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1.
Viruses ; 13(8)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34452505

RESUMO

Viral infection is a global public health threat causing millions of deaths. A suitable small animal model is essential for viral pathogenesis and host response studies that could be used in antiviral and vaccine development. The tree shrew (Tupaia belangeri or Tupaia belangeri chinenesis), a squirrel-like non-primate small mammal in the Tupaiidae family, has been reported to be susceptible to important human viral pathogens, including hepatitis viruses (e.g., HBV, HCV), respiratory viruses (influenza viruses, SARS-CoV-2, human adenovirus B), arboviruses (Zika virus and dengue virus), and other viruses (e.g., herpes simplex virus, etc.). The pathogenesis of these viruses is not fully understood due to the lack of an economically feasible suitable small animal model mimicking natural infection of human diseases. The tree shrew model significantly contributes towards a better understanding of the infection and pathogenesis of these important human pathogens, highlighting its potential to be used as a viable viral infection model of human viruses. Therefore, in this review, we summarize updates regarding human viral infection in the tree shrew model, which highlights the potential of the tree shrew to be utilized for human viral infection and pathogenesis studies.


Assuntos
Modelos Animais de Doenças , Tupaia , Viroses , Infecções por Adenoviridae/imunologia , Infecções por Adenoviridae/virologia , Animais , COVID-19/virologia , Dengue/imunologia , Dengue/patologia , Dengue/virologia , Infecções por HIV/virologia , Hepatite B/imunologia , Hepatite B/virologia , Hepatite C/imunologia , Hepatite C/patologia , Hepatite C/virologia , Herpes Simples/patologia , Herpes Simples/virologia , Humanos , Influenza Humana/imunologia , Influenza Humana/virologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
3.
BMC Infect Dis ; 21(1): 716, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330230

RESUMO

BACKGROUND: Hepatitis B virus (HBV) remains a major global public health problem worldwide; in endemic areas, mother-to-child transmission (MTCT) of HBV is the most common transmission route. Previous studies have shown that amniocentesis for prenatal diagnosis increases the risk of MTCT of HBV among highly viraemic mothers. However, no data is available on MTCT related fetal blood sampling (FBS) because of the paucity of cases or lack of attention. We present a case series of HBV-infected women who underwent FBS with or without antiviral therapy during pregnancy and discuss the risk of MTCT after FBS. CASE PRESENTATION: Six hepatitis B surface antigen (HBsAg)-positive pregnant women who underwent FBS for prenatal diagnosis were retrospectively reviewed. Their infants were followed up with HBV serology parameters until at least 12 months of age. Among 6 cases, two hepatitis B e-antigen (HBeAg)-positive mothers had high viral loads > 7.0 log10 IU/mL, and one of them received antiviral therapy at 26+ 3 gestational weeks and achieved an anticipated level of 4.52 log10 IU/mL before FBS, while the other one did not receive any antiviral treatment. The other 4 cases were HBeAg-negative with low viral loads. Only a child born to the HBeAg-positive mother, who had no antiviral therapy with a viral load of 7.48 log10 IU/mL before FBS, was found to have MTCT with HBsAg persistently positive from birth to 12 months of age. The other 5 children were both HBsAg-negative and HBsAb-positive at the end of follow-up. CONCLUSIONS: FBS may increase the risk of MTCT of HBV in women with HBeAg-positive and high viral loads; therefore, FBS should be avoided in this high-risk population. Maternal HBV serologic testing and awareness of the potential risk of MTCT should be recommended before FBS. Antiviral therapy may be effective to decrease the risk of MTCT after FBS in highly viraemic women.


Assuntos
Sangue Fetal/virologia , Hepatite B/transmissão , Transmissão Vertical de Doenças Infecciosas , Complicações Infecciosas na Gravidez , Adulto , Feminino , Hepatite B/diagnóstico , Hepatite B/terapia , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/isolamento & purificação , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/virologia , Diagnóstico Pré-Natal , Estudos Retrospectivos , Fatores de Risco , Carga Viral , Viremia/terapia , Viremia/transmissão
4.
Viruses ; 13(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208172

RESUMO

The envelope of hepatitis B virus (HBV), which is required for the entry to hepatocytes, consists of a lipid bilayer derived from hepatocyte and HBV envelope proteins, large/middle/small hepatitis B surface antigen (L/M/SHBs). The mechanisms and host factors for the envelope formation in the hepatocytes are being revealed. HBV-infected hepatocytes release a large amount of subviral particles (SVPs) containing L/M/SHBs that facilitate escape from the immune system. Recently, novel drugs inhibiting the functions of the viral envelope and those inhibiting the release of SVPs have been reported. LHBs that accumulate in ER is considered to promote carcinogenesis and, especially, deletion mutants in the preS1/S2 domain have been reported to be associated with the development of hepatocellular carcinoma (HCC). In this review, we summarize recent reports on the findings regarding the biological characteristics of HBV envelope proteins, their involvement in HCC development and new agents targeting the envelope.


Assuntos
Transformação Celular Viral , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Hepatite B/virologia , Proteínas do Envelope Viral/metabolismo , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Gerenciamento Clínico , Regulação Viral da Expressão Gênica , Variação Genética , Genoma Viral , Hepatite B/complicações , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/ultraestrutura , Interações Hospedeiro-Patógeno , Humanos , Neoplasias Hepáticas/etiologia , Técnicas de Diagnóstico Molecular , Vírion
5.
J Gen Virol ; 102(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34328828

RESUMO

Bangladesh is one of the top-ten most heavily burdened countries for viral hepatitis, with hepatitis B (HBV) infections responsible for the majority of cases. Recombinant and occult HBV infections (OBI) have been reported previously in the region. We investigated an adult fever cohort (n=201) recruited in Dhaka, to determine the prevalence of HBV and OBI. A target-enrichment deep sequencing pipeline was applied to samples with HBV DNA >3.0 log10 IU ml-1. HBV infection was present in 16/201 (8 %), among whom 3/16 (19 %) were defined as OBI (HBsAg-negative but detectable HBV DNA). Whole genome deep sequences (WGS) were obtained for four cases, identifying genotypes A, C and D. One OBI case had sufficient DNA for sequencing, revealing multiple polymorphisms in the surface gene that may contribute to the occult phenotype. We identified mutations associated with nucleos(t)ide analogue resistance in 3/4 samples sequenced, although the clinical significance in this cohort is unknown. The high prevalence of HBV in this setting illustrates the importance of opportunistic clinical screening and DNA testing of transfusion products to minimise OBI transmission. WGS can inform understanding of diverse disease phenotypes, supporting progress towards international targets for HBV elimination.


Assuntos
Vírus da Hepatite B/genética , Hepatite B/epidemiologia , Hepatite B/virologia , Pacientes Internados , Adulto , Bangladesh/epidemiologia , DNA Viral/análise , DNA Viral/genética , Doenças Endêmicas , Feminino , Genoma Viral , Genótipo , Antígenos de Superfície da Hepatite B/análise , Antígenos de Superfície da Hepatite B/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Prevalência , Estudos Prospectivos , DNA Polimerase Dirigida por RNA/genética , Sequenciamento Completo do Genoma
6.
Elife ; 102021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34328417

RESUMO

The molecular events that drive hepatitis B virus (HBV)-mediated transformation and tumorigenesis have remained largely unclear, due to the absence of a relevant primary model system. Here we propose the use of human liver organoids as a platform for modeling HBV infection and related tumorigenesis. We first describe a primary ex vivo HBV-infection model derived from healthy donor liver organoids after challenge with recombinant virus or HBV-infected patient serum. HBV-infected organoids produced covalently closed circular DNA (cccDNA) and HBV early antigen (HBeAg), expressed intracellular HBV RNA and proteins, and produced infectious HBV. This ex vivo HBV-infected primary differentiated hepatocyte organoid platform was amenable to drug screening for both anti-HBV activity and drug-induced toxicity. We also studied HBV replication in transgenically modified organoids; liver organoids exogenously overexpressing the HBV receptor sodium taurocholate co-transporting polypeptide (NTCP) after lentiviral transduction were not more susceptible to HBV, suggesting the necessity for additional host factors for efficient infection. We also generated transgenic organoids harboring integrated HBV, representing a long-term culture system also suitable for viral production and the study of HBV transcription. Finally, we generated HBV-infected patient-derived liver organoids from non-tumor cirrhotic tissue of explants from liver transplant patients. Interestingly, transcriptomic analysis of patient-derived liver organoids indicated the presence of an aberrant early cancer gene signature, which clustered with the hepatocellular carcinoma (HCC) cohort on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset and away from healthy liver tissue, and may provide invaluable novel biomarkers for the development of HCC and surveillance in HBV-infected patients.


Assuntos
Carcinoma Hepatocelular/virologia , Hepatite B/virologia , Neoplasias Hepáticas/virologia , Organoides/virologia , Células Hep G2 , Hepatite B/complicações , Vírus da Hepatite B/patogenicidade , Humanos , Fígado/patologia , Fígado/virologia , Doadores Vivos , Modelos Biológicos , Replicação Viral
7.
Lancet Oncol ; 22(7): 977-990, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143971

RESUMO

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , China , Progressão da Doença , Feminino , Hepatite B/virologia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sorafenibe/efeitos adversos , Fatores de Tempo , Adulto Jovem
8.
Virus Genes ; 57(4): 327-337, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34091827

RESUMO

Argentina exhibits low serological prevalence for Hepatitis B virus (HBV); however, occult hepatitis B infection (OBI) has been reported in blood donors, Amerindians and individuals coinfected with hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV). The aim of this study was to analyze the genetic diversity of HBV and to evaluate serological marker associations and coinfections with HCV and HIV in patients attending and treated in a public hospital in the province of Buenos Aires, Argentina. A total of 189 HBV reactive samples (HBsAg and/or anti-HBc) were analyzed for HBV DNA characterization. All reactive samples were tested for anti-HCV and HIV-antigen/antibody using CMIA assays. Thirty-six samples exhibited detectable HBV DNA, 7 of which were OBI. HBV sequences were classified as subgenotypes A1, A2, B2, D3, F1b, F3 and F4. Mutations related to the ability to escape the host's immune response, resistance to antiviral therapy and progression to disease were found in patients, partly due to the variable sensitivity of HBsAg, the reverse transcriptase, the basal core promoter and the preCore. HCV and HIV prevalence was 10% and most of the genotypes found in the sequences were genotype 1 and B/F recombinant subtype, respectively. Of the total samples analyzed, 7 exhibited coinfections. This study shows the frequency of OBI, subgenotype distribution, HBV mutations and coinfections, which may have important clinical implications in public hospital patients. Planned prevention, detection and treatment adherence are needed to reduce transmission and morbidity in vulnerable populations.


Assuntos
Coinfecção/genética , Hepatite B Crônica/genética , Hepatite B/genética , Hepatite C/genética , Adolescente , Adulto , Idoso , Argentina/epidemiologia , Doadores de Sangue , Coinfecção/sangue , Coinfecção/tratamento farmacológico , Coinfecção/virologia , Farmacorresistência Viral/genética , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/genética , Infecções por HIV/virologia , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite B/sangue , Hepatite B/tratamento farmacológico , Hepatite B/virologia , Anticorpos Anti-Hepatite B/sangue , Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/genética , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Hepatite C/sangue , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Hospitais Públicos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Sangue Oculto , Adulto Jovem
9.
Viruses ; 13(6)2021 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070832

RESUMO

Hepatitis B virus (HBV) chronic infection causes progressive liver damage, although about 20% of patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV). Clinical manifestations range from mild to moderate (purpura, asthenia, arthralgia) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, non-Hodgkin lymphoma). A comprehensive review of therapeutic options for HBV-related CV is lacking. Nucleos(t)ide analogues (NA) suppress HBV replication in 90-100% of cases and induce clinical response in most patients with mild-to-moderate CV. Plasma exchange can be performed in patients with severe CV and should be considered in severe or life-threatening cases combined with high doses of corticosteroids and antiviral treatment. A cautious use of rituximab can be considered only in association with NA treatment in refractory cases. A review of the literature and an analysis of data collected by six centers of the Italian Group for the Study of Cryoglobulinemia on 18 HBV-CV nucleotide/nucleoside analogues (NAs)-treated patients were carried out.


Assuntos
Crioglobulinemia/etiologia , Crioglobulinemia/terapia , Vírus da Hepatite B , Hepatite B/complicações , Vasculite/etiologia , Vasculite/terapia , Idoso , Terapia Combinada , Crioglobulinemia/diagnóstico , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Seguimentos , Hepatite B/virologia , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Nucleosídeos/análogos & derivados , Nucleosídeos/uso terapêutico , Fenótipo , Resultado do Tratamento , Vasculite/diagnóstico
10.
BMC Infect Dis ; 21(1): 610, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34174833

RESUMO

BACKGROUND: Current clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients. METHODS: We studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively. RESULTS: We included 206 adults (60 on TDF, 146 untreated), with a median ± IQR follow-up duration of 3.3 ± 2.8 years. The TDF group was significantly older (median age 39 vs. 35 years, p = 0.004) and more likely to be male (63% vs. 47%, p = 0.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group. CONCLUSIONS: Risk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population.


Assuntos
Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Rim/fisiologia , Fígado/fisiologia , Tenofovir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Estudos de Coortes , Técnicas de Imagem por Elasticidade , Feminino , Hepatite B/tratamento farmacológico , Hepatite B/fisiopatologia , Hepatite B/virologia , Antígenos E da Hepatite B , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/fisiopatologia , Humanos , Rim/efeitos dos fármacos , Rim/virologia , Fígado/efeitos dos fármacos , Fígado/virologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido/epidemiologia , Carga Viral/efeitos dos fármacos , Carga Viral/fisiologia , Adulto Jovem
11.
Viruses ; 13(5)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067884

RESUMO

The Myr47 lipopeptide, consisting of hepatitis B virus (HBV) pre-S1 domain (myristoylated 2-48 peptide), is an effective commercialized anti-HBV drug that prevents the interaction of HBV with sodium taurocholate cotransporting polypeptide (NTCP) on human hepatocytes, an activity which requires both N-myristoylation residue and specific amino acid sequences. We recently reported that Myr47 reduces the cellular uptake of HBV surface antigen (HBsAg, subviral particle of HBV) in the absence of NTCP expression. In this study, we analyzed how Myr47 reduces the cellular uptake of lipid nanoparticles (including liposomes (LPs) and HBsAg) without NTCP expression. By using Myr47 mutants lacking the HBV infection inhibitory activity, they could reduce the cellular uptake of LPs in an N-myristoylation-dependent manner and an amino acid sequence-independent manner, not only in human liver-derived cells but also in human non-liver-derived cells. Moreover, Myr47 and its mutants could reduce the interaction of LPs with apolipoprotein E3 (ApoE3) in an N-myristoylation-dependent manner regardless of their amino acid sequences. From these results, lipopeptides are generally anchored by inserting their myristoyl residue into the lipid bilayer and can inhibit the interaction of LPs/HBsAg with apolipoprotein, thereby reducing the cellular uptake of LPs/HBsAg. Similarly, Myr47 would interact with HBV, inhibiting the uptake of HBV into human hepatic cells, while the inhibitory effect of Myr47 may be secondary to its ability to protect against HBV infection.


Assuntos
Endocitose/efeitos dos fármacos , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Sequência de Aminoácidos , Apolipoproteínas E/metabolismo , Transporte Biológico , Linhagem Celular , Hepatite B/metabolismo , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/química , Hepatócitos/metabolismo , Hepatócitos/virologia , Interações Hospedeiro-Patógeno , Humanos , Lipossomos , Oligopeptídeos/química , Ligação Proteica
12.
Viruses ; 13(5)2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066744

RESUMO

Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy.


Assuntos
Deleção de Genes , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Hepatite B/virologia , Animais , Biomarcadores , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Ciclo Celular , Transformação Celular Viral , Centrossomo , Dano ao DNA , Modelos Animais de Doenças , Suscetibilidade a Doenças , Estresse do Retículo Endoplasmático , Regulação Viral da Expressão Gênica , Hepatite B/complicações , Vírus da Hepatite B/fisiologia , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Prognóstico , Transdução de Sinais , Replicação Viral
13.
Arch Virol ; 166(9): 2435-2442, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34146173

RESUMO

Little is known about the usefulness of saliva samples for hepatitis B virus (HBV) genotyping and mutation analysis. The aim of this study was to evaluate the usefulness of oral fluid samples to determine HBV genotype distribution, S/polymerase mutations, and HBV subpopulation diversity among chronically HBV-infected individuals. Serum and oral fluid samples were obtained from 18 individuals for PCR and nucleotide sequencing of the HBV surface antigen gene. Biochemical analysis of liver enzymes (ALT, AST, GGT) and HBV, HCV, and HIV serological tests were also performed. All serum samples were HBsAg (+), anti-HBc (+), and anti-HBs (-); 55.6% were HBeAg (+)/anti-HBe (-), and 11.1% were anti-HIV (+). The mean HBV DNA viral load was 6.1 ± 2.3 log IU/mL. The HBV genotype distribution was as follows: A, 72.2%; D, 11.1%; E, 5.6%; F, 11.1%. A concordance of 100% in genotype classification and 99.8% in sequence similarity between paired oral fluid and serum samples was observed. HBsAg mutations were detected in all samples, but no resistance mutations were found in the polymerase gene. This study demonstrates that oral fluid samples can be used reliably for tracking HBV mutations, genotyping, and phylogenetic analysis. This could be important for molecular epidemiology studies with hard-to-reach populations.


Assuntos
Genótipo , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Mutação , Filogenia , Adulto , Sequência de Bases , DNA Viral/sangue , DNA Viral/genética , Feminino , Hepatite B/virologia , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Testes Sorológicos
14.
Cell Death Dis ; 12(7): 641, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162831

RESUMO

A major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to target and promote apoptosis of infected hepatocytes. Presently there is no clinically relevant strategy that has been shown to effectively remove persistent episomal covalently closed circular HBV DNA (cccDNA) from the nucleus of hepatocytes. We used linearized single genome length HBV DNA of various genotypes to establish a cccDNA-like reservoir in immunocompetent mice and showed that clinical-stage orally administered drugs that antagonize the function of cellular inhibitor of apoptosis proteins can eliminate HBV replication and episomal HBV genome in the liver. Primary human liver organoid models were used to confirm the clinical relevance of these results. This study underscores a clinically tenable strategy for the potential elimination of chronic HBV reservoirs in patients.


Assuntos
Antivirais/farmacologia , Azocinas/farmacologia , Compostos Benzidrílicos/farmacologia , Genoma Viral , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Fígado/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Modelos Animais de Doenças , Células Hep G2 , Hepatite B/metabolismo , Hepatite B/patologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatócitos/virologia , Interações Hospedeiro-Patógeno , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Organoides , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Replicação Viral/efeitos dos fármacos
15.
Biomed Res Int ; 2021: 5387856, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104647

RESUMO

People infected with chronic hepatitis B virus (HBV) might progress to acute-on-chronic liver failure (ACLF) with a high fatality rate. Long noncoding RNAs (lncRNAs) are involved in human diseases, but it is unknown whether lncRNAs are involved in the progression of chronic HBV infection to ACLF. Hence, this study is aimed at systemically identifying and characterizing the landscape and the molecular mechanism of lncRNAs in the pathogenesis of chronic HBV infection progress to ACLF. RNA sequencing (RNA-Seq) of peripheral blood samples from 5 ACLF and 5 HBV infection patients was performed. We detected 9733 lncRNAs, including 406 annotated lncRNAs and 9327 novel lncRNAs. A total of 407 lncRNAs were found to be significantly dysregulated in the patients with ACLF as compared with those in the chronic HBV infection patients. The flanking protein-coding genes of differentially expressed lncRNAs were enriched with pathways that might contribute to the pathogenesis of ACLF, such as the WNT signaling pathway. Furthermore, 9 selected differentially expressed lncRNAs validated by the qRT-PCR, showing that the expression patterns of these 9 lncRNAs were consistent with the RNA-Seq data. Four selected differentially expressed lncRNAs were also validated in another patient cohort comprising 80 patients with ACLF and 65 patients with chronic HBV infection. Aberrant lncRNAs might be used to develop novel diagnostic biomarkers or drug targets for ACLF.


Assuntos
RNA Longo não Codificante/genética , Transcriptoma/genética , Insuficiência Hepática Crônica Agudizada/virologia , Adulto , Estudos de Coortes , Feminino , Hepatite B/genética , Hepatite B/virologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/genética
16.
Mol Carcinog ; 60(9): 620-626, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34133796

RESUMO

Genome-wide association study recently identified a novel antiviral gene INTS10 (index rs7000921) in suppression of hepatitis B virus (HBV) replication. However, data were lacking on single nucleotide polymorphisms (SNPs) of INTS10 in the context of hepatocellular carcinoma (HCC) induced by HBV infection. Herein, we conducted a case-control study, including 737 HBV-related HCC cases and 750 persistently HBV-infected controls, to investigate the effect of INTS10 SNPs and their gene-environment interactions on HBV-related HCC. In multivariate analysis, the CT genotype of rs7000921 conferred a decreased risk of HBV-related HCC compared to the TT genotype (adjusted odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64-0.98, p for permutation test = .038). Among the 12 tagSNPs, the rs4268139 yielded a borderline significant association with disease risk under the additive model (adjusted OR = 0.80, 95% CI = 0.63-1.00, p for permutation test = .061). Random forest model further suggested the rs7000921 and rs7822495 as the two-top ranked important SNPs, and thus a weighted genetic risk score (wGRS) was generated from these two SNPs plus rs4268139. The highest tertile of wGRS was associated with an increased risk, with an adjusted OR of 1.36 (95% CI = 1.05-1.75, p for permutation test = .016) compared to the lowest wGRS. Furthermore, an additive interaction was seen between wGRS and drinking (attributable proportion due to interaction [AP] = 0.21, 95% CI = 0.02-0.43, p = .016). The additive interaction between wGRS and smoking approached near significance (AP = 0.15, 95% CI = 0.00-0.32, p = .045). INTS10 polymorphisms may contribute to the progression from HBV infection to HCC. More importantly, INTS10 polymorphisms interact with drinking and smoking to affect the progression.


Assuntos
Carcinoma Hepatocelular/etiologia , Proteínas de Transporte/genética , Interação Gene-Ambiente , Hepatite B/complicações , Neoplasias Hepáticas/etiologia , Alelos , Estudos de Casos e Controles , Suscetibilidade a Doenças , Predisposição Genética para Doença , Genótipo , Hepatite B/virologia , Vírus da Hepatite B , Humanos , Mutação , Polimorfismo de Nucleotídeo Único
17.
BMC Cancer ; 21(1): 686, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112124

RESUMO

BACKGROUND: Hepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people. METHODS: The expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells. RESULT: ALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells' growth and migration in vitro and in vivo. CONCLUSIONS: HBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase/genética , Carcinoma Hepatocelular/genética , Hepatite B/patologia , Neoplasias Hepáticas/genética , Transativadores/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Retroalimentação Fisiológica , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células Hep G2 , Hepatite B/virologia , Vírus da Hepatite B/patogenicidade , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/patologia , Fígado/virologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , RNA-Seq , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Mol Sci ; 22(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063629

RESUMO

Hepatitis B remains a major global public health challenge, with particularly high prevalence in medically disadvantaged western Pacific and African regions. Although clinically available technologies for the qPCR detection of HBV are well established, research on point-of-care testing has not progressed substantially. The development of a rapid, accurate point-of-care test is essential for the prevention and control of hepatitis B in medically disadvantaged rural areas. The development of the CRISPR/Cas system in nucleic acid detection has allowed for pathogen point-of-care detection. Here, we developed a rapid and accurate point-of-care assay for HBV based on LAMP-Cas12a. It innovatively solves the problem of point-of-care testing in 10 min, particularly the problem of sample nucleic acid extraction. Based on LAMP-Cas12a, visualization of the assay results is presented by both a fluorescent readout and by lateral flow test strips. The lateral flow test strip technology can achieve results visible to the naked eye, while fluorescence readout can achieve real-time high-sensitivity detection. The fluorescent readout-based Cas12a assay can achieve HBV detection with a limit of detection of 1 copy/µL within 13 min, while the lateral flow test strip technique only takes 20 min. In the evaluation of 73 clinical samples, the sensitivity and specificity of both the fluorescence readout and lateral flow test strip method were 100%, and the results of the assay were fully comparable to qPCR. The LAMP-Cas12a-based HBV assay relies on minimal equipment to provide rapid, accurate test results and low costs, providing significant practical value for point-of-care HBV detection.


Assuntos
Técnicas Biossensoriais , Vírus da Hepatite B/isolamento & purificação , Hepatite B/diagnóstico , Testes Imediatos , Sistemas CRISPR-Cas/genética , Fluorescência , Hepatite B/genética , Hepatite B/virologia , Vírus da Hepatite B/patogenicidade , Humanos , Sistemas Automatizados de Assistência Junto ao Leito
19.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069902

RESUMO

Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.


Assuntos
Carcinoma Hepatocelular/metabolismo , Colesterol/metabolismo , Fígado/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Colesterol/fisiologia , Feminino , Alemanha/epidemiologia , Hepacivirus/metabolismo , Hepatite B/virologia , Vírus da Hepatite B/metabolismo , Hepatite C/virologia , Humanos , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade
20.
Front Immunol ; 12: 661204, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995383

RESUMO

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Epigênese Genética/imunologia , Vírus da Hepatite B/imunologia , Hepatite B/imunologia , Neoplasias Hepáticas/imunologia , MicroRNAs/imunologia , Transativadores/imunologia , Proteínas Virais Reguladoras e Acessórias/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Regulação Neoplásica da Expressão Gênica/imunologia , Hepatite B/genética , Hepatite B/virologia , Vírus da Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , MicroRNAs/genética , Transativadores/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo
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