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1.
Proc Natl Acad Sci U S A ; 118(13)2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33753499

RESUMO

Hepadnaviruses, with the human hepatitis B virus as prototype, are small, enveloped hepatotropic DNA viruses which replicate by reverse transcription of an RNA intermediate. Replication is initiated by a unique protein-priming mechanism whereby a hydroxy amino acid side chain of the terminal protein (TP) domain of the viral polymerase (P) is extended into a short DNA oligonucleotide, which subsequently serves as primer for first-strand synthesis. A key component in the priming of reverse transcription is the viral RNA element epsilon, which contains the replication origin and serves as a template for DNA primer synthesis. Here, we show that recently discovered non-enveloped fish viruses, termed nackednaviruses [C. Lauber et al., Cell Host Microbe 22, 387-399 (2017)], employ a fundamentally similar replication mechanism despite their huge phylogenetic distance and major differences in genome organization and viral lifestyle. In vitro cross-priming studies revealed that few strategic nucleotide substitutions in epsilon enable site-specific protein priming by heterologous P proteins, demonstrating that epsilon is functionally conserved since the two virus families diverged more than 400 Mya. In addition, other cis elements crucial for the hepadnavirus-typical replication of pregenomic RNA into relaxed circular double-stranded DNA were identified at conserved positions in the nackednavirus genomes. Hence, the replication mode of both hepadnaviruses and nackednaviruses was already established in their Paleozoic common ancestor, making it a truly ancient and evolutionary robust principle of genome replication that is more widespread than previously thought.


Assuntos
Replicação do DNA , DNA Viral/biossíntese , Evolução Molecular , Hepadnaviridae/fisiologia , Transcrição Reversa , Proteínas Virais/metabolismo , Replicação Viral , Sequência Conservada , Hepadnaviridae/classificação , Hepadnaviridae/genética , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Filogenia , RNA Viral/genética , Origem de Replicação , Proteínas Virais/genética
2.
Vet Microbiol ; 254: 108999, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33524809

RESUMO

Hepatitis B virus (HBV) is a major cause of liver disease in humans including chronic hepatitis and hepatocellular carcinoma. Domestic cat hepadnavirus (DCH), a novel HBV-like hepadnavirus, was identified in domestic cats in 2018. From 6.5 %-10.8 % of pet cats are viremic for DCH and altered serological markers suggestive of liver damage have been identified in 50 % of DCH-infected cats. DCH DNA has been detected in association with characteristic lesions of chronic hepatitis and with hepatocellular carcinoma in cats, suggesting a possible association. In this study longitudinal molecular screening of cats infected with DCH was performed to determine if DCH can cause chronic infections in cats. Upon re-testing of sera from five DCH-positive animals, 2-10 months after the initial diagnosis, three cats tested negative for DCH on two consecutive occasions using quantitative PCR. Two other cats remained DCH-positive, including an 8-month-old female cat re-tested four months after the initial positive result, and a 9-year-old male cat, which tested positive for DCH on six occasions over an 11-month period. The latter had a history of chronic hepatopathy with jaundice, lethargy and elevated serum alanine transaminase levels (ALT). During the period of observation, DCH titers ranged between 1.64 × 105 and 2.09 × 106 DNA copies/mL and ALT was persistently elevated, suggesting chronic infection. DCH DNA was not detected in oral, conjunctival, preputial and rectal swabs from the two animals collected at several time points. Long-term (chronic) infection would be consistent with the relatively high number of viremic cats identified in epidemiological investigations, with the possible association of DCH with chronic hepatic pathologies and with what described with HBV in human patients.


Assuntos
Doenças do Gato/virologia , Gatos/virologia , Infecções por Hepadnaviridae/veterinária , Hepadnaviridae/genética , Vírus da Hepatite B/genética , Animais , Doenças do Gato/diagnóstico , DNA Viral/sangue , Feminino , Genoma Viral , Hepadnaviridae/isolamento & purificação , Hepadnaviridae/patogenicidade , Infecções por Hepadnaviridae/virologia , Estudos Longitudinais , Masculino , Viremia
3.
BMC Vet Res ; 17(1): 9, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407487

RESUMO

BACKGROUND: A new domestic cat hepadnavirus (DCH, family Hepadnaviridae) was first reported from whole blood samples of domestic cats in Australia in 2018, and from cat serum samples in Italy in 2019. The pathogenesis of DCH is unknown, but it was reported in cats with viraemia (6.5-10.8%), chronic hepatitis (43%) and hepatocellular carcinoma (28%). Recent reports suggest that DCH resembles the human hepatitis B virus (HBV) and its related hepatopathies. This study aims to detect and characterize DCH among domestic cats in Malaysia. A cross-sectional study was performed on 253 cats, of which 87 had paired blood and liver samples, entailing whole-genome sequencing and phylogenetic analysis of DCH from a liver tissue sample. RESULTS: Among the 253 cats included in this study, 12.3% of the whole blood samples tested positive for DCH. The detection rate was significantly higher in pet cats (16.6%, n = 24/145) compared to shelter cats (6.5%, n = 7/108). Liver tissues showed higher a DCH detection rate (14.9%, n = 13/87) compared to blood; 5 out of these 13 cats tested positive for DCH in their paired liver and blood samples. Serum alanine transaminase (ALT) was elevated (> 95 units/L) in 12 out of the 23 DCH-positive cats (52.2%, p = 0.012). Whole-genome sequence analysis revealed that the Malaysian DCH strain, with a genome size of 3184 bp, had 98.3% and 97.5% nucleotide identities to the Australian and Italian strains, respectively. The phylogenetic analysis demonstrated that the Malaysian DCH genome was clustered closely to the Australian strain, suggesting that they belong to the same geographically-determined genetic pool (Australasia). CONCLUSIONS: This study provided insights into a Malaysian DCH strain that was detected from a liver tissue. Interestingly, pet cats or cats with elevated ALT were significantly more likely to be DCH positive. Cats with positive DCH detection from liver tissues may not necessarily have viraemia. The impact of this virus on inducing liver diseases in felines warrants further investigation.


Assuntos
Doenças do Gato/virologia , Infecções por Hepadnaviridae/veterinária , Hepadnaviridae/isolamento & purificação , Fígado/virologia , Animais , Doenças do Gato/sangue , Gatos , Estudos Transversais , DNA Viral/análise , Feminino , Genoma Viral , Infecções por Hepadnaviridae/sangue , Infecções por Hepadnaviridae/virologia , Malásia , Masculino , Filogenia , Reação em Cadeia da Polimerase/veterinária
4.
PLoS One ; 15(10): e0241212, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33095800

RESUMO

Hepatitis B virus (HBV) is a human pathogen of global concern, while a high diversity of viruses related to HBV have been discovered in other animals during the last decade. Recently, the novel mammalian hepadnavirus, tentatively named domestic cat hepadnavirus (DCH), was detected in an immunocompromised cat. Herein, a collection of 209 cat sera and 15 hepato-diseased cats were screened for DCH using PCR, resulting in 12.4% and 20% positivity in the tested sera and necropsied cats, respectively. Among the DCH-positive sera, a significantly high level of co-detection with retroviral infection was found, with the highest proportion being co-detection with feline immunodeficiency virus (FIV). Full-length genome characterization of DCH revealed the genetic diversity between the nine Thai DCH sequences obtained, and that they phylogenetically formed three distinct monophyletic clades. A putative DCH recombinant strain was found, suggesting a possible role of recombination in DCH evolution. Additionally, quantitative PCR was used to determine the viral copy number in various organs of the DCH-moribund cats, while the pathological findings were compared to the viral localization in hepatocytes, adjacent to areas of hepatic fibrosis, by immunohistochemical (IHC) and western blot analysis. In addition to the liver, positive-DCH immunoreactivity was found in various other organs, including kidneys, lung, heart, intestine, brain, and lymph nodes, providing evidence of systemic infection. Ultrastructure of infected cells revealed electron-dense particles in the nucleus and cytoplasm of hepatocytes, bronchial epithelial cells, and fibroblasts. We propose the intracellular development mechanism of this virus. Although the definitive roles of pathogenicity of DCH remains undetermined, a contributory role of the virus associated with systemic diseases is possible.


Assuntos
Coinfecção/veterinária , Síndrome de Imunodeficiência Adquirida Felina/virologia , Infecções por Hepadnaviridae/veterinária , Hepadnaviridae/genética , Animais de Estimação/virologia , Animais , Brônquios/citologia , Brônquios/virologia , Gatos , Coinfecção/virologia , Citoplasma/virologia , Células Epiteliais/citologia , Células Epiteliais/ultraestrutura , Células Epiteliais/virologia , Síndrome de Imunodeficiência Adquirida Felina/sangue , Feminino , Fibroblastos/citologia , Fibroblastos/virologia , Variação Genética , Genoma Viral/genética , Hepadnaviridae/isolamento & purificação , Infecções por Hepadnaviridae/virologia , Hepatócitos/citologia , Hepatócitos/ultraestrutura , Hepatócitos/virologia , Vírus da Imunodeficiência Felina/isolamento & purificação , Masculino , Microscopia Eletrônica de Transmissão , Filogenia , Recombinação Genética , Mucosa Respiratória/citologia , Mucosa Respiratória/virologia , Tailândia , Replicação Viral , Eliminação de Partículas Virais
5.
Proc Natl Acad Sci U S A ; 117(30): 17977-17983, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32651267

RESUMO

Hepatitis delta virus (HDV) is a human hepatitis-causing RNA virus, unrelated to any other taxonomic group of RNA viruses. Its occurrence as a satellite virus of hepatitis B virus (HBV) is a singular case in animal virology for which no consensus evolutionary explanation exists. Here we present a mammalian deltavirus that does not occur in humans, identified in the neotropical rodent species Proechimys semispinosus The rodent deltavirus is highly distinct, showing a common ancestor with a recently described deltavirus in snakes. Reverse genetics based on a tandem minus-strand complementary DNA genome copy under the control of a cytomegalovirus (CMV) promoter confirms autonomous genome replication in transfected cells, with initiation of replication from the upstream genome copy. In contrast to HDV, a large delta antigen is not expressed and the farnesylation motif critical for HBV interaction is absent from a genome region that might correspond to a hypothetical rodent large delta antigen. Correspondingly, there is no evidence for coinfection with an HBV-related hepadnavirus based on virus detection and serology in any deltavirus-positive animal. No other coinfecting viruses were detected by RNA sequencing studies of 120 wild-caught animals that could serve as a potential helper virus. The presence of virus in blood and pronounced detection in reproductively active males suggest horizontal transmission linked to competitive behavior. Our study establishes a nonhuman, mammalian deltavirus that occurs as a horizontally transmitted infection, is potentially cleared by immune response, is not focused in the liver, and possibly does not require helper virus coinfection.


Assuntos
Coinfecção , Infecções por Hepadnaviridae/veterinária , Hepadnaviridae/fisiologia , Hepatite D/veterinária , Vírus Delta da Hepatite/fisiologia , Doenças dos Roedores/virologia , Roedores/virologia , Animais , Linhagem Celular Tumoral , Genoma Viral , Genômica/métodos , Hepadnaviridae/classificação , Vírus Delta da Hepatite/classificação , Humanos , Filogenia
6.
J Virol ; 94(17)2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32581092

RESUMO

Covalently closed circular DNA (cccDNA) of hepadnaviruses exists as an episomal minichromosome in the nucleus of an infected hepatocyte and serves as the template for the transcription of viral mRNAs. It had been demonstrated by others and us that interferon alpha (IFN-α) treatment of hepatocytes induced a prolonged suppression of human and duck hepatitis B virus cccDNA transcription, which is associated with the reduction of cccDNA-associated histone modifications specifying active transcription (H3K9ac or H3K27ac), but not the histone modifications marking constitutive (H3K9me3) or facultative (H3K27me3) heterochromatin formation. In our efforts to identify IFN-induced cellular proteins that mediate the suppression of cccDNA transcription by the cytokine, we found that downregulating the expression of signal transducer and activator of transcription 1 (STAT1), structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1), or promyelocytic leukemia (PML) protein increased basal level of cccDNA transcription activity and partially attenuated IFN-α suppression of cccDNA transcription. In contrast, ectopic expression of STAT1, SMCHD1, or PML significantly reduced cccDNA transcription activity. SMCHD1 is a noncanonical SMC family protein and implicated in epigenetic silencing of gene expression. PML is a component of nuclear domain 10 (ND10) and is involved in suppressing the replication of many DNA viruses. Mechanistic analyses demonstrated that STAT1, SMCHD1, and PML were recruited to cccDNA minichromosomes and phenocopied the IFN-α-induced posttranslational modifications of cccDNA-associated histones. We thus conclude that STAT1, SMCHD1, and PML may partly mediate the suppressive effect of IFN-α on hepadnaviral cccDNA transcription.IMPORTANCE Pegylated IFN-α is the only therapeutic regimen that can induce a functional cure of chronic hepatitis B in a small, but significant, fraction of treated patients. Understanding the mechanisms underlying the antiviral functions of IFN-α in hepadnaviral infection may reveal molecular targets for development of novel antiviral agents to improve the therapeutic efficacy of IFN-α. By a loss-of-function genetic screening of individual IFN-stimulated genes (ISGs) on hepadnaviral mRNAs transcribed from cccDNA, we found that downregulating the expression of STAT1, SMCHD1, or PML significantly increased the level of viral RNAs without altering the level of cccDNA. Mechanistic analyses indicated that those cellular proteins are recruited to cccDNA minichromosomes and induce the posttranslational modifications of cccDNA-associated histones similar to those induced by IFN-α treatment. We have thus identified three IFN-α-induced cellular proteins that suppress cccDNA transcription and may partly mediate IFN-α silencing of hepadnaviral cccDNA transcription.


Assuntos
DNA Circular/metabolismo , Hepadnaviridae/efeitos dos fármacos , Hepadnaviridae/genética , Interferon-alfa/metabolismo , Interferon-alfa/farmacologia , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Linhagem Celular , Galinhas , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/metabolismo , DNA Viral/genética , Epigênese Genética , Infecções por Hepadnaviridae/virologia , Vírus da Hepatite B do Pato/efeitos dos fármacos , Vírus da Hepatite B , Hepatite B Crônica/virologia , Hepatócitos/virologia , Código das Histonas , Histonas/metabolismo , Humanos , Interferon-alfa/genética , Proteína da Leucemia Promielocítica/metabolismo , Processamento de Proteína Pós-Traducional , RNA Viral , Fator de Transcrição STAT1/metabolismo , Transcrição Genética , Replicação Viral
7.
J Gen Virol ; 101(6): 571-572, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32416744

RESUMO

The family Hepadnaviridae comprises small enveloped viruses with a partially double-stranded DNA genome of 3.0-3.4 kb. All family members express three sets of proteins (preC/C, polymerase and preS/S) and replication involves reverse transcription within nucleocapsids in the cytoplasm of hepatocytes. Hepadnaviruses are hepatotropic and infections may be transient or persistent. There are five genera: Parahepadnavirus, Metahepadnavirus, Herpetohepadnavirus, Avihepadnavirus and Orthohepadnavirus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Hepadnaviridae, which is available at ictv.global/report/hepadnaviridae.


Assuntos
Hepadnaviridae/classificação , Hepadnaviridae/genética , Citoplasma/virologia , Genoma Viral/genética , Hepatócitos/virologia , Humanos , Replicação Viral/genética
8.
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
9.
Genome ; 63(6): 307-317, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32308030

RESUMO

The Himalayan marmot (Marmota himalayana), a natural host and transmitter of plague, is also susceptible to the hepadnavirus infection. To reveal the genetic basis of the hepadnavirus susceptibility and the immune response to plague, we systematically characterized the features of immune genes in Himalayan marmot with those of human and mouse. We found that the entire major histocompatibility complex region and the hepatitis B virus pathway genes of the Himalayan marmot were conserved with those of humans. A Trim (tripartite motif) gene cluster involved in immune response and antiviral activity displays dynamic evolution, which is reflected by the duplication of Trim5 and the absence of Trim22 and Trim34. Three key regions of Ntcp, which is critical for hepatitis B virus entry, had high identity among seven species of Marmota. Moreover, we observed a severe alveolar hemorrhage, inflammatory infiltrate in the infected lungs and livers from Himalayan marmots after infection of EV76, a live attenuated Yersinia pestis strain. Lots of immune genes were remarkably up-regulated, which several hub genes Il2rγ, Tra29, and Nlrp7 are placed at the center of the gene network. These findings suggest that Himalayan marmot is a potential animal model for study on the hepadnavirus and plague infection.


Assuntos
Hepadnaviridae/genética , Imunidade Inata/genética , Marmota/virologia , Peste/genética , Animais , Modelos Animais de Doenças , Hepadnaviridae/patogenicidade , Humanos , Fígado/virologia , Marmota/genética , Camundongos , Peste/virologia , Proteínas com Motivo Tripartido , Yersinia pestis/genética , Yersinia pestis/patogenicidade
10.
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
11.
Virus Res ; 276: 197825, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785305

RESUMO

Hepatitis B virus (HBV) is the prototype of hepadnaviruses, which can be subgrouped into orthohepadnaviruses infecting mammals, avihehepadnaviruses of birds, metahepadnaviruses of fish, and herpetohepadnaviruses of amphibians and reptiles. The middle (M) envelope protein and e antigen are new additions in the evolution of hepadnaviruses. They are alternative translation products of the transcripts for small (S) envelope and core proteins, respectively. For HBV, e antigen is converted from precore/core protein by removal of N-terminal signal peptide followed by furin-mediated cleavage of the basic C-terminus. This study compared old and newly discovered hepadnaviruses for their envelope protein and e antigen expression or processing. The S protein of bat hepatitis B virus (BHBV) and two metahepadnaviruses is probably myristoylated, in addition to two avihepadnaviruses. While most orthohepadnaviruses express a functional M protein with N-linked glycosylation near the amino-terminus, most metahepadnaviruses and herpetohepadnaviruses probably do not. These viruses and one orthohepadnavirus, the shrew hepatitis B virus, lack an open precore region required for e antigen expression. Potential furin cleavage sites (RXXR sequence) can be found in e antigen precursors of orthohepadnaviruses and avihepadnaviruses. Despite much larger precore/core proteins of avihepadnaviruses and their limited sequence homology with those of orthohepadnaviruses, their proximal RXXR motif can be aligned with a distal RXXR motif for orthohepadnaviruses. Thus, furin or another basic endopeptidase is probably the shared enzyme for hepadnaviral e antigen maturation. A precore-derived cysteine residue is involved in forming intramolecular disulfide bond of HBV e antigen to prevent particle formation, and such a cysteine residue is conserved for both orthohepadnaviruses and avihepadnaviruses. All orthohepadnaviruses have an X gene, while all avihepadnaviruses can express the e antigen. M protein expression appears to be the most recent event in the evolution of hepadnaviruses.


Assuntos
Antígenos Virais/genética , Evolução Biológica , Regulação Viral da Expressão Gênica , Infecções por Hepadnaviridae/virologia , Hepadnaviridae/genética , Proteínas do Envelope Viral/genética , Sequência de Aminoácidos , Antígenos Virais/imunologia , Evolução Molecular , Genoma Viral , Genômica/métodos , Hepadnaviridae/imunologia , Infecções por Hepadnaviridae/imunologia , Hepatite B/imunologia , Hepatite B/virologia , Antígenos E da Hepatite B/genética , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/imunologia
12.
Viruses ; 11(10)2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640283

RESUMO

In 2015, over 850,000 people died from chronic hepatitis and hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV). A novel hepatitis B-like virus has recently been identified in domestic cats. The pathogenic potential of domestic cat hepadnavirus (DCH), for which 6.5% to 10.8% of pet cats are viremic, is unknown. We evaluated stored formalin-fixed, paraffin-embedded biopsies of diseased and normal feline liver for the presence of DCH using PCR and in situ hybridization (ISH). DCH was detected in 43% (6/14) of chronic hepatitis cases and 28% (8/29) of HCCs, whereas cholangitis (n = 6), biliary carcinoma (n = 18) and normal liver (n = 15) all tested negative for DCH. Furthermore, in DCH-associated cases, the histologic features of inflammation and neoplasia, and the viral distribution on ISH were strikingly similar to those seen with HBV-associated disease. Several histological features common in human HBV-associated hepatitis, including piecemeal necrosis and apoptotic bodies, were identified in DCH-positive cases of chronic hepatitis. In two cases of HCC examined, the proliferation index in regions that were ISH-positive was higher than in ISH-negative regions. The intracellular distribution of virus in both hepatitis and HCC demonstrated that viral nucleic acid is present in both nuclear and cytoplasmic forms. Collectively, these findings demonstrate a compelling association between DCH and some cases of chronic hepatitis and hepatocellular carcinoma in the cat that mirrors features of HBV-associated hepatopathies. Future investigations of viral epidemiology and natural history are needed to establish the impact of DCH on feline health.


Assuntos
Carcinoma Hepatocelular/veterinária , Doenças do Gato/virologia , Infecções por Hepadnaviridae/veterinária , Hepadnaviridae/patogenicidade , Hepatite Crônica/veterinária , Neoplasias Hepáticas/veterinária , Animais , Carcinoma Hepatocelular/virologia , Gatos/virologia , DNA Viral , Genoma Viral , Hepadnaviridae/genética , Infecções por Hepadnaviridae/complicações , Hepatite Crônica/virologia , Imuno-Histoquímica , Fígado/patologia , Fígado/virologia , Neoplasias Hepáticas/virologia , Masculino , Inclusão em Parafina , Viremia
13.
Sci Rep ; 9(1): 10668, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337847

RESUMO

Hepadnaviruses infect several animal species. The prototype species, human hepatitis B virus (HBV), increases the risk of liver diseases and may cause cirrhosis and hepatocellular carcinoma. Recently a novel hepadnavirus, similar to HBV, has been identified through transcriptomics studies in a domestic cat with large cell lymphoma in Australia. Herewith, a collection of 390 feline serum samples was screened for hepadnavirus. Overall, the virus was identified in 10.8% of the sera with a significantly higher prevalence (17.8%) in the sera of animals with a clinical suspect of infectious disease. Upon genome sequencing, the virus was closely related (97.0% nt identity) to the prototype Australian feline virus Sydney 2016. The mean and median values of hepadnavirus in the feline sera were 1.3 × 106 and 2.1 × 104 genome copies per mL (range 3.3 × 100-2.5 × 107 genome copies per mL). For a subset of hepadnavirus-positive samples, information on the hemato-chemical parameters was available and in 10/20 animals a profile suggestive of liver damage was present. Also, in 7/10 animals with suspected hepatic disease, virus load was >104 genome copies per mL, i.e. above the threshold considered at risk of active hepatitis and liver damage for HBV.


Assuntos
Doenças do Gato/diagnóstico , Infecções por Hepadnaviridae/veterinária , Hepadnaviridae/isolamento & purificação , Animais , Doenças do Gato/sangue , Gatos , Genoma Viral , Infecções por Hepadnaviridae/sangue , Infecções por Hepadnaviridae/diagnóstico , Carga Viral
15.
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
16.
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
17.
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
18.
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
20.
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
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