scholarly journals Strong Replication Interference Between Hepatitis Delta Viruses in Human Liver Chimeric Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Katja Giersch ◽  
Lennart Hermanussen ◽  
Tassilo Volz ◽  
Annika Volmari ◽  
Lena Allweiss ◽  
...  
Keyword(s):  
Human Liver ◽  
Sequence Divergence ◽  
Chimeric Mice ◽  
Hepatitis D ◽  
Viral Interference ◽  
B Virus ◽  
Infected Cells ◽  
Super Infection

BackgroundHepatitis D Virus (HDV) is classified into eight genotypes with distinct clinical outcomes. Despite the maintenance of highly conserved functional motifs, it is unknown whether sequence divergence between genotypes, such as HDV-1 and HDV-3, or viral interference mechanisms may affect co-infection in the same host and cell, thus hindering the development of HDV inter-genotypic recombinants. We aimed to investigate virological differences of HDV-1 and HDV-3 and assessed their capacity to infect and replicate within the same liver and human hepatocyte in vivo.MethodsHuman liver chimeric mice were infected with hepatitis B virus (HBV) and with one of the two HDV genotypes or with HDV-1 and HDV-3 simultaneously. In a second set of experiments, HBV-infected mice were first infected with HDV-1 and after 9 weeks with HDV-3, or vice versa. Also two distinct HDV-1 strains were used to infect mice simultaneously and sequentially. Virological parameters were determined by strain-specific qRT-PCR, RNA in situ hybridization and immunofluorescence staining.ResultsHBV/HDV co-infection studies indicated faster spreading kinetics and higher intrahepatic levels of HDV-3 compared to HDV-1. In mice that simultaneously received both HDV strains, HDV-3 became the dominant genotype. Interestingly, antigenomic HDV-1 and HDV-3 RNA were detected within the same liver but hardly within the same cell. Surprisingly, sequential super-infection experiments revealed a clear dominance of the HDV strain that was inoculated first, indicating that HDV-infected cells may acquire resistance to super-infection.ConclusionInfection with two largely divergent HDV genotypes could be established in the same liver, but rarely within the same hepatocyte. Sequential super-infection with distinct HDV genotypes and even with two HDV-1 isolates was strongly impaired, suggesting that virus interference mechanisms hamper productive replication in the same cell and hence recombination events even in a system lacking adaptive immune responses.

scholarly journals Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice

2018 ◽  
Vol 149 ◽  
pp. 41-47 ◽  
Author(s):  
Kelly R. Long ◽  
Elena Lomonosova ◽  
Qilan Li ◽  
Nathan L. Ponzar ◽  
Juan A. Villa ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Human Liver ◽  
Ribonuclease H ◽  
Chimeric Mice ◽  
New Class ◽  
B Virus

scholarly journals Variable In Vivo Hepatitis D Virus (HDV) RNA Editing Rates According to the HDV Genotype

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1572
Author(s):  
Samira Dziri ◽  
Christophe Rodriguez ◽  
Athenaïs Gerber ◽  
Ségolène Brichler ◽  
Chakib Alloui ◽  
...  
Keyword(s):  
Rna Editing ◽  
Stop Codon ◽  
Genome Replication ◽  
Hepatitis D ◽  
Reading Frame ◽  
Delta Antigen ◽  
B Virus ◽  
Virion Morphogenesis ◽  
Kinetics Of

Human hepatitis delta virus (HDV) is a small defective RNA satellite virus that requires hepatitis B virus (HBV) envelope proteins to form its own virions. The HDV genome possesses a single coding open reading frame (ORF), located on a replicative intermediate, the antigenome, encoding the small (s) and the large (L) isoforms of the delta antigen (s-HDAg and L-HDAg). The latter is produced following an editing process, changing the amber/stop codon on the s-HDAg-ORF into a tryptophan codon, allowing L-HDAg synthesis by the addition of 19 (or 20) C-terminal amino acids. The two delta proteins play different roles in the viral cell cycle: s-HDAg activates genome replication, while L-HDAg blocks replication and favors virion morphogenesis and propagation. L-HDAg has also been involved in HDV pathogenicity. Understanding the kinetics of viral editing rates in vivo is key to unravel the biology of the virus and understand its spread and natural history. We developed and validated a new assay based on next-generation sequencing and aimed at quantifying HDV RNA editing in plasma. We analyzed plasma samples from 219 patients infected with different HDV genotypes and showed that HDV editing capacity strongly depends on the genotype of the strain.

In vivo protein delivery to human liver-derived cells using hepatitis B virus envelope pre-S region

2008 ◽  
Vol 106 (1) ◽  
pp. 99-102 ◽  
Author(s):  
Takeshi Kasuya ◽  
Tadanori Yamada ◽  
Atsuko Uyeda ◽  
Takashi Matsuzaki ◽  
Toshihide Okajima ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Protein Delivery ◽  
Human Liver ◽  
Virus Envelope ◽  
B Virus

scholarly journals CMCdG, a Novel Nucleoside Analog with Favorable Safety Features, Exerts Potent Activity against Wild-Type and Entecavir-Resistant Hepatitis B Virus

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Nobuyo Higashi-Kuwata ◽  
Sanae Hayashi ◽  
Debananda Das ◽  
Satoru Kohgo ◽  
Shuko Murakami ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Human Liver ◽  
Nucleoside Analog ◽  
Peroral Administration ◽  
Chimeric Mice ◽  
Wild Type ◽  
Hbv Genotype ◽  
Huh7 Cells ◽  
B Virus

ABSTRACTWe designed, synthesized, and characterized a novel nucleoside analog, (1S,3S,5S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-hydroxy-1-(hydroxymethyl)-2-methylene-cyclopentanecarbonitrile, or 4′-cyano-methylenecarbocyclic-2′-deoxyguanosine (CMCdG), and evaluated its anti-hepatitis B virus (anti-HBV) activity, safety, and related features. CMCdG’sin vitroactivity was determined using quantitative PCR and Southern blotting assays, and its cytotoxicity was determined with a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, while itsin vivoactivity and safety were determined in human liver-chimeric mice infected with wild-type HBV genotype Ce (HBVWTCe) and an entecavir (ETV)-resistant HBV variant containing the amino acid substitutions L180M, S202G, and M204V (HBVETV-RL180M/S202G/M204V). CMCdG potently inhibited HBV production in HepG2.2.15 cells (50% inhibitory concentration [IC50], ∼30 nM) and HBVWTCeplasmid-transfected Huh7 cells (IC50, 206 nM) and efficiently suppressed ETV-resistant HBVETV-RL180M/S202G/M204V(IC50, 2,657 nM), while it showed no or little cytotoxicity (50% cytotoxic concentration, >500 μM in most hepatocytic cells examined). Two-week peroral administration of CMCdG (1 mg/kg of body weight/day once a day [q.d.]) to HBVWTCe-infected human liver-chimeric mice reduced the level of viremia by ∼2 logs. CMCdG also reduced the level of HBVETV-RL180M/S202G/M204Vviremia by ∼1 log in HBVETV-RL180M/S202G/M204V-infected human liver-chimeric mice, while ETV (1 mg/kg/day q.d.) completely failed to reduce the viremia. None of the CMCdG-treated mice had significant drug-related changes in body weights or serum human albumin levels. Structural analyses using homology modeling, semiempirical quantum methods, and molecular dynamics revealed that although ETV triphosphate (TP) forms good van der Waals contacts with L180 and M204 of HBVWTCereverse transcriptase (RT), its contacts with the M180 substitution are totally lost in the HBVETV-RL180M/S202G/M204VRT complex. However, CMCdG-TP retains good contacts with both the HBVWTCeRT and HBVETV-RL180M/S202G/M204VRT complexes. The present data warrant further studies toward the development of CMCdG as a potential therapeutic for patients infected with drug-resistant HBV and shed light on the further development of more potent and safer anti-HBV agents.

scholarly journals Absence of viral interference and different susceptibility to interferon between hepatitis B virus and hepatitis C virus in human hepatocyte chimeric mice

2009 ◽  
Vol 51 (6) ◽  
pp. 1046-1054 ◽  
Author(s):  
Nobuhiko Hiraga ◽  
Michio Imamura ◽  
Tsuyoshi Hatakeyama ◽  
Shosuke Kitamura ◽  
Fukiko Mitsui ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Human Hepatocyte ◽  
Chimeric Mice ◽  
Viral Interference ◽  
B Virus ◽  
Human Hepatocyte Chimeric Mice

scholarly journals Vaccinia Virus Infection during Murine Pregnancy: a New Pathogenesis Model for Vaccinia Fetalis

2004 ◽  
Vol 78 (6) ◽  
pp. 3133-3139 ◽  
Author(s):  
Nicola Benning ◽  
Daniel E. Hassett
Keyword(s):  
Vaccinia Virus ◽  
Virus Infections ◽  
Fatal Complication ◽  
Vertical Transfer ◽  
Maternal Infections ◽  
Acute Viral Infection ◽  
Infected Cells ◽  
Murine Pregnancy

ABSTRACT Vaccinia fetalis, the vertical transfer of vaccinia virus from mother to fetus, is a relatively rare but often fatal complication of primary vaccinia virus vaccination during pregnancy. To date there has been no attempt to develop an animal model to study the pathogenesis of this acute viral infection in vivo. Here we report that infection of gestating BALB/c mice by either intravenous or intraperitoneal routes with the Western Reserve strain of vaccinia virus results in the rapid colonization of the placenta and vertical transfer of virus to the developing fetus. Systemic maternal infections during gestation lead to the death of all offspring prior to or very shortly after birth. Using in situ hybridization for vaccinia virus mRNA to identify infected cells, we show that the virus initially colonizes cells lining maternal lacunae within the trophospongium layer of the placenta. The study of this model will significantly enhance our understanding of the pathogenesis of fetal vaccinia virus infections and aid in the development of effective treatments designed to reduce the risk of vaccinia virus-associated complications during pregnancy.

scholarly journals Stimulation of Cellular Proliferation by Hepatitis B Virus X Protein

2001 ◽  
Vol 17 (3) ◽  
pp. 153-157 ◽  
Author(s):  
Charles R. Madden ◽  
Betty L. Slagle
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cellular Proliferation ◽  
X Protein ◽  
Hepatitis Viruses ◽  
B Virus ◽  
Infected Cells ◽  
Proliferation In Vitro

Chronic infection with the hepatitis B virus (HBV) is a known risk factor in the development of human hepatocellular carcinoma (HCC). The HBV-encoded X protein, HBx, has been investigated for properties that may explain its cancer cofactor role in transgenic mouse lines. We discuss here recent data showing that HBx is able to induce hepatocellular proliferation in vitro and in vivo. This property of HBx is predicted to sensitize hepatocytes to other HCC cofactors, including exposure to carcinogens and to other hepatitis viruses. Cellular proliferation is intimately linked to the mechanism(s) by which most tumor-associated viruses transform virus-infected cells. The HBx alteration of the cell cycle provides an additional mechanism by which chronic HBV infection may contribute to HCC.

scholarly journals Human genome integration of SARS-CoV-2 contradicted by long-read sequencing

2021 ◽  
Author(s):  
Nathan Smits ◽  
Jay Rasmussen ◽  
Gabriela O Bodea ◽  
Alberto A Amarilla ◽  
Patricia Gerdes ◽  
...  
Keyword(s):  
Genome Integration ◽  
Oxford Nanopore ◽  
B Virus ◽  
Long Read ◽  
Complete Sequences ◽  
Infected Cells ◽  
Cancer Tissues ◽  
Oxford Nanopore Technologies

A recent study proposed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks the LINE-1 (L1) retrotransposition machinery to integrate into the DNA of infected cells. If confirmed, this finding could have significant clinical implications. Here, we applied deep (>50x) long-read Oxford Nanopore Technologies (ONT) sequencing to HEK293T cells infected with SARS-CoV-2, and did not find any evidence of the virus existing as DNA. By examining ONT data from separate HEK293T cultivars, we resolved the complete sequences of 78 L1 insertions arising in vitro in the absence of L1 overexpression systems. ONT sequencing applied to hepatitis B virus (HBV) positive liver cancer tissues located a single HBV insertion. These experiments demonstrate reliable resolution of retrotransposon and exogenous virus insertions via ONT sequencing. That we found no evidence of SARS-CoV-2 integration suggests such events in vivo are highly unlikely to drive later oncogenesis or explain post-recovery detection of the virus.

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