highest intensity of hepatic cellular inflammation, fibrosis, and PV congestion was associated with HBV/HCV viremia and the lowest with intrahepatic localization of both viruses.
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Wagner, Markus, Michael Alt, Peter Hans Hofschneider, and Matthias Renner. "A novel negative cis-regulatory element on the hepatitis B virus S-(+)-strand." Journal of General Virology 80, no. 10 (October 1, 1999): 2673–83. http://dx.doi.org/10.1099/0022-1317-80-10-2673.
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Hepatitis B virus (HBV) has a double-stranded DNA genome. The minus-strand contains coding regions for all known HBV proteins and most of the cis-regulatory elements. Little is known about transcription from the S-(+)-strand and its regulation. Thus, the presence of regulatory elements located on the S-(+)-strand was investigated by inserting nt 1038–1783 of HBV in both orientations between the human cytomegalovirus (HCMV) promoter and a luciferase gene. Transfection experiments revealed that the plasmid containing this HBV DNA fragment in an orientation allowing expression from the S-(+)-strand (antisense) led to inhibition of luciferase gene expression compared to the plasmid containing this sequence in an orientation that allows gene expression from the L-(−)-strand (sense). Deletion analyses delimit the sequence essential for the inhibitory effect to a 150 bp region that also carries part of the enhancerII/core promoter complex. However, the possible influence of this regulatory element has been excluded in various experiments. The repressing HBV sequence acts in an orientation- and position-dependent manner; no inhibition was observed when this DNA element was inserted upstream of the HCMV promoter or downstream of the luciferase gene. Northern blot analyses revealed reduced luciferase mRNA steady-state levels in cells transfected with constructs containing the essential HBV sequence in antisense orientation compared to plasmids containing this sequence in sense orientation. Since nuclear run-on experiments showed similar transcription initiation rates with these plasmids, the diminished luciferase mRNA steady-state levels must be due to altered stabilities, suggesting that nt 1783–1638 of HBV encode an RNA-destabilizing element.
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Niscola, Pasquale, Maria Ilaria Del Giudice, Luca Maurillo, Mariacarmela Solmone, Maria Rosaria Capobianchi, Fabrizio Carletti, Daniela Piccioni, Adriano Venditti, Sergio Amadori, and Giovanni Del Poeta. "Fulminant B Hepatitis in a Hepatitis B Surface Antigen-Negative Patient after Rituximab Therapy for B-CLL." Blood 106, no. 11 (November 16, 2005): 5025. http://dx.doi.org/10.1182/blood.v106.11.5025.5025.
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Abstract Concerns about safety of rituximab in hepatitis B virus (HBV) carriers have risen at the light of reported cases of HBV reactivation following the administration of this agent. We recently observed a patient affected by B-cell Chronic Lymphocytic Leukemia (B-CLL) who developed this complication without any serological evidence of HBsAg expression. Case report: the patient, a 51 old year’s male, was diagnosed as having B-CLL in November 1998 and followed until his death due to acute liver failure due to HBV reactivation of a mutant HBV strain in September 2004 (Table). At diagnosis of B-CLL no risk factors regarding liver diseases or viral infections were reported; serum HBsAg and HBeAg, antibodies against the B-core antigen (HBcAb), HBe (HBeAB), HBsAg (HBsAb), HCV, hepatitis A and Delta virus, Cytomegalovirus, and Epstein Barr virus were negative while HBcAb alone were positive. He presented stable disease until November 2001, when fludarabine was started because of progressive disease. A good partial response (GPR) was achieved so that he received four weekly standard doses (375 mg/m2) of rituximab as consolidation therapy (July 2002). A complete remission (CR) was obtained and he was then closely followed-up until about two years later (February 2004) when, for a disease recurrence, rituximab was given again. At that time all the above hepatitis markers remained unmodified. After four weekly standard doses of rituximab a GPR was recorded, and then six monthly courses (150 mg/m2) of the same agent were administered as maintenance therapy. In September 2004, being the patient in CR, he was admitted with acute hepatitis. HBV DNA strains (200,000 copies/mL) and HbcAb IgM were detected, whereas HbsAg-negative status persisted. The viral form was characterized as having D genotype and ayw3 serotype respectively. Sequence analysis of polymerase chain reaction (PCR) products amplified from the S region revealed 5 remarkable mutations in the major antigenic regions (C124Y, A128V, G130D, P135R and G145R). These mutations were associated with the lack of HbsAg production and were compatible with an escape of a rare HBV strain from the patient’s own HbsAb. Despite treatment with lamivudine, the patient died of fulminant hepatic failure. Conclusion: our experience indicates that patients receiving rituximab who are negative for HBsAg but positive for anti-HBc are still at risk for reactivation of latent HBV and should be considered for HBV DNA testing and prophylaxis with lamivudine. Patient clinical features Clinical features Diagnosis (November 1998) Disease Progression (November 2001) Disease Recurrence (February 2004) B Hepatitis onset (September 2004) *D genotype, ayw3 serotype; C124Y, A128V, G130D, P135R and G145R mutations in the S region. NA:not available. Rai Clinical Stage I II II 0 CD38 Negative Negative Negative Negative Zap 70 Positive Positive Positive Negative CD4/CD8 0.95 0.90 0.85 0.80 Beta 2 microglobulin (mcg/L) 1503 1825 1844 1325 Serum Ig level (gr/L) 0,980 0,790 0,660 0,620 HBsAg Negative Negative Negative Negative HBsAb Negative Negative Negative Negative HBcAb Positive Positive Positive Positive HBeAg Negatrive Negative Negative Positive HBeAb Positive Positive Positive Positive HBV DNA* NA NA NA 200.000/μL
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Walters, Kathie-Anne, Graham A. Tipples, Marchelle I. Allen, Lynn D. Condreay, William R. Addison, and Lorne Tyrrell. "Generation of Stable Cell Lines Expressing Lamivudine-Resistant Hepatitis B Virus for Antiviral-Compound Screening." Antimicrobial Agents and Chemotherapy 47, no. 6 (June 2003): 1936–42. http://dx.doi.org/10.1128/aac.47.6.1936-1942.2003.
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ABSTRACT Lamivudine [β-l-(−)-2′,3′-dideoxy-3′-thiacytidine] is a potent inhibitor of hepadnavirus replication and is used both to treat chronic hepatitis B virus (HBV) infections and to prevent reinfection of transplanted livers. Unfortunately, lamivudine-resistant HBV variants do arise during prolonged therapy, indicating a need for additional antiviral drugs. Replication-competent HBV constructs containing the reverse transcriptase domain L180M/M204V and M204I (rtL180M/M204V and rtM204I) mutations associated with lamivudine resistance were used to produce stable cell lines that express the resistant virus. These cell lines contain stable integrations of HBV sequences and produce both intracellular and extracellular virus. HBV produced by these cell lines was shown to have a marked decrease in sensitivity to lamivudine, with 450- and 3,000-fold shifts in the 50% inhibitory concentrations for the rtM204I and rtL180M/M204V viruses, respectively, compared to that for the wild-type virus. Drug assays indicated that the lamivudine-resistant virus exhibited reduced sensitivity to penciclovir [9-(4-hydroxy-3-hydroxymethyl-but-1-yl) guanine] but was still inhibited by the nucleoside analogues CDG (carbocyclic 2′-deoxyguanosine) and abacavir {[1S,4R]-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol}. Screening for antiviral compounds active against the lamivudine-resistant HBV can now be done with relative ease.
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Barrera, Azeneth, Bernadette Guerra, Helen Lee, and Robert E. Lanford. "Analysis of Host Range Phenotypes of Primate Hepadnaviruses by In Vitro Infections of Hepatitis D Virus Pseudotypes." Journal of Virology 78, no. 10 (May 15, 2004): 5233–43. http://dx.doi.org/10.1128/jvi.78.10.5233-5243.2004.
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ABSTRACT Hepatitis B virus (HBV) and woolly monkey hepatitis B virus (WMHBV) have natural host ranges that are limited to closely related species. The barrier for infection of primates seems to be at the adsorption and/or entry steps of the viral replication cycle, since a human hepatoma cell line is permissive for HBV and WMHBV replication following transfection of cloned DNA. We hypothesized that the HBV and WMHBV envelope proteins contain the principal viral determinants of host range. As previously shown by using the hepatitis D virus (HDV) system, recombinant HBV-HDV particles were infectious in chimpanzee as well as human hepatocytes. We extended the HDV system to include HDV particles pseudotyped with the WMHBV envelope. In agreement with the natural host ranges of HBV and WMHBV, in vitro infections demonstrated that HBV-HDV and WM-HDV particles preferentially infected human and spider monkey cells, respectively. Previous studies have implicated the pre-S1 region of the large (L) envelope protein in receptor binding and host range; therefore, recombinant HDV particles were pseudotyped with the hepadnaviral envelopes containing chimeric L proteins with the first 40 amino acids from the pre-S1 domain exchanged between HBV and WMHBV. Surprisingly, addition of the human amino terminus to the WMHBV L protein increased infectivity on spider monkey hepatocytes but did not increase infectivity for human hepatocytes. Based upon these data, we discuss the possibility that the L protein may be comprised of two domains that affect infectivity and that sequences downstream of residue 40 may influence host range and receptor binding or entry.
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Ni, Yi, Jessika Sonnabend, Stefan Seitz, and Stephan Urban. "The Pre-S2 Domain of the Hepatitis B Virus Is Dispensable for Infectivity but Serves a Spacer Function for L-Protein-Connected Virus Assembly." Journal of Virology 84, no. 8 (February 3, 2010): 3879–88. http://dx.doi.org/10.1128/jvi.02528-09.
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ABSTRACT The envelope of the human hepatitis B virus (HBV) contains three membrane proteins (L, M, and S). They accomplish different functions in HBV infectivity and nucleocapsid envelopment. Infectivity determinants have been assigned to the N-terminal part of the pre-S1 domain of the L protein and the antigenic loop of the S domain in the L and/or S protein. Nucleocapsid envelopment requires a C-terminal sequence within pre-S1, including the five N-terminal amino acids of pre-S2 as part of the L protein. However, the role of the M protein and the pre-S2 domain of the L protein are not entirely understood. We addressed this question and analyzed assembly competence and infectivity of viruses that lack the M protein and, at the same time, carry alterations in the pre-S2 domain of L. These include deletions, in part frameshift mutations and a randomization of virtually the entire pre-S2 sequence. We found that the M protein is dispensable for HBV in vitro infectivity. Viruses that lack the M protein and contain a mostly randomized pre-S2 sequence assemble properly and are infectious in HepaRG cells and primary human hepatocytes. While deletions of 20 amino acids in the pre-S2 domain of L protein allowed the production of infectious virions, more extended deletions interfered with assembly. This indicates that the pre-S2 domain of the L protein serves an important role for virus assembly, presumably as a spacer that supports conformational changes of L protein but does not participate as part of the M protein or as a subdomain of the L protein in virus entry.
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Aguesse-Germon, Stéphanie, Shwu-Huey Liu, Michèle Chevallier, Christian Pichoud, Catherine Jamard, Christelle Borel, Chung K. Chu, Christian Trépo, Yung-Chi Cheng, and Fabien Zoulim. "Inhibitory Effect of 2′-Fluoro-5-Methyl-β-l-Arabinofuranosyl-Uracil on Duck Hepatitis B Virus Replication." Antimicrobial Agents and Chemotherapy 42, no. 2 (February 1, 1998): 369–76. http://dx.doi.org/10.1128/aac.42.2.369.
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ABSTRACT The antiviral activity of 2′-fluoro-5-methyl-β-l-arabinofuranosyluracil (l-FMAU), a novel l-nucleoside analog of thymidine known to be an inhibitor of hepatitis B virus (HBV) replication in hepatoma cells (2.2.1.5 cell line), was evaluated in the duck HBV (DHBV) model. Short-term oral administration (5 days) ofl-FMAU (40 mg/kg of body weight/day) to experimentally infected ducklings induced a significant decrease in the level of viremia. This antiviral effect was sustained in animals when therapy was prolonged for 8 days. The histological study showed no evidence of liver toxicity in the l-FMAU-treated group. By contrast, microvesicular steatosis was found in the livers of dideoxycytidine-treated animals. l-FMAU administration in primary duck hepatocyte cultures infected with DHBV induced a dose-dependent inhibition of both virion release in culture supernatants and intracellular viral DNA synthesis, without clearance of viral covalently closed circular DNA. By using a cell-free system for the expression of an enzymatically active DHBV reverse transcriptase, it was shown that l-FMAU triphosphate exhibits an inhibitory effect on the incorporation of dAMP in the viral DNA primer. Thus, our data demonstrate that l-FMAU inhibits DHBV replication in vitro and in vivo. Long-term administration of l-FMAU for the eradication of viral infection in animal models of HBV infection should be evaluated.
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Zhu, Yong-Lian, Ginger E. Dutschman, Shwu-Huey Liu, Edward G. Bridges, and Yung-Chi Cheng. "Anti-Hepatitis B Virus Activity and Metabolism of 2′,3′-Dideoxy-2′,3′-Didehydro-β-l(−)-5-Fluorocytidine." Antimicrobial Agents and Chemotherapy 42, no. 7 (July 1, 1998): 1805–10. http://dx.doi.org/10.1128/aac.42.7.1805.
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ABSTRACT 2′,3′-Dideoxy-2′,3′-didehydro-β-l(−)-5-fluorocytidine [l(−)Fd4C] was found to be at least 10 times more potent than β-l-2′,3′-dideoxy-3′-thiacytidine [l(−)SddC; also called 3TC, or lamivudine]against hepatitis B virus (HBV) in culture. Its cytotoxicity against HepG2 growth in culture was also greater than that of l(−)SddC (3TC). There was no activity of this compound against mitochondrial DNA synthesis in cells at concentrations up to 10 μM. The dynamics of recovery of virus from the medium of cells pretreated with equal drug concentrations were slower with l(−)Fd4C than with l(−)SddC (3TC). l(−)Fd4C could be metabolized to mono-, di-, and triphosphate forms. The degree of l(−)Fd4C phosphorylation to the 5′-triphosphate metabolite was higher than the degree ofl(−)SddC (3TC) phosphorylation when equal extracellular concentrations of the two drugs were used. The apparentKm of l(−)Fd4C phosphorylated metabolites formed intracellularly was higher than that forl(−)SddC (3TC). This may be due in part to a difference in the behavior of l(−)Fd4C andl(−)SddC (3TC) towards cytosolic deoxycytidine kinase. Furthermore, l(−)Fd4C 5′-triphosphate was retained longer within cells than l(−)SddC (3TC) 5′-triphosphate.l(−)Fd4C 5′-triphosphate inhibited HBV DNA polymerase in competition with dCTP with a Ki of 0.069 ± 0.015 μM. Given the antiviral potency and unique pharmacodynamic properties of l(−)Fd4C, this compound should be considered for development as an expanded-spectrum anti-HBV drug.
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Papachristou, A. A., A. S. Dumas, and V. C. Katsouyannopoulos. "Dissociation of alanine aminotransferase values in acute hepatitis A patients with and without past experience to the hepatitis B virus." Epidemiology and Infection 106, no. 2 (April 1991): 397–402. http://dx.doi.org/10.1017/s0950268800048548.
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SUMMARYSerological markers and peak serum alanine aminotransferase (ALT) values of 140 in-patients with acute hepatitis, either type A (n= 90), or type B (n= 50) were prospectively assessed. In 23 out of the 90 patients with acute hepatitis A, evidence of previous experience with hepatitis B virus (HBV) was found, whereas 35 out of the 50 patients with acute hepatitis B had past contact with hepatitis A virus (HAV). The mean peak ALT values [S.D.] were significantly higher in hepatitis A patients with previous experience with HBV (1413 [704] i.u./l), when compared to those without such experience (842 [464] i.u./l, P < 0·001). Such a difference was not evident between acute hepatitis B patients, whether or not they had previous contact with HAV. We conclude that when acute hepatitis A is superimposed on past HBV infection an augmented transaminaemia, indicative of enhanced liver cell necrosis, takes place although a definite explanation is lacking. We suggest that individuals with markers of HBV infection should be early candidates for HAV immunization.
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Gripon, Philippe, Isabelle Cannie, and Stephan Urban. "Efficient Inhibition of Hepatitis B Virus Infection by Acylated Peptides Derived from the Large Viral Surface Protein." Journal of Virology 79, no. 3 (February 1, 2005): 1613–22. http://dx.doi.org/10.1128/jvi.79.3.1613-1622.2005.
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ABSTRACT The lack of an appropriate in vitro infection system for the major human pathogen hepatitis B virus (HBV) has prevented a molecular understanding of the early infection events of HBV. We used the novel HBV-infectible cell line HepaRG and primary human hepatocytes to investigate the interference of infection by HBV envelope protein-derived peptides. We found that a peptide consisting of the authentically myristoylated N-terminal 47 amino acids of the pre-S1 domain of the large viral envelope protein (L protein) specifically prevented HBV infection, with a 50% inhibitory concentration (IC50) of 8 nM. The replacement of myristic acid with other hydrophobic moieties resulted in changes in the inhibitory activity, most notably by a decrease in the IC50 to picomolar concentrations for longer unbranched fatty acids. The obstruction of HepaRG cell susceptibility to HBV infection after short preincubation times with the peptides suggested that the peptides efficiently target and inactivate a receptor at the hepatocyte surface. Our data both shed light on the molecular mechanism of HBV entry into hepatocytes and provide a basis for the development of potent hepadnaviral entry inhibitors as a novel therapeutic concept for the treatment of hepatitis Β.
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Jaoudé, Georges Abou, and Camille Sureau. "Role of the Antigenic Loop of the Hepatitis B Virus Envelope Proteins in Infectivity of Hepatitis Delta Virus." Journal of Virology 79, no. 16 (August 15, 2005): 10460–66. http://dx.doi.org/10.1128/jvi.79.16.10460-10466.2005.
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ABSTRACT The infectious particles of hepatitis B virus (HBV) and hepatitis delta virus (HDV) are coated with the large, middle, and small envelope proteins encoded by HBV. While it is clear that the N-terminal pre-S1 domain of the large protein, which is exposed at the virion surface, is implicated in binding to a cellular receptor at viral entry, the role in infectivity of the envelope protein antigenic loop, also exposed to the virion surface and accessible to neutralizing antibodies, remains to be established. In the present study, mutations were created in the antigenic loop of the three envelope proteins, and the resulting mutants were evaluated for their capacity to assist in the maturation and infectivity of HDV. We observed that short internal combined deletions and insertions, affecting residues 109 to 133 in the antigenic loop, were tolerated for secretion of both subviral HBV particles and HDV virions. However, when assayed for infectivity on primary cultures of human hepatocytes or on the recently described HepaRG cell line, virions carrying deletions between residues 118 and 129 were defective. Single amino acid substitutions in this region revealed that Gly-119, Pro-120, Cys-121, Arg-122, and Cys-124 were instrumental in viral entry. These results demonstrate that in addition to a receptor-binding site previously identified in the pre-S1 domain of the L protein, a determinant of infectivity resides in the antigenic loop of HBV envelope proteins.
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Chin, Ruth, Tim Shaw, Joseph Torresi, Vittina Sozzi, Christian Trautwein, Thomas Bock, Michael Manns, Harriet Isom, Phil Furman, and Stephen Locarnini. "In Vitro Susceptibilities of Wild-Type or Drug-Resistant Hepatitis B Virus to (−)-β-d-2,6-Diaminopurine Dioxolane and 2′-Fluoro-5-Methyl-β-l-Arabinofuranosyluracil." Antimicrobial Agents and Chemotherapy 45, no. 9 (September 1, 2001): 2495–501. http://dx.doi.org/10.1128/aac.45.9.2495-2501.2001.
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ABSTRACT Prolonged treatment of chronic hepatitis B virus (HBV) infection with lamivudine ([−]-β-l-2′,3′-dideoxy-3′ thiacytidine) or famciclovir may select for viral mutants that are drug resistant due to point mutations in the polymerase gene. Determining whether such HBV mutants are sensitive to new antiviral agents is therefore important. We used a transient transfection system to compare the sensitivities of wild-type HBV and four lamivudine- and/or famciclovir-resistant HBV mutants to adefovir [9-(2-phosphonyl-methoxyethyl)-adenine; PMEA] and the nucleoside analogues (−)-β-d-2, 6-diaminopurine dioxolane (DAPD) and 2′-fluoro-5-methyl-β-l-arabinofuranosyluracil (l-FMAU). The drug-resistant mutants contained amino acid substitutions in the polymerase protein. We found that the M550I and M550V plus L526M substitutions, which confer lamivudine resistance, did not confer cross-resistance to adefovir or DAPD, but conferred cross-resistance to l-FMAU. The M550V substitution in isolation conferred a similar phenotype to M550I, except that it did not confer significant resistance to l-FMAU. The L526M substitution, which is associated with famciclovir resistance, conferred cross-resistance to l-FMAU but not to adefovir or DAPD. Inhibition of HBV secretion by DAPD, l-FMAU, and adefovir did not always correlate with inhibition of the generation of intracellular HBV replicative intermediates, suggesting that these analogs may preferentially inhibit specific stages of the viral replication cycle.
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King, Robert W., Stephanie K. Ladner, Thomas J. Miller, Katie Zaifert, Robert B. Perni, Sameul C. Conway, and Michael J. Otto. "Inhibition of Human Hepatitis B Virus Replication by AT-61, a Phenylpropenamide Derivative, Alone and in Combination with (−)β-l-2′,3′-Dideoxy-3′-Thiacytidine." Antimicrobial Agents and Chemotherapy 42, no. 12 (December 1, 1998): 3179–86. http://dx.doi.org/10.1128/aac.42.12.3179.
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ABSTRACT AT-61, a member of a novel class of phenylpropenamide derivatives, was found to be a highly selective and potent inhibitor of human hepatitis B virus (HBV) replication in four different human hepatoblastoma cell lines which support the replication of HBV (i.e., HepAD38, HepAD79, 2.2.15, and transiently transfected HepG2 cells). This compound was equally effective at inhibiting both the formation of intracellular immature core particles and the release of extracellular virions, with 50% effective concentrations ranging from 0.6 to 5.7 μM. AT-61 (27 μM) was able to reduce the amount of HBV covalently closed circular DNA found in the nuclei of HepAD38 cells by >99%. AT-61 at concentrations of >27 μM had little effect on the amount of viral RNA found within the cytoplasms of induced HepAD38 cells but reduced the number of immature virions which contained pregenomic RNA by >99%. The potency of AT-61 was not affected by one of the mutations responsible for (−)-β-l-2′,3′-dideoxy-3′ thiacytidine (3TC) resistance in HBV, and AT-61 acted synergistic with 3TC to inhibit HBV replication. AT-61 (81 μM) was not cytotoxic or antiproliferative to several cell lines and had no antiviral effect on woodchuck or duck HBV, human immunodeficiency virus type 1, herpes simplex virus type 1, vesicular stomatitis virus, or Newcastle disease virus. Therefore, we concluded that the antiviral activity of AT-61 is specific for HBV replication and most likely occurs at one of the steps between the synthesis of viral RNA and the packaging of pregenomic RNA into immature core particles.
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Al-khazraji, A., H. Alkhawam, and B. Garrido. "ID: 30: HEPATITIS B VIRUS REACTIVATION IN AN INACTIVE CARRIER OF CHRONIC HBV AFTER THE INITIATION OF TREATMENT FOR TIBERCULOSIS." Journal of Investigative Medicine 64, no. 4 (March 22, 2016): 939.1–939. http://dx.doi.org/10.1136/jim-2016-000120.56.
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Case PresentationA 32-year-old female with a history of chronic HBV in the inactive carrier state (HBV Surface Antigen (HBsAg) reactive, HBV Surface Antibody (anti-HBs) non-reactive, HBV Core Antibody (anti-HBc) reactive and IgM anti-HBc nonreactive) and tuberculous lymphadenitis presented to the emergency department with generalized weakness, dizziness, vomiting, and an unintentional 8 pound weight loss over the past month. She reported yellowing of the skin and light colored stools during this time. She had recently been started on Ethambutol, Levofloxacin and Capreomycin by her medical doctor for tuberculosis treatment. She denied use of any other medications or herbal supplements. She denied alcohol or illicit drug use. Her family history was unremarkable for liver disease. Physical examination was notable for scleral icterus but otherwise unremarkable. Her complete blood count and basic metabolic panel were within normal limits. HIV test was negative. Her hepatic function tests returned as follows; aspartate transaminase 1397 U/L, alanine transaminase 1234 U/L, gamma-glutamyl transpeptidase 107 IU/L, total bilirubin 2.3 mg/dL, and direct bilirubin 0.6 mg/dL. Hepatic function tests were normal 4 months prior to admission. Due to concern for drug-induced liver injury, her anti-tuberculosis medications were discontinued and she was started on intravenous N-acetyl cysteine with plans for further workup. An abdominal ultrasound revealed mild increased liver echogenicity and a polyp in the gall bladder. Hepatitis C Virus antibody was non-reactive. HBsAg was reactive, anti-HBs was non-reactive, and anti-HBc was reactive and IgM anti-HBc nonreactive. HBV DNA level was greater than 1,000,000,000 IU/mL consistent with a diagnosis of reactivation of HBV. The patient was started on tenofovir 300 mg PO daily ultimately the patient was discharged home. Follow up one month later revealed normalizing liver enzymes and an HBV DNA level of 471 IU/mL.DiscussionHBV reactivation is diagnosed by an increase HBV DNA in chronic carrier with undetectable viral load or rise HBV DNA ≥10-fold increase in HBV DNA compared with baseline. Reactivation of HBV after starting chemotherapy or immunosuppressive medications is well described. Our case report is the first to describe HBV reactivation after starting Ethambutol, levofloxacin and Capreomycin against multidrug resistant mycobacterium tuberculosis.Most studies reported that RIPE (Rifampin, Isoniazid, Pyrazinamide, and Ethambutol) tuberculosis therapy has shown no risk of HBV reactivation. One of the Multidrug resistant tuberculosis therapy agents which is levofloxacin can cause hepatoxicity but all previous studies did not report HBV reactivation.Capreomycin can cause severe hepatotoxic injury especially if combined with other potential hepatotoxic, especially medications which interferes with metabolism of P450 as reported in our case with levofloxacin. That is could be explained hepatitis B reactivation after starting capreomycin, ethambutol and levofloxacin.
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Hu, Jianhua, Yong Wang, Gongying Jiang, Jie Zheng, Tuxiang Chen, Zhiping Chen, Meifang Yang, Xuan Zhang, Hong Zhao, and Lanjuan Li. "Predictors of inflammatory activity in treatment-naive hepatitis B e-antigen-negative patients with chronic hepatitis B infection." Journal of International Medical Research 48, no. 11 (November 2020): 030006052096958. http://dx.doi.org/10.1177/0300060520969582.
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Objective Liver inflammatory activity staging is critical to guide the treatment of chronic hepatitis B virus (CHB) infection. Here, we aimed to identify practical clinical biomarkers of moderate inflammatory activity in hepatitis B e-antigen (HBeAg)-negative CHB patients. Methods Treatment-naïve HBeAg-negative CHB patients who underwent liver biopsy at our hospital from 1 January 2013 to 31 December 2016 were enrolled. Markers of inflammatory activity were analyzed using binary logistic regression. The area under the receiver operator characteristic curve (AUROCC) was used to assess diagnostic accuracy. Results A total of 106 HBeAg-negative treatment-naive CHB patients were enrolled. According to their METAVIR inflammatory scores, 30.2% of patients were in stage ≥A2. Total triiodothyronine (TT3) and hepatitis B virus (HBV) DNA levels were predictors of moderate inflammatory activity (A ≥ 2). The AUROCCs of TT3 and HBV DNA levels were 0.651 and 0.797, respectively. The optimal cut-off values for TT3 and HBV DNA were 1.755 nmol/L and 4.61 log10 IU/mL, respectively. Conclusions A sizable proportion of treatment-naive HBeAg-negative CHB patients required antiviral treatment (30.2%) after undergoing liver biopsy. TT3 and HBV DNA helps identify patients with moderate inflammatory activity (A ≥ 2), potentially reducing the need for liver biopsies and helping guide treatment of CHB patients.
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Villeneuve, Edith, Jean Vincelette, and Jean-Pierre Villeneuve. "Ineffectiveness of hepatitis B vaccination in cirrhotic patients waiting for liver transplantation." Canadian Journal of Gastroenterology 14, suppl b (2000): 59B—63B. http://dx.doi.org/10.1155/2000/548206.
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Cirrhotic patients who undergo liver transplantation are at risk of acquiring de novo hepatitis B virus (HBV) infection at the time of transplantation. It is common practice to immunize these patients against HBV, but the efficacy of vaccination is uncertain. The response to vaccination with a recombinant HBV vaccine was examined in 49 patients with cirrhosis before liver transplantation. Patients received three doses (20 µg) of Engerix-B (SmithKline Beecham) at zero, one and two months before transplantation, and their response was measured on the day of liver transplantation (9.3±1.2 months after the initial dose of vaccine). Results were compared with those reported in healthy adults vaccinated according to the same schedule. Fourteen of 49 cirrhotic patients (28%) developed antibodies to hepatitis B surface antigen (anti-HBs) levels of more than 10 U/L after vaccination compared with 97% of healthy controls. Four patients (8%) had anti-HBs levels of more than 100 U/L compared with 83% in healthy individuals. Mean anti-HBs titre in the 14 responders was 62 U/L compared with 348 U/L in controls. No factor was identified that predicted response to vaccination. One of 49 patients acquired de novo HBV infection at the time of liver transplantation. Current HBV vaccination of cirrhotic patients waiting for liver transplantation is ineffective, and new strategies need to be developed to increase the response rate.
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Hakami, Abdulrahim, Abdelwahid Ali, and Ahmed Hakami. "Effects of Hepatitis B Virus Mutations on its Replication and Liver Disease Severity." Open Virology Journal 7, no. 1 (January 23, 2013): 12–18. http://dx.doi.org/10.2174/1874357901307010012.
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Hepatitis B virus (HBV), nowadays, is one of the major human pathogens worldwide. Approximately, 400 million people worldwide have chronic HBV infection. Only 5% of persons infected during adulthood develop chronic infection. The reverse is true for those infected at birth or in early childhood, i.e. more than 90% of these persons progress to chronic infection. Currently, eight different genotypes o f HBV have been identified, differing in nucleotide sequence by greater than 8%. In addition, numerous subgenotypes have a l s o been recognized based on the nucleotide sequence variability of 4- 8%. It has invariably been found that these genotypes and mutations play a pivotal role in the liver disease aggravation and virus replication. The precore mutations (G1896A) and the double mutation (T1762/A1764) in the basal core promoter are important mutations that alter expression of the hepatitis B e antigen (HBeAg). The HBeAg is important for establishing viral persistence. The precore G1896A mutation abrogates the expression of HBeAg. Numerous other mutations alter the disease severity and progression. It is predictive that the infected patient has high risk of hepatocellular carcinoma if the genotype C is incriminated or if HBV possesses basal core promoter double mutation. Association of the remaining genotypes have been noted but with less degree than genotype C. Phenotypic assays of the different HBV protein markers with different molecular techniques illustrate the replication efficiency of the virus in cell lines. This review will discuss various mutations into their association with liver disease severity and progression as well as virus replication.
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Stuyver, Lieven, Caroline Van Geyt, Sija De Gendt, Georges Van Reybroeck, Fabien Zoulim, Geert Leroux-Roels, and Rudi Rossau. "Line Probe Assay for Monitoring Drug Resistance in Hepatitis B Virus-Infected Patients during Antiviral Therapy." Journal of Clinical Microbiology 38, no. 2 (2000): 702–7. http://dx.doi.org/10.1128/jcm.38.2.702-707.2000.
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Since the introduction of antiviral compounds such as lamivudine and famciclovir in the treatment schedules of patients with chronic hepatitis B virus (HBV) infection, the accumulation of a variety of mutations in the HBV polymerase gene has been observed. The selection of these mutations is generally considered the cause of viral nonresponsiveness and treatment failure. Therefore, the detection of these mutations is of clinical importance. Previously genotyped HBV strains isolated from treated and untreated patients were amplified with primers specific for the HBV polymerase region from amino acids 465 to 562. Amplified products were cloned into plasmid vectors. The clones were used as reference strains. A set of 38 highly specific oligonucleotide probes covering three different codon positions, L528M, M552V/I, and V/L/M555I, were selected. These probes were applied as 19 different lines on a membrane strip. The strips were then hybridized with PCR fragments from the reference panel, revealing the amino acids at the three codon positions simultaneously for each clone. PCR products generated from two patients infected with HBV genotypes A and C, respectively, and treated with nucleoside analogs were analyzed on these strips. A gradual increase in genetic HBV polymerase complexity was observed in follow-up samples compared to that in pretreatment samples. Additional analysis of HBV polymerase DNA fragments in recombinant plasmid clones demonstrated the existence of (i) clones with double mutations, (ii) clones with single mutations at either codon 528, 552, or 555, and (iii) the simultaneous occurrence of two or more viral populations within one sample. This line probe assay detected the complex quasispecies nature of HBV and provided some insight into the dynamics of resistance mutations.
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Blanchet, Matthieu, and Camille Sureau. "Analysis of the Cytosolic Domains of the Hepatitis B Virus Envelope Proteins for Their Function in Viral Particle Assembly and Infectivity." Journal of Virology 80, no. 24 (October 4, 2006): 11935–45. http://dx.doi.org/10.1128/jvi.00621-06.
Full textAbstract:
ABSTRACT The hepatitis B virus (HBV) envelope proteins have the ability to assemble three types of viral particles, (i) the empty subviral particles (SVPs), (ii) the mature HBV virions, and (iii) the hepatitis delta virus (HDV) particles, in cells that are coinfected with HBV and HDV. To gain insight into the function of the HBV envelope proteins in morphogenesis of HBV or HDV virions, we have investigated subdomains of the envelope proteins that have been shown or predicted to lie at the cytosolic face of the endoplasmic reticulum membrane during synthesis, a position prone to interaction with the inner core structure. These domains, referred to here as cytosolic loops I and II (CYL-I and -II, respectively), were subjected to mutagenesis. The mutations were introduced in the three HBV envelope proteins, designated small, middle, and large (S-HBsAg, M-HBsAg, and L-HBsAg, respectively). The mutants were expressed in HuH-7 cells to evaluate their capacity for self-assembly and formation of HBV or HDV virions when HBV nucleocapsid or HDV ribonucleoprotein, respectively, was provided. We found that SVP-competent CYL-I mutations between positions 23 and 78 of the S domain were permissive to HBV or HDV virion assembly. One mutation (P29A) was permissive for synthesis of the S- and M-HBsAg but adversely affected the synthesis or stability of L-HBsAg, thereby preventing the assembly of HBV virions. Furthermore, using an in vitro infection assay based on the HepaRG cells and the HDV model, we have shown that particles coated with envelope proteins bearing CYL-I mutations were fully infectious, hence indicating the absence of an infectivity determinant in this region. Finally, we demonstrated that the tryptophan residues at positions 196, 199, and 201 in CYL-II, which were shown to exert a matrix function for assembly of HDV particles (I. Komla-Soukha and C. Sureau, J. Virol. 80:4648-4655, 2006), were dispensable for both assembly and infectivity of HBV virions.