scholarly journals Comprehensive Analysis of Hepatitis Delta Virus Assembly Determinants According to Genotypes: Lessons From a Study of 526 Hepatitis Delta Virus Clinical Strains

2021 ◽  
Vol 12 ◽  
Author(s):  
Athenaïs Gerber ◽  
Frédéric Le Gal ◽  
Samira Dziri ◽  
Chakib Alloui ◽  
Dominique Roulot ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Hepatitis Delta Virus ◽  
Virus Assembly ◽  
Envelope Proteins ◽  
Comprehensive Analysis ◽  
Serum Samples ◽  
Hepatitis Delta ◽  
Rich Domain ◽  
Functional Features ◽  
Delta Virus

Human hepatitis Delta virus (HDV) infection is associated to the most severe viral hepatic disease, including severe acute liver decompensation and progression to cirrhosis, and hepatocellular carcinoma. HDV is a satellite of hepatitis B virus (HBV) that requires the HBV envelope proteins for assembly of HDV virions. HDV and HBV exhibit a large genetic diversity that extends, respectively to eight (HDV-1 to -8) and to ten (HBV/A to/J) genotypes. Molecular determinants of HDV virion assembly consist of a C-terminal Proline-rich domain in the large Hepatitis Delta Antigen (HDAg) protein, also known as the Delta packaging domain (DPD) and of a Tryptophan-rich domain, the HDV matrix domain (HMD) in the C-terminal region of the HBV envelope proteins. In this study, we performed a systematic genotyping of HBV and HDV in a cohort 1,590 HDV-RNA-positive serum samples collected between 2001 to 2014, from patients originated from diverse parts of the world, thus reflecting a large genetic diversity. Among these samples, 526 HBV (HBV/A, B, C, D, E, and G) and HDV (HDV-1, 2, 3, and 5 to -8) genotype couples could be obtained. We provide results of a comprehensive analysis of the amino-acid sequence conservation within the HMD and structural and functional features of the DPD that may account for the yet optimal interactions between HDV and its helper HBV.

scholarly journals Parameters of Human Hepatitis Delta Virus Genome Replication: the Quantity, Quality, and Intracellular Distribution of Viral Proteins and RNA

2002 ◽  
Vol 76 (8) ◽  
pp. 3709-3719 ◽  
Author(s):  
Severin Gudima ◽  
Jinhong Chang ◽  
Gloria Moraleda ◽  
Anna Azvolinsky ◽  
John Taylor
Keyword(s):  
Hepatitis Delta Virus ◽  
Virus Assembly ◽  
Intracellular Distribution ◽  
Molar Ratio ◽  
Genome Replication ◽  
Cell Fractionation ◽  
Pcr Cloning ◽  
Hepatitis Delta ◽  
Initiation Of Replication ◽  
Delta Virus

ABSTRACT Assembly of hepatitis delta virus (HDV) in infected human hepatocytes involves association of the 1,679- nucleotide single-stranded genomic RNA (δRNA) with multiple copies of both small and large forms of the delta protein (δAg) to form a ribonucleoprotein particle which in turn interacts with envelope proteins of the natural helper virus, hepatitis B virus. Subsequently, for initiation of a new round of replication, the amount of small δAg within the assembled HDV particle is both necessary and sufficient. Quantitative assays were used in order to better understand just how much δAg is needed. The molar ratio of δAg species to genomic δRNA in assembled HDV particles was approximately 200. Next, this ratio was determined for cells under several different experimental situations in which HDV genome replication was occurring. These included replication in woodchuck liver and also in mouse liver and skeletal muscle, as well as replication in stably and transiently transfected cultured human hepatoblastoma cells. Surprisingly, in almost all these situations the molar ratios were comparable to that observed for HDV particles. This was true for different times after the initiation of replication and was independent of whether or not virus assembly was occurring. Cell fractionation combined with quantitative assays was used to test whether the majority of δAg and δRNA were colocalized during HDV replication in transfected cells. The cytoplasmic fraction contained the majority of δAg and genomic δRNA. Finally, the quality of δAg and δRNA, especially at relatively late times after the initiation of replication, was examined by using reverse transcription-PCR, cloning, and sequencing through the entire δAg open reading frame. When virus assembly and spread were not possible, 20% or less of the predicted δAg would have been able to support HDV replication. In summary, an examination of the quantity, quality and intracellular distribution of δAg and δRNA in several different experimental systems has provided a better understanding of the parameters associated with the initiation, maintenance, and ultimate decline of HDV genome replication.

scholarly journals Role of N Glycosylation of Hepatitis B Virus Envelope Proteins in Morphogenesis and Infectivity of Hepatitis Delta Virus

2003 ◽  
Vol 77 (9) ◽  
pp. 5519-5523 ◽  
Author(s):  
Camille Sureau ◽  
Chantal Fournier-Wirth ◽  
Patrick Maurel
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis Delta Virus ◽  
Envelope Proteins ◽  
Virus Envelope ◽  
Hepatitis Delta ◽  
B Virus ◽  
L Proteins ◽  
Delta Virus

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.

scholarly journals Characterization of the Genotypic Profile of Hepatitis Delta Virus: Isolation of HDV Genotype-1 in the Western Amazon Region of Brazil

Intervirology ◽  
2015 ◽  
Vol 58 (3) ◽  
pp. 166-171 ◽  
Author(s):  
Luan Felipo Botelho-Souza ◽  
Deusilene Souza Vieira ◽  
Alcione de Oliveira dos Santos ◽  
André Vinycius Cunha Pereira ◽  
Juan Miguel Villalobos-Salcedo
Keyword(s):  
Hepatitis B ◽  
Hepatitis Delta Virus ◽  
Clinical Characteristics ◽  
Amazon Region ◽  
Viral Envelope ◽  
Serum Samples ◽  
Hepatitis Delta ◽  
Pcr Rflp ◽  
Hdv Infection ◽  
Delta Virus

The hepatitis delta virus (HDV) is a hepatotropic subvirus that is dependent on the hepatitis B virus (HBV) and supplies the viral envelope containing the surface antigen of hepatitis B. Viral genetic diversity is related to the geographical origin of the isolates, and there are at least eight genotypes that are referred to as HDV-1 through HDV-8. HDV-3 is responsible for epidemics of severe and fulminant hepatitis, which are common in northeastern South America. HDV-3 is prevalent in the Brazilian Amazon and is associated with the increased aggressiveness of HDV infections. Although isolated, the characteristics of the clinical presentation of HDV-1 in the Amazon region have not yet been clearly reported. Objective: This study aims to assess the genotypic and clinical characteristics of individuals with the HDV-1 genotype in the western Amazon region. Methods: The HDV was genotyped by nested PCR-RFLP and sequencing from serum samples of 56 patients with HBV/HDV infection. The genotypes were correlated with the clinical characteristics presented by patients with HBV/HDV infection. Results: A prevalence of 92.3% for the HDV-3 genotype (n = 48) and 7.6% (n = 4) for the HDV-1 genotype was observed. Conclusion: To date, this is the most extensive clinical study of HDV-1 genotype infections in the nonindigenous population of Western Amazonia.

scholarly journals Identification of novel avian and mammalian deltaviruses provides new insights into deltavirus evolution

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Masashi Iwamoto ◽  
Yukino Shibata ◽  
Junna Kawasaki ◽  
Shohei Kojima ◽  
Yung-Tsung Li ◽  
...  
Keyword(s):  
Hepatitis Delta Virus ◽  
Envelope Proteins ◽  
Interspecies Transmission ◽  
Passerine Birds ◽  
Molecular Surveillance ◽  
Hepatitis Delta ◽  
The Past ◽  
Satellite Virus ◽  
Experimental Analyses ◽  
Delta Virus

Abstract Hepatitis delta virus (HDV) is a satellite virus that requires hepadnavirus envelope proteins for its transmission. Although recent studies identified HDV-related deltaviruses in certain animals, the evolution of deltaviruses, such as the origin of HDV and the mechanism of its coevolution with its helper viruses, is unknown, mainly because of the phylogenetic gaps among deltaviruses. Here, we identified novel deltaviruses of passerine birds, woodchucks, and white-tailed deer by extensive database searches and molecular surveillance. Phylogenetic and molecular epidemiological analyses suggest that HDV originated from mammalian deltaviruses and the past interspecies transmission of mammalian and passerine deltaviruses. Further, metaviromic and experimental analyses suggest that the satellite–helper relationship between HDV and hepadnavirus was established after the divergence of the HDV lineage from non-HDV mammalian deltaviruses. Our findings enhance our understanding of deltavirus evolution, diversity, and transmission, indicating the importance of further surveillance for deltaviruses.

scholarly journals Nucleic acid polymers are active against Hepatitis Delta Virus infection in vitro.

2017 ◽  
pp. JVI.01416-17 ◽  
Author(s):  
Frauke Beilstein ◽  
Matthieu Blanchet ◽  
Andrew Vaillant ◽  
Camille Sureau
Keyword(s):  
Nucleic Acid ◽  
Viral Entry ◽  
Hepatitis Delta Virus ◽  
Immune Escape ◽  
Envelope Proteins ◽  
Infection Model ◽  
Hepatitis Delta ◽  
Hdv Infection ◽  
Delta Virus

In this study, an in vitro infection model for the hepatitis delta virus (HDV) was used to evaluate the antiviral effects of phosphorothioate nucleic acid polymers (NAPs) and investigate their mechanism of action. The results show that NAPs inhibit HDV infection at less than 4 micromolar concentrations in cultures of differentiated human hepatoma cells. NAPs were shown to be active at viral entry, but inactive post entry on HDV RNA replication. Inhibition was independent of the NAPs nucleotide sequence, but dependent on both size and amphipathicity of the polymer. NAPs antiviral activity was effective against HDV virions bearing the main hepatitis B virus (HBV) immune escape substitutions (D144A and G145R) and was pangenomic with regard to HBV envelope proteins. Furthermore, similar to immobilized heparin, immobilized NAPs could bind HDV particles suggesting that entry inhibition was due, at least in part, to preventing attachment of the virus to cell surface glycosaminoglycans. The results document NAPs as a novel class of antiviral compounds that can prevent HDV propagation.IMPORTANCEHDV infection causes the most severe form of viral hepatitis in humans and one of the most difficult to cure. Currently, treatments are limited to long-term administration of interferon at high doses, which provide only partial efficacy. There is thus an urgent need for innovative approaches to identify new antiviral against HDV. The significance of our study is in demonstrating that nucleic acid polymers (NAPs) are active against HDV by targeting the envelope of HDV virions. In an in vitro infection assay, NAPs activity was recorded at less than 4 micromolar concentrations in the absence of cell toxicity. Furthermore, the fact that NAPs could block HDV at viral entry, suggest their potential to control the spread of HDV in a chronically HBV-infected liver. In addition, NAPs anti-HDV activity was pangenomic with regard to HBV envelope proteins and not circumvented by HBsAg substitutions associated with HBV immune escape.

scholarly journals Assembly of Hepatitis Delta Virus: Particle Characterization, Including the Ability To Infect Primary Human Hepatocytes

2007 ◽  
Vol 81 (7) ◽  
pp. 3608-3617 ◽  
Author(s):  
Severin Gudima ◽  
Yiping He ◽  
Anja Meier ◽  
Jinhong Chang ◽  
Rongji Chen ◽  
...  
Keyword(s):  
Hepatitis Delta Virus ◽  
Envelope Proteins ◽  
Human Hepatocytes ◽  
Cell Junctions ◽  
Host Cells ◽  
Hepatitis Delta ◽  
Primary Human Hepatocytes ◽  
Natural Helper ◽  
Huh7 Cells ◽  
Delta Virus

ABSTRACT Efficient assembly of hepatitis delta virus (HDV) was achieved by cotransfection of Huh7 cells with two plasmids: one to provide expression of the large, middle, and small envelope proteins of hepatitis B virus (HBV), the natural helper of HDV, and another to initiate replication of the HDV RNA genome. HDV released into the media was assayed for HDV RNA and HBV envelope proteins and characterized by rate-zonal sedimentation, immunoaffinity purification, electron microscopy, and the ability to infect primary human hepatocytes. Among the novel findings were that (i) immunostaining for delta antigen 6 days after infection with 300 genome equivalents (GE) per cell showed only 1% of cells as infected, but this was increased to 16% when 5% polyethylene glycol was present during infection; (ii) uninfected cells did not differ from infected cells in terms of albumin accumulation or the presence of E-cadherin at cell junctions; and (iii) sensitive quantitative real-time PCR assays detected HDV replication even when the multiplicity of infection was 0.2 GE/cell. In the future, this HDV assembly and infection system can be further developed to better understand the mechanisms shared by HBV and HDV for attachment and entry into host cells.

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