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1.
Hum Genet ; 139(6-7): 877-884, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32285199

RESUMO

In rare cases, hepatitis A virus (HAV) and hepatitis B virus (HBV) can cause fulminant viral hepatitis (FVH), characterized by massive hepatocyte necrosis and an inflammatory infiltrate. Other viral etiologies of FVH are rarer. FVH is life-threatening, but the patients are typically otherwise healthy, and normally resistant to other microbes. Only a small minority of infected individuals develop FVH, and this is the key issue to be addressed for this disease. In mice, mouse hepatitis virus 3 (MHV3) infection is the main model for dissecting FVH pathogenesis. Susceptibility to MHV3 differs between genetic backgrounds, with high and low mortality in C57BL6 and A/J mice, respectively. FVH pathogenesis in mice is related to uncontrolled inflammation and fibrinogen deposition. In humans, FVH is typically sporadic, but rare familial forms also exist, suggesting that there may be causal monogenic inborn errors. A recent study reported a single-gene inborn error of human immunity underlying FVH. A patient with autosomal recessive complete IL-18BP deficiency was shown to have FVH following HAV infection. The mechanism probably involves enhanced IL-18- and IFN-γ-dependent killing of hepatocytes by NK and CD8 T cytotoxic cells. Proof-of-principle that FVH can be genetic is important clinically, for the affected patients and their families, and immunologically, for the study of immunity to viruses in the liver. Moreover, the FVH-causing IL18BP genotype suggests that excessive IL-18 immunity may be a general mechanism underlying FVH, perhaps through the enhancement of IFN-γ immunity.


Assuntos
Citocinas/imunologia , Hepadnaviridae/genética , Hepatite Viral Humana/genética , Hepatite Viral Humana/patologia , Hepadnaviridae/patogenicidade , Hepatite Viral Humana/imunologia , Hepatite Viral Humana/virologia , Humanos
2.
Arch Virol ; 165(3): 557-570, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32036428

RESUMO

Codon usage bias (CUB) arises from the preference for a codon over codons for the same amino acid. The major factors contributing to CUB are evolutionary forces, compositional properties, gene expression, and protein properties. The present analysis was performed to investigate the compositional properties and the extent of CUB across the genomes of members of the family Hepadnaviridae, as previously no work using bioinformatic tools has been reported. The viral genes were found to be AT rich with low CUB. Analysis of relative synonymous codon usage (RSCU) was used to identify overrepresented and underrepresented codons for each amino acid. Correlation analysis of overall nucleotide composition and its composition at the third codon position suggested that mutation pressure might influence the CUB. A highly significant correlation was observed between GC12 and GC3 (r = 0.910, p < 0.01), indicating that directional mutation affected all three codon positions across the genome. Translational selection (P2) and mutational responsive index (MRI) values of genes suggested that mutation plays a more important role than translational selection in members of the family Hepadnaviridae.


Assuntos
Uso do Códon , Regulação Viral da Expressão Gênica/fisiologia , Genoma Viral/fisiologia , Hepadnaviridae/metabolismo , Proteínas Virais/metabolismo , Evolução Biológica , Hepadnaviridae/genética , Mutação , RNA Mensageiro , RNA Viral , Especificidade da Espécie , Proteínas Virais/genética
4.
Virology ; 531: 162-170, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30884426

RESUMO

Limited sampling means that relatively little is known about the diversity and evolutionary history of mammalian members of the Hepadnaviridae (genus Orthohepadnavirus). An important case in point are shrews, the fourth largest group of mammals, but for which there is limited knowledge on the role they play in viral evolution and emergence. Here, we report the discovery of a novel shrew hepadnavirus. The newly discovered virus, denoted shrew hepatitis B virus (SHBV), is divergent to be considered a new species of Orthohepadnavirus. Phylogenetic analysis revealed that these viruses were usually most closely related to TBHBV (tent-making bat hepatitis B virus), known to be able to infect human hepatocytes, and had a similar genome structure, although SHBV fell in a more basal position in the surface protein phylogeny. In sum, these data suggest that shrews are natural hosts for hepadnaviruses and may have played an important role in their long-term evolution.


Assuntos
Evolução Molecular , Infecções por Hepadnaviridae/veterinária , Infecções por Hepadnaviridae/virologia , Hepadnaviridae/isolamento & purificação , Musaranhos/virologia , Sequência de Aminoácidos , Animais , China , Genoma Viral , Hepadnaviridae/química , Hepadnaviridae/classificação , Hepadnaviridae/genética , Infecções por Hepadnaviridae/transmissão , Hepatócitos/virologia , Humanos , Orthohepadnavirus/classificação , Orthohepadnavirus/genética , Orthohepadnavirus/isolamento & purificação , Filogenia , Alinhamento de Sequência , Musaranhos/classificação , Proteínas Virais/química , Proteínas Virais/genética
5.
Ecohealth ; 16(1): 82-94, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30564998

RESUMO

The tent-making bat hepatitis B virus (TBHBV) is a hepadnavirus closely related to human hepatitis B virus. The ecology of TBHBV is unclear. We show that it is widespread and highly diversified in Peters' tent-making bats (Uroderma bilobatum) within Panama, while local prevalence varied significantly between sample sites, ranging from 0 to 14.3%. Females showed significantly higher prevalence than males, and pregnant females were more often acutely infected than non-reproductive ones. The distribution of TBHBV in bats was significantly affected by forest cover, with higher infection rates in areas with lower forest cover. Our data indicate that loss of natural habitat may lead to positive feedback on the biotic factors driving infection possibility. These results underline the necessity of multidisciplinary studies for a better understanding of mechanisms in pathogen-host relationships and for predictions in disease ecology.


Assuntos
Quirópteros/virologia , Infecções por Hepadnaviridae/veterinária , Hepadnaviridae/isolamento & purificação , Animais , Ecossistema , Feminino , Infecções por Hepadnaviridae/virologia , Masculino , Panamá , Especificidade da Espécie
6.
Biomolecules ; 8(3)2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-30013006

RESUMO

Alternative therapeutic approaches against chronic hepatitis B virus (HBV) infection need to be urgently developed because current therapies are only virostatic. In this context, cell penetration peptides (CPPs) and their Peptide Nucleic Acids (PNAs) cargoes appear as a promising novel class of biologically active compounds. In this review we summarize different in vitro and in vivo studies, exploring the potential of CPPs as vehicles for intracellular delivery of PNAs targeting hepadnaviral replication. Thus, studies conducted in the duck HBV (DHBV) infection model showed that conjugation of (D-Arg)8 CPP to PNA targeting viral epsilon (ε) were able to efficiently inhibit viral replication in vivo following intravenous administration to ducklings. Unexpectedly, some CPPs, (D-Arg)8 and Decanoyl-(D-Arg)8, alone displayed potent antiviral effect, altering late stages of DHBV and HBV morphogenesis. Such antiviral effects of CPPs may affect the sequence-specificity of CPP-PNA conjugates. By contrast, PNA conjugated to (D-Lys)4 inhibited hepadnaviral replication without compromising sequence specificity. Interestingly, Lactose-modified CPP mediated the delivery of anti-HBV PNA to human hepatoma cells HepaRG, thus improving its antiviral activity. In light of these promising data, we believe that future studies will open new perspectives for translation of CPPs and CPP-PNA based technology to therapy of chronic hepatitis B.


Assuntos
Antivirais/administração & dosagem , Peptídeos Penetradores de Células/administração & dosagem , Hepadnaviridae/fisiologia , Ácidos Nucleicos Peptídicos/administração & dosagem , Administração Intravenosa , Animais , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Modelos Animais de Doenças , Patos , Hepadnaviridae/efeitos dos fármacos , Vírus da Hepatite B do Pato/efeitos dos fármacos , Vírus da Hepatite B do Pato/fisiologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Humanos , Ácidos Nucleicos Peptídicos/química , Ácidos Nucleicos Peptídicos/farmacologia , Replicação Viral/efeitos dos fármacos
7.
Viruses ; 10(5)2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29772771

RESUMO

High-throughput transcriptome sequencing allows for the unbiased detection of viruses in host tissues. The application of this technique to immunosuppressed animals facilitates the detection of viruses that might otherwise be excluded or contained in immunocompetent individuals. To identify potential viral pathogens infecting domestic cats we performed high-throughput transcriptome sequencing of tissues from cats infected with feline immunodeficiency virus (FIV). A novel member of the Hepadnaviridae, tentatively named domestic cat hepadnavirus, was discovered in a lymphoma sample and its complete 3187 bp genome characterized. Phylogenetic analysis placed the domestic cat hepadnavirus as a divergent member of mammalian orthohepadnaviruses that exhibits no close relationship to any other virus. DNA extracted from whole blood from pet cats was positive for the novel hepadnavirus by PCR in 6 of 60 (10%) FIV-infected cats and 2 of 63 (3.2%) FIV-uninfected cats. The higher prevalence of hepadnavirus viraemia detected in FIV-infected cats mirrors that seen in human immunodeficiency virus-infected humans coinfected with hepatitis B virus. In summary, we report the first hepadnavirus infection in a carnivore and the first in a companion animal. The natural history, epidemiology and pathogenic potential of domestic cat hepadnavirus merits additional investigation.


Assuntos
Síndrome de Imunodeficiência Adquirida Felina/imunologia , Síndrome de Imunodeficiência Adquirida Felina/virologia , Hepadnaviridae/classificação , Hepadnaviridae/isolamento & purificação , Hospedeiro Imunocomprometido , Filogenia , Animais , Gatos , Coinfecção , DNA Viral/genética , Síndrome de Imunodeficiência Adquirida Felina/patologia , Perfilação da Expressão Gênica/veterinária , Variação Genética , Genoma Viral , Hepadnaviridae/genética , Sequenciamento de Nucleotídeos em Larga Escala/veterinária , Vírus da Imunodeficiência Felina/genética , Vírus da Imunodeficiência Felina/imunologia , Masculino , Proteínas Virais/genética , Viremia/veterinária , Viremia/virologia
9.
Virology ; 514: 88-97, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29153861

RESUMO

To better understand the evolution of hepadnaviruses, we sampled bats from Guizhou, Henan and Zhejiang provinces, China, and rodents from Zhejiang province. Genetically diverse hepadnaviruses were identified in a broad range of bat species, with an overall prevalence of 13.3%. In contrast, no rodent hepadnaviruses were identified. The newly discovered bat hepadnaviruses fell into two distinct phylogenetic groups. The viruses within the first group exhibited high diversity, with some closely related to viruses previously identified in Yunnan province. Strikingly, the newly discovered viruses sampled from Jiyuan city in the second phylogenetic group were most closely related to those found in bats from West Africa, suggestive of a long-term association between bats and hepadnaviruses. A co-phylogenetic analysis revealed frequent cross-species transmission among bats from different species, genera, and families. Overall, these data suggest that there are likely few barriers to the cross-species transmission of bat hepadnaviruses.


Assuntos
Quirópteros/virologia , Evolução Molecular , Variação Genética , Infecções por Hepadnaviridae/veterinária , Hepadnaviridae/genética , Hepadnaviridae/isolamento & purificação , Animais , China , Genoma Viral , Hepadnaviridae/classificação , Infecções por Hepadnaviridae/virologia , Filogenia
10.
PLoS Pathog ; 13(12): e1006784, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29287110

RESUMO

Hepadnavirus covalently closed circular (ccc) DNA is the bona fide viral transcription template, which plays a pivotal role in viral infection and persistence. Upon infection, the non-replicative cccDNA is converted from the incoming and de novo synthesized viral genomic relaxed circular (rc) DNA, presumably through employment of the host cell's DNA repair mechanisms in the nucleus. The conversion of rcDNA into cccDNA requires preparation of the extremities at the nick/gap regions of rcDNA for strand ligation. After screening 107 cellular DNA repair genes, we herein report that the cellular DNA ligase (LIG) 1 and 3 play a critical role in cccDNA formation. Ligase inhibitors or functional knock down/out of LIG1/3 significantly reduced cccDNA production in an in vitro cccDNA formation assay, and in cccDNA-producing cells without direct effect on viral core DNA replication. In addition, transcomplementation of LIG1/3 in the corresponding knock-out or knock-down cells was able to restore cccDNA formation. Furthermore, LIG4, a component in non-homologous end joining DNA repair apparatus, was found to be responsible for cccDNA formation from the viral double stranded linear (dsl) DNA, but not rcDNA. In conclusion, we demonstrate that hepadnaviruses utilize the whole spectrum of host DNA ligases for cccDNA formation, which sheds light on a coherent molecular pathway of cccDNA biosynthesis, as well as the development of novel antiviral strategies for treatment of hepatitis B.


Assuntos
DNA Ligases/metabolismo , DNA Circular/biossíntese , DNA Viral/biossíntese , Hepadnaviridae/metabolismo , Linhagem Celular , DNA Ligase Dependente de ATP/antagonistas & inibidores , DNA Ligase Dependente de ATP/genética , DNA Ligase Dependente de ATP/metabolismo , DNA Ligases/antagonistas & inibidores , DNA Ligases/genética , Reparo do DNA/genética , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Células HEK293 , Células Hep G2 , Hepadnaviridae/genética , Hepadnaviridae/patogenicidade , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Vírus da Hepatite B/patogenicidade , Hepatócitos/metabolismo , Hepatócitos/virologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Redes e Vias Metabólicas , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo
12.
Cell Host Microbe ; 22(3): 387-399.e6, 2017 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-28867387

RESUMO

Hepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome organization with extensive gene overlap. Remarkably, the ∼1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via protein-primed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras.


Assuntos
Evolução Molecular , Doenças dos Peixes/virologia , Hepadnaviridae/genética , Vírus da Hepatite B/genética , Hepatite B/virologia , Sequência de Aminoácidos , Animais , Capsídeo/química , Capsídeo/metabolismo , Peixes , Genoma Viral , Hepadnaviridae/química , Hepadnaviridae/classificação , Hepadnaviridae/isolamento & purificação , Vírus da Hepatite B/química , Vírus da Hepatite B/classificação , Vírus da Hepatite B/isolamento & purificação , Humanos , Dados de Sequência Molecular , Filogenia , Alinhamento de Sequência , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética
13.
J Viral Hepat ; 24(11): 982-989, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28414893

RESUMO

While HBV and HCV are risk factors for HCC, uncertainty exists as to whether these viral infections have prognostic significance in HCC. Thus, we compared the overall survival of patients with HBV, HCV and nonviral HCC, and evaluated whether the presence of HBV and HCV predicts patient outcomes. We conducted a multicentre study of HCC cases diagnosed at six Melbourne tertiary hospitals between Jan 2000-Dec 2014. Patient demographics, liver disease and tumour characteristics and patient outcomes were obtained from hospital databases, computer records and the Victorian Death Registry. Survival outcomes were compared between HBV, HCV and nonviral hepatitis cases and predictors of survival determined using Cox proportional hazards regression. There were 1436 new HCC cases identified including 776 due to viral hepatitis (HBV 235, HCV 511, HBV-HCV 30) and 660 from nonviral causes. The median survival of HBV, HCV and nonviral HCC patients was 59.1, 28.4 and 20.9 months, respectively (P<.0001). On multivariate analysis, independent risk factors for survival included HCC aetiology, gender, BCLC stage, serum AFP, total number and size of lesions, and serum creatinine and albumin. After adjusting for these and method of detection, HBV remained an independent predictor of improved overall survival when compared to both nonviral (HR 0.60%, 95% CI 0.35-0.98; P=.03) and HCV-related HCC (HR 0.51%, 95% CI 0.30-0.85; P=.01). In this large multicentre study, HBV is independently associated with improved overall survival compared with HCV and nonviral-related HCC. Further studies are needed to determine the underlying factor(s) responsible.


Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Hepadnaviridae , Hepatite Viral Humana/complicações , Hepatite Viral Humana/virologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Idoso , Austrália/epidemiologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico
14.
Virol J ; 14(1): 40, 2017 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28222808

RESUMO

BACKGROUND: In recent years, novel hepadnaviruses, hepeviruses, hepatoviruses, and hepaciviruses have been discovered in various species of bat around the world, indicating that bats may act as natural reservoirs for these hepatitis viruses. In order to further assess the distribution of hepatitis viruses in bat populations in China, we tested the presence of these hepatitis viruses in our archived bat liver samples that originated from several bat species and various geographical regions in China. METHODS: A total of 78 bat liver samples (involving two families, five genera, and 17 species of bat) were examined using nested or heminested reverse transcription PCR (RT-PCR) with degenerate primers. Full-length genomic sequences of two virus strains were sequenced followed by phylogenetic analyses. RESULTS: Four samples were positive for hepadnavirus, only one was positive for hepevirus, and none of the samples were positive for hepatovirus or hepacivirus. The hepadnaviruses were discovered in the horseshoe bats, Rhinolophus sinicus and Rhinolophus affinis, and the hepevirus was found in the whiskered bat Myotis davidii. The full-length genomic sequences were determined for one of the two hepadnaviruses identified in R. sinicus (designated BtHBVRs3364) and the hepevirus (designated BtHEVMd2350). A sequence identity analysis indicated that BtHBVRs3364 had the highest degree of identity with a previously reported hepadnavirus from the roundleaf bat, Hipposideros pomona, from China, and BtHEVMd2350 had the highest degree of identity with a hepevirus found in the serotine bat, Eptesicus serotinus, from Germany, but it exhibited high levels of divergence at both the nucleotide and the amino acid levels. CONCLUSIONS: This is the first study to report that the Chinese horseshoe bat and the Chinese whiskered bat have been found to carry novel hepadnaviruses and a novel hepevirus, respectively. The discovery of BtHBVRs3364 further supports the significance of host switches evolution while opposing the co-evolutionary theory associated with hepadnaviruses. According to the latest criterion of the International Committee on Taxonomy of Viruses (ICTV), we hypothesize that BtHEVMd2350 represents an independent genotype within the species Orthohepevirus D of the family Hepeviridae.


Assuntos
Quirópteros/virologia , Hepadnaviridae/classificação , Hepadnaviridae/isolamento & purificação , Hepevirus/classificação , Hepevirus/isolamento & purificação , Fígado/virologia , Filogenia , Animais , China , Análise por Conglomerados , Genoma Viral , Hepadnaviridae/genética , Hepevirus/genética , Reação em Cadeia da Polimerase , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
15.
Biochem Biophys Res Commun ; 478(2): 825-30, 2016 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-27501758

RESUMO

Endogenous viral elements (EVE) in animal genomes are the fossil records of ancient viruses and provide invaluable information on the origin and evolution of extant viruses. Extant hepadnaviruses include avihepadnaviruses of birds and orthohepadnaviruses of mammals. The core promoter (Cp) of hepadnaviruses is vital for viral gene expression and replication. We previously identified in the budgerigar genome two EVEs that contain the full-length genome of an ancient budgerigar hepadnavirus (eBHBV1 and eBHBV2). Here, we found eBHBV1 Cp and eBHBV2 Cp were active in several human and chicken cell lines. A region from nt -85 to -11 in eBHBV1 Cp was critical for the promoter activity. Bioinformatic analysis revealed a putative binding site of nuclear factor Y (NF-Y), a ubiquitous transcription factor, at nt -64 to -50 in eBHBV1 Cp. The NF-Y core binding site (ATTGG, nt -58 to -54) was essential for eBHBV1 Cp activity. The same results were obtained with eBHBV2 Cp and duck hepatitis B virus Cp. The subunit A of NF-Y (NF-YA) was recruited via the NF-Y core binding site to eBHBV1 Cp and upregulated the promoter activity. Finally, the NF-Y core binding site is conserved in the Cps of all the extant avihepadnaviruses but not of orthohepadnaviruses. Interestingly, a putative and functionally important NF-Y core binding site is located at nt -21 to -17 in the Cp of human hepatitis B virus. In conclusion, our findings have pinpointed an evolutionary conserved and functionally critical NF-Y binding element in the Cps of avihepadnaviruses.


Assuntos
Fator de Ligação a CCAAT/genética , Elementos de DNA Transponíveis , DNA Viral/genética , Genoma , Hepadnaviridae/genética , Hepatócitos/metabolismo , Animais , Sítios de Ligação , Evolução Biológica , Doenças das Aves/virologia , Fator de Ligação a CCAAT/química , Fator de Ligação a CCAAT/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Embrião de Galinha , Galinhas , Sequência Conservada , DNA Viral/metabolismo , Extinção Biológica , Fibroblastos/metabolismo , Fibroblastos/virologia , Fósseis , Células HEK293 , Hepadnaviridae/classificação , Hepadnaviridae/metabolismo , Infecções por Hepadnaviridae/veterinária , Infecções por Hepadnaviridae/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatócitos/virologia , Interações Hospedeiro-Patógeno , Humanos , Melopsittacus , Filogenia , Regiões Promotoras Genéticas , Ligação Proteica
16.
J Virol ; 90(17): 7920-33, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27334580

RESUMO

UNLABELLED: Hepadnaviruses (hepatitis B viruses [HBVs]) are the only animal viruses that replicate their DNA by reverse transcription of an RNA intermediate. Until recently, the known host range of hepadnaviruses was limited to mammals and birds. We obtained and analyzed the first amphibian HBV genome, as well as several prototype fish HBVs, which allow the first comprehensive comparative genomic analysis of hepadnaviruses from four classes of vertebrates. Bluegill hepadnavirus (BGHBV) was characterized from in-house viral metagenomic sequencing. The African cichlid hepadnavirus (ACHBV) and the Tibetan frog hepadnavirus (TFHBV) were discovered using in silico analyses of the whole-genome shotgun and transcriptome shotgun assembly databases. Residues in the hydrophobic base of the capsid (core) proteins, designated motifs I, II, and III, are highly conserved, suggesting that structural constraints for proper capsid folding are key to capsid protein evolution. Surface proteins in all vertebrate HBVs contain similar predicted membrane topologies, characterized by three transmembrane domains. Most striking was the fact that BGHBV, ACHBV, and the previously described white sucker hepadnavirus did not form a fish-specific monophyletic group in the phylogenetic analysis of all three hepadnaviral genes. Notably, BGHBV was more closely related to the mammalian hepadnaviruses, indicating that cross-species transmission events have played a major role in viral evolution. Evidence of cross-species transmission was also observed with TFHBV. Hence, these data indicate that the evolutionary history of the hepadnaviruses is more complex than previously realized and combines both virus-host codivergence over millions of years and host species jumping. IMPORTANCE: Hepadnaviruses are responsible for significant disease in humans (hepatitis B virus) and have been reported from a diverse range of vertebrates as both exogenous and endogenous viruses. We report the full-length genome of a novel hepadnavirus from a fish and the first hepadnavirus genome from an amphibian. The novel fish hepadnavirus, sampled from bluegills, was more closely related to mammalian hepadnaviruses than to other fish viruses. This phylogenetic pattern reveals that, although hepadnaviruses have likely been associated with vertebrates for hundreds of millions of years, they have also been characterized by species jumping across wide phylogenetic distances.


Assuntos
Anfíbios/virologia , Evolução Molecular , Peixes/virologia , Variação Genética , Hepadnaviridae/classificação , Hepadnaviridae/isolamento & purificação , Animais , Biologia Computacional , DNA Viral/química , DNA Viral/genética , Genoma Viral , Hepadnaviridae/genética , Filogenia , Análise de Sequência de DNA
17.
Vaccine ; 34(25): 2821-33, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27109565

RESUMO

Human hepatitis B virus (HBV) core antigen (HBcAg) can act as an adjuvant in hepatitis C virus (HCV)-based DNA vaccines. Since two billion people are, or have been, in contact with HBV, one may question the use of human HBV sequences as adjuvant. We herein evaluated non-human stork hepatitis B virus core gene-sequences from stork as DNA vaccine adjuvants. Full-length and fragmented stork HBcAg gene-sequences were added to an HCV non-structural (NS) 3/4A gene (NS3/4A-stork-HBcAg). This resulted in an enhanced priming of HCV-specific IFN-γ and IL-2 responses in both wild-type (wt)- and NS3/4A-transgenic (Tg) mice, the latter with dysfunctional NS3/4A-specific T cells. The NS3/4A-stork-HBcAg vaccine primed NS3/4A-specific T cells in hepatitis B e antigen (HBeAg)-Tg mice with dysfunctional T cells to HBcAg and HBeAg. Repeated immunizations boosted expansion of IFN-γ and IL-2-producing NS3/4A-specific T cells in wt- and NS3/4A-Tg mice. Importantly, NS3/4A-stork-HBcAg-DNA induced in vivo long-term functional memory T cell responses, whose maintenance required CD4(+) T cells. Thus, avian HBcAg gene-sequences from stork can effectively act as a DNA vaccine adjuvant. This technology can most likely be universally expanded to other genetic vaccine antigens, as this completely avoids the use of sequences from a human virus where a pre-existing immunity may interfere with its adjuvant effect.


Assuntos
Adjuvantes Imunológicos/farmacologia , Hepadnaviridae/imunologia , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Hepatite C/prevenção & controle , Vacinas de DNA/imunologia , Vacinas contra Hepatite Viral/imunologia , Proteínas não Estruturais Virais/imunologia , Animais , Aves , Feminino , Células Hep G2 , Hepacivirus , Humanos , Imunização Secundária , Interferon gama/imunologia , Interleucina-12/administração & dosagem , Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T/imunologia
18.
Curr Opin Virol ; 16: 86-94, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26897577

RESUMO

The origin of primate HBV (family Hepadnaviridae) is unknown. Hepadnaviruses are ancient pathogens and may have been associated with old mammalian lineages like bats for prolonged time. Indeed, the genetic diversity of bat hepadnaviruses exceeds that of extant hepadnaviruses in other host orders, suggesting a long evolution of hepadnaviruses in bats. Strikingly, a recently detected New World bat hepadnavirus is antigenically related to HBV and can infect human hepatocytes. Together with genetically diverse hepadnaviruses from New World rodents and a non-human primate, these viruses argue for a New World origin of ancestral orthohepadnaviruses. Multiple host switches of bat and primate viruses are evident and bats are likely sources of ancestral hepadnaviruses acquired by primates.


Assuntos
Hepadnaviridae/fisiologia , Vírus da Hepatite B/fisiologia , Hepatite Viral Animal/virologia , Animais , Quirópteros , Reservatórios de Doenças/virologia , Evolução Molecular , Variação Genética , Hepadnaviridae/classificação , Vírus da Hepatite B/classificação , Hepatite Viral Animal/transmissão , Especificidade de Hospedeiro , Primatas , Tropismo Viral
19.
Cold Spring Harb Perspect Med ; 6(1): a021360, 2016 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-26729756

RESUMO

Members of the family Hepadnaviridae fall into two subgroups: mammalian and avian. The detection of endogenous avian hepadnavirus DNA integrated into the genomes of zebra finches has revealed a deep evolutionary origin of hepadnaviruses that was not previously recognized, dating back at least 40 million and possibly >80 million years ago. The nonprimate mammalian members of the Hepadnaviridae include the woodchuck hepatitis virus (WHV), the ground squirrel hepatitis virus, and arctic squirrel hepatitis virus, as well as a number of members of the recently described bat hepatitis virus. The identification of hepatitis B viruses (HBVs) in higher primates, such as chimpanzee, gorilla, orangutan, and gibbons that cluster with the human HBV, as well as a number of recombinant forms between humans and primates, further implies a more complex origin of this virus. We discuss the current theories of the origin and evolution of HBV and propose a model that includes cross-species transmissions and subsequent recombination events on a genetic backbone of genotype C HBV infection. The hepatitis delta virus (HDV) is a defective RNA virus requiring the presence of the HBV for the completion of its life cycle. The origins of this virus remain unknown, although some recent studies have suggested an ancient African radiation. The age of the association between HDV and HBV is also unknown.


Assuntos
Evolução Molecular , Genoma Viral/genética , Vírus da Hepatite B/genética , Hepatite B/virologia , Hepatite D/virologia , Vírus Delta da Hepatite/genética , Animais , Coinfecção/virologia , Fósseis , Hepadnaviridae/genética , Humanos , Filogenia , Recombinação Genética , Zoonoses
20.
Artigo em Inglês | MEDLINE | ID: mdl-25833941

RESUMO

Australian antigen, the envelope protein of hepatitis B virus (HBV), was discovered in 1967 as a prevalent serum antigen in hepatitis B patients. Early electron microscopy (EM) studies showed that this antigen was present in 22-nm particles in patient sera, which were believed to be incomplete virus. Complete virus, much less abundant than the 22-nm particles, was finally visualized in 1970. HBV was soon found to infect chimpanzees, gorillas, orangutans, gibbon apes, and, more recently, tree shrews (Tupaia belangeri) and cynomolgus macaques (Macaca fascicularis). This restricted host range placed limits on the kinds of studies that might be performed to better understand the biology and molecular biology of HBV and to develop antiviral therapies to treat chronic infections. About 10 years after the discovery of HBV, this problem was bypassed with the discovery of viruses related to HBV in woodchucks, ground squirrels, and ducks. Although unlikely animal models, their use revealed the key steps in hepadnavirus replication and in the host response to infection, including the fact that the viral nuclear episome is the ultimate target for immune clearance of transient infections and antiviral therapy of chronic infections. Studies with these and other animal models have also suggested interesting clues into the link between chronic HBV infection and hepatocellular carcinoma.


Assuntos
Modelos Animais de Doenças , Infecções por Hepadnaviridae/virologia , Hepadnaviridae/genética , Animais , DNA Viral/biossíntese , Genoma Viral , Hepadnaviridae/classificação , Hepadnaviridae/fisiologia , Vírus da Hepatite B do Pato , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/virologia , Orthohepadnavirus
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