Objective To identify the difference and significance of dominant types of hepatitis B virus(HBV) pre-S mutation between liver tumor tissues and paired adjacent non-tumor tissues and to test if the mutations were tumo...Objective To identify the difference and significance of dominant types of hepatitis B virus(HBV) pre-S mutation between liver tumor tissues and paired adjacent non-tumor tissues and to test if the mutations were tumor tissue specific.Methods HBV DNA isolated from 34 paired intratumoral and peritumoral tissues of Hepatocellular Carcinoma(HCC) patients were screened by PCR and direct sequencing. All patients carried HBV with genotype C, except for one B/C heterozygote. The expression,localization and excretion of LHBs mutant carrying pre-S deletions were characterized in vitro. The expression of endoplasmic reticulum(ER) GRP78 mRNA was assayed.Results Four patterns of pre-S mutations were identified: pre-S1 in-frame deletion involving the first start codon; pre-S2 in-frame deletion;pre-S2 start codon mutation with or without in-frame deletion; and S promoter in-frame deletion(ΔSP). The first two types were evenly found in both tumor and non-tumor tissues. They were rarely present as dominant strains. The last two types were frequently found in the dominant strains in tumor tissues. The overall prevalence of HBV carrying ΔSP was 17.64%(6/34) in tumor tissues, but none were dominant in non-tumor tissues. HBV carrying ΔSP was unable to produce S protein in vitro. Immunocytofluorescence assay showed that the ΔSP LHBs mutant aggregated in the cytoplasm, accumulating mainly in the ER. Transient transfection and expression of ΔSP mutant caused GRP78 up-regulation in vitro.Conclusion HBV S promoter deletion was found dominantly in HCC tumor tissue. The aggregation of mutant large surface proteins in the ER possibly involved in HBV-related HCC.展开更多
Objective To identify the difference and significance of dominant types of hepatitis B virus(HBV) pre-S mutation between liver tumor tissues and paired adjacent non-tumor tissues and to test if the mutations were tumo...Objective To identify the difference and significance of dominant types of hepatitis B virus(HBV) pre-S mutation between liver tumor tissues and paired adjacent non-tumor tissues and to test if the mutations were tumor tissue specific.Methods HBV DNA isolated from 34 paired intratumoral and peritumoral tissues of Hepatocellular Carcinoma(HCC) patients were screened by PCR and direct sequencing. All patients carried HBV with genotype C, except for one B/C heterozygote. The expression, localization and excretion of LHBs mutant carrying pre-S deletions were characterized in vitro. The expression of endoplasmic reticulum(ER) GRP78 m RNA was assayed.Results Four patterns of pre-S mutations were identified: pre-S1 in-frame deletion involving the first start codon; pre-S2 in-frame deletion; pre-S2 start codon mutation with or without in-frame deletion; and S promoter in-frame deletion(ΔSP). The first two types were evenly found in both tumor and non-tumor tissues. They were rarely present as dominant strains. The last two types were frequently found in the dominant strains in tumor tissues. The overall prevalence of HBV carrying ΔSP was 17.64%(6/34) in tumor tissues, but none were dominant in non-tumor tissues. HBV carrying ΔSP was unable to produce S protein in vitro. Immunocytofluorescence assay showed that the ΔSP LHBs mutant aggregated in the cytoplasm, accumulating mainly in the ER. Transient transfection and expression of ΔSP mutant caused GRP78 up-regulation in vitro.Conclusion HBV S promoter deletion was found dominantly in HCC tumor tissue. The aggregation of mutant large surface proteins in the ER possibly involved in HBV-related HCC.展开更多
Hepatitis B virus(HBV)produces and releases various particle types,including complete virions,subviral particles with envelope proteins,and naked capsids.Recent studies demonstrate that HBV exploits distinct intracell...Hepatitis B virus(HBV)produces and releases various particle types,including complete virions,subviral particles with envelope proteins,and naked capsids.Recent studies demonstrate that HBV exploits distinct intracellular membrane trafficking pathways,including the endosomal vesicle trafficking and autophagy pathway,to assemble and release viral and subviral particles.Herein,we summarize the findings about the distinct roles of autophagy and endosomal membrane trafficking and the interaction of both pathways in HBV replication,assembly,and release.展开更多
Objective To explore the optimal primer ratio and concentration of asymmetric polymerase chain reaction (A-PCR) in producing hepatitis B virus (HBV) single-stranded DNA (ssDNA) for pyrosequencing. Methods A-PCR was ca...Objective To explore the optimal primer ratio and concentration of asymmetric polymerase chain reaction (A-PCR) in producing hepatitis B virus (HBV) single-stranded DNA (ssDNA) for pyrosequencing. Methods A-PCR was carried out to generate HBV ssDNA with forward to reverse primers of different ratios (50∶1, 100∶1) and concentrations (13.0 pmol/25μL and 0.14 pmol/25μL, 19.5 pmol/25μL and 0.21 pmol/25μL), and the product yield and quality were compared respectively. Results The forward to reverse primer ratio of 50∶1 provided better yield and concentration of 19.5 pmol/25μL and 0.21 pmol//25μL generated a clearer band. Conclusion A simple and feasible method to produce HBV ssDNA for pyrosequencing in batch is established.展开更多
Covalently closed circular(ccc)DNA of hepatitis B virus(HBV)existed in the nuclei of HBV infected hepatocytes with a half-life time of 14.3 years in a mathmatic model.Viral protein feedback regulation in HBV life cycl...Covalently closed circular(ccc)DNA of hepatitis B virus(HBV)existed in the nuclei of HBV infected hepatocytes with a half-life time of 14.3 years in a mathmatic model.Viral protein feedback regulation in HBV life cycle to maintain vital viral replication is an important mechanism.Interleukin-6,epithelial growth factor,heme oxygenase-1,histones,and hepatocyte nuclear factors are demonstrated as the key regulators for HBV life cycle.CpG island structure and methylation status are involved in the regulation of HBV DNA replication.Nucleos(t)ide analogues are widely used in the clinical practice for the treatment of chronic hepatitis B patients,although no evidence indicating a direct inhibiton of HBV cccDNA.In the future,along with the study of HBV life cycle,new drugs including RNA interference technique,will pave the way to eliminate the HBV cccDNA from infected hepatocytes resulting final cure of chronic hepatitis B.展开更多
Reversible phosphorylation and dephosphorylation play important roles in cell function and cell signal transduction. PPP2R5A (protein phosphatase 2 regulatory subunit B’ alpha) is responsible for specifically regulat...Reversible phosphorylation and dephosphorylation play important roles in cell function and cell signal transduction. PPP2R5A (protein phosphatase 2 regulatory subunit B’ alpha) is responsible for specifically regulating the catalytic function, substrate specificity and intracellular localization of the tumor suppressor phosphatase PP2A (serine/threonine protein phosphatase 2A). Therefore, the abnormal expression and function of PPP2R5A may be related to canceration. The aim of this study was to reveal its role in the occurrence and development of hepatocellular carcinoma (HCC). It is hoped that the results of this study can provide guidance for the prevention and treatment of HCC. The results showed that PPP2R5A inhibited the proliferation and metastasis of HCC cells, and acted as a tumor suppressor in HCC cells, but it had no significant effect on cell cycle. Further research found that PPP2R5A exerted tumor suppressor efficacy by inhibiting the MAPK/AKT/WNT signaling pathway. Combined with analysis of clinical tissue samples and TCGA database, it was found that the expression of PPP2R5A in tumor tissues of Chinese HCC patients was down-regulated and significantly correlated with the progression-free survival (PFS) of HCC patients. On the contrary, PPP2R5A showed an up-regulation trend in HCC cases in TCGA database although its effect on PFS was the same with that in Chinese HCC patients. Hepatitis B virus (HBV) infection is the main pathogenic factor of HCC in China. It was found that HBV infection reduced the content of PPP2R5A in cells. It was concluded that HBV inhibited the initiation of the protective mechanism mediated by PPP2R5A, making the occurrence and progress of HCC more “unimpeded”. This conclusion will further reveal the role of PPP2R5A in HBV-induced and HBV-unrelated HCC, therefore, providing clues for the prevention and treatment of the two types of HCC, respectively.展开更多
Background and aims:Hepatitis B virus(HBV)infection is a major global health problem which progresses to liver cirrhosis(LC)and hepatocellular carcinoma(HCC).Early prediction of disease changes and intervention are es...Background and aims:Hepatitis B virus(HBV)infection is a major global health problem which progresses to liver cirrhosis(LC)and hepatocellular carcinoma(HCC).Early prediction of disease changes and intervention are essential to slow disease progression and protect liver function.This study aimed to analyze the clinical characteristics of patients with HBV-related LC and HCC at different serum alanine aminotransferase(ALT)levels and explore the risk factors of HBV infection progressing to LC/HCC.Methods:A total of 379 patients with HBV infection treated in The Third People's Hospital of Shenzhen between January 2014 and December 2016 without any antiviral drug therapy were enrolled.Patients were divided into the LC/HCC and non-LC/HCC groups based on clinical diagnosis,which was determined through imaging and expressions of pathological and laboratory test markers,and patients with LC/HCC were further divided into three groups according to the serum ALT levels.Differences in general information,clinical symptoms,and expression levels of serological indices of the above groups were compared and analyzed,logistic regression was used to analyze the risk factors for LC/HCC development,and the clinical diagnostic efficacy of indicators was judged by the receiver operator characteristic(ROC).Results:LC/HCC mainly occurred in the ALT normal and mildly elevated groups,with 70.83% of patients with HCC having an LC background.In the comparison of different ALT level groups,the moderately eseverely elevated group had the highest proportion of patients with skin jaundice,abdominal varices,rebound tenderness,higher white blood cell and neutrophil(NEUT)counts;and higher levels of aspartate aminotransferase,glutamyl transpeptidase,total bilirubin,and direct bilirubin.The LC/HCC group was older and had significantly higher proportions of male patients,alcohol consumption,and combined hypertension than the non-LC/HCC group(all P<0.05).Logistic regression analysis showed that age,combined hypertension,abdominal varicose veins,subcostal palpation,and NEUT count were risk factors for LC/HCC development;and the area under the curve for this model on the ROC analysis was 0.935(95%confidence interval 0.899e0.972)with specificity and sensitivity of 97.4%and 70.7%,respectively.展开更多
Background:To evaluate the association between corneal central endothelial cell count(CECC)with reactivity for hepatitis B virus(HBV),hepatitis C virus(HCV),human immunodeficiency virus(HIV),human T-lymphotropic virus...Background:To evaluate the association between corneal central endothelial cell count(CECC)with reactivity for hepatitis B virus(HBV),hepatitis C virus(HCV),human immunodeficiency virus(HIV),human T-lymphotropic virus-1(HTLV1),and syphilis from an eye bank database.Methods:Eye bank data included 19,159 donors and 38,318 corneas screened for HBV,HCV,HIV,HTLV1,and syphilis from July 2007-May 2015.Linear and binary mixed effects models were used to determine the adjusted marginal effect a positive viral screening test had on CECC and morphology,respectively.The models were adjusted for age,race,gender,lens status,and death to preservation.Eyes with missing data were excluded from the analysis.Statistical significance was defined as P values<0.05.Results:A total of 18,097 donors and 35,136 corneas were included in the final analysis.Average CECC for eyes with negative viral screening was 2,597±436 while the average CECC for eyes screening positive for syphilis,HBV,HCV,HIV,and HTLV1 were 2,638±392(P=0.073),2,569±419(P=0.815),2,603±363(P=0.207),2,615±360(P=0.733),and 2,625±436(P=0.362)respectively.Conclusions:The presence of HBV,HCV,HIV,HTLV1,and syphilis display no association with a statistically significant difference in CECC when compared to normal non-diseased donors.展开更多
Hepatitis B virus(HBV)is regarded as a stealth virus,invading and replicating efficiently in human liver undetected by host innate antiviral immunity.Here,we show that type I interferon(IFN)induction but not its downs...Hepatitis B virus(HBV)is regarded as a stealth virus,invading and replicating efficiently in human liver undetected by host innate antiviral immunity.Here,we show that type I interferon(IFN)induction but not its downstream signaling is blocked by HBV replication in HepG2.2.15 cells.This effect may be partially due to HBV X protein(HBx),which impairs IFNβpromoter activation by both Sendai virus(SeV)and components implicated in signaling by viral sensors.As a deubiquitinating enzyme(DUB),HBx cleaves Lys63-linked polyubiquitin chains from many proteins except TANK-binding kinase 1(TBK1).It binds and deconjugates retinoic acid-inducible gene I(RIG I)and TNF receptor-associated factor 3(TRAF3),causing their dissociation from the downstream adaptor CARDIF or TBK1 kinase.In addition to RIG I and TRAF3,HBx also interacts with CARDIF,TRIF,NEMO,TBK1,inhibitor of kappa light polypeptide gene enhancer in B-cells,kinase epsilon(IKKi)and interferon regulatory factor 3(IRF3).Our data indicate that multiple points of signaling pathways can be targeted by HBx to negatively regulate production of type I IFN.展开更多
Chronic hepatitis B infection is caused by hepatitis B virus(HBV) and a total cure is yet to be achieved. The viral covalently closed circular DNA(ccc DNA) is the key to establish a persistent infection within hepatoc...Chronic hepatitis B infection is caused by hepatitis B virus(HBV) and a total cure is yet to be achieved. The viral covalently closed circular DNA(ccc DNA) is the key to establish a persistent infection within hepatocytes. Current antiviral strategies have no effect on the pre-existing ccc DNA reservoir. Therefore, the study of the molecular mechanism of ccc DNA formation is becoming a major focus of HBV research. This review summarizes the current advances in ccc DNA molecular biology and the latest studies on the elimination or inactivation of ccc DNA, including three major areas:(1) epigenetic regulation of ccc DNA by HBV X protein,(2) immune-mediated degradation,and(3) genome-editing nucleases. All these aspects provide clues on how to finally attain a cure for chronic hepatitis B infection.展开更多
Commensal microbiota is closely related to Hepatitis B virus(HBV)infection.Gut bacteria maturation accelerates HBV immune clearance in hydrodynamic injection(HDI)HBV mouse model.However,the effect of gut bacteria on H...Commensal microbiota is closely related to Hepatitis B virus(HBV)infection.Gut bacteria maturation accelerates HBV immune clearance in hydrodynamic injection(HDI)HBV mouse model.However,the effect of gut bacteria on HBV replication in recombinant adeno-associated virus(AAV)-HBV mouse model with immune tolerance remains obscure.We aim to investigate its role on HBV replication in AAV-HBV mouse model.C57BL/6 mice were administrated with broad-spectrum antibiotic mixtures(ABX)to deplete gut bacteria and intravenously injected with AAV-HBV to establish persistent HBV replication.Gut microbiota community was analyzed by fecal qPCR assay and 16S ribosomal RNA(rRNA)gene sequencing.HBV replication markers in blood and liver were determined by ELISA,qPCR assay and Western blot at indicated time points.Immune response in AAV-HBV mouse model was activated through HDI of HBV plasmid or poly(I:C)and then detected by quantifying the percentage of IFN-γ^(+)/CD8^(+)T cells in the spleen via flow cytometry as well as the splenic IFN-γmRNA level via qPCR assay.We found that antibiotic exposure remarkably decreased gut bacteria abundance and diversity.Antibiotic treatment failed to alter the levels of serological HBV antigens,intrahepatic HBV RNA transcripts and HBc protein in AAV-HBV mouse model,but contributed to HBsAg increase after breaking of immune tolerance.Overall,our data uncovered that antibiotic-induced gut bacteria depletion has no effect on HBV replication in immune tolerant AAV-HBV mouse model,providing new thoughts for elucidating the correlation between gut bacteria dysbiosis by antibiotic abuse and clinical chronic HBV infection.展开更多
Chronic hepatitis B virus(HBV)infection remains a major public health concern globally,and T cell responses are widely believed to play a pivotal role in mediating HBV clearance.Accordingly,research on the characteris...Chronic hepatitis B virus(HBV)infection remains a major public health concern globally,and T cell responses are widely believed to play a pivotal role in mediating HBV clearance.Accordingly,research on the characteristics of HBV-specific T cell responses,from activation to exhaustion,has advanced rapidly.Here,we summarize recent developments in characterizing T cell immunity in HBV infection by reviewing basic and clinical research published in the last five years.We provide a comprehensive summary of the mechanisms that induce effective anti-HBV T cell immunity,as well as the latest developments in understanding T cell dysfunction in chronic HBV infection.Furthermore,we briefly discuss current novel treatment strategies aimed at restoring anti-HBV T cell responses.展开更多
Hepatitis B virus(HBV)is a primary cause of chronic liver diseases in humans.HBV infection exhibits strict host and tissue tropism.HBV core promoter(Cp)drives transcription of pregenomic RNA(pg RNA)and plays a key rol...Hepatitis B virus(HBV)is a primary cause of chronic liver diseases in humans.HBV infection exhibits strict host and tissue tropism.HBV core promoter(Cp)drives transcription of pregenomic RNA(pg RNA)and plays a key role in the viral life cycle.Hepatocyte nuclear factor 4α(HNF4α)acts as a major transcriptional factor that stimulates Cp.In this work,we reported that BEL7404 cell line displayed a high efficiency of DNA transfection and high levels of HBV antigen expression after transfection of HBV replicons without prominent viral replication.The introduction of exogenous HNF4αand human sodium taurocholate cotransporting polypeptide(h NTCP)expression into BEL7404made it permissive for HBV replication and susceptible to HBV infection.BEL7404-derived cell lines with induced HBV permissiveness and susceptibility were constructed by stable co-transfection of h NTCP and Tet-inducible HNF4αfollowed by limiting dilution cloning.HBV replication in such cells was sensitive to inhibition by nucleotide analog tenofovir,while the infection was inhibited by HBV entry inhibitors.This cell culture system provides a new and additional tool for the study of HBV replication and infection as well as the characterization of antiviral agents.展开更多
Our recent study reported that ATP1B3 inhibits hepatitis B virus(HBV)replication via inducing NF-κB activation.However,ATP1B3 mutants which were defective in NF-κB activation still maintained the moderate degree of ...Our recent study reported that ATP1B3 inhibits hepatitis B virus(HBV)replication via inducing NF-κB activation.However,ATP1B3 mutants which were defective in NF-κB activation still maintained the moderate degree of suppression on HBV replication,suggesting that another uncharacterized mechanism is also responsible for ATP1B3-mediated HBV suppression.Here,we demonstrated that ATP1B3 reduced the expression of HBV envelope proteins LHBs,MHBs and SHBs,but had no effect on intracellular HBV DNA,RNA levels as well as HBV promoter activities.Further investigation showed that proteasome inhibitor MG132 rescued ATP1B3-mediated envelope proteins degradation,demonstrating that proteasome-dependent pathway is involved in ATP1B3-induced degradation of envelope proteins.Co-IP showed that ATP1B3 interacts with LHBs and MHBs and induces LHBs and MHBs polyubiquitination.Immunofluorescence colocalization analysis confirmed LHBs and MHBs colocalized with ATP1B3 together.Our work provides important information for targeting ATP1B3 as a potential therapeutic molecule for HBV infection.展开更多
Mammalian target of rapamycin(m TOR) is a conserved Ser/Thr kinase that includes m TOR complex(m TORC) 1 and m TORC2. The m TOR pathway is activated in viral hepatitis, including hepatitis B virus(HBV) infection-induc...Mammalian target of rapamycin(m TOR) is a conserved Ser/Thr kinase that includes m TOR complex(m TORC) 1 and m TORC2. The m TOR pathway is activated in viral hepatitis, including hepatitis B virus(HBV) infection-induced hepatitis.Currently, chronic HBV infection remains one of the most serious public health issues worldwide. The unavailability of effective therapeutic strategies for HBV suggests that clarification of the pathogenesis of HBV infection is urgently required. Increasing evidence has shown that HBV infection can activate the m TOR pathway, indicating that HBV utilizes or hijacks the m TOR pathway to benefit its own replication. Therefore, the m TOR signaling pathway might be a crucial target for controlling HBV infection. Here, we summarize and discuss the latest findings from model biology research regarding the interaction between the m TOR signaling pathway and HBV replication.展开更多
Background and aims:Effective hepatic blood flow(EHBF)decreases with liver disease progression,and identifying liver pathology is critical for patients with liver disease.This study was designed to elucidate the corre...Background and aims:Effective hepatic blood flow(EHBF)decreases with liver disease progression,and identifying liver pathology is critical for patients with liver disease.This study was designed to elucidate the correlation between EHBF and liver pathology and explore the potential of EHBF for predicting the degree of liver pathology.Methods:In this study,207 patients with hepatitis B virus(HBV)who underwent liver biopsy and indocyanine green(ICG)clearance tests were enrolled.EHBF was measured using the ICG clearance test,and liver tissue was histologically analyzed to determine the pathological stage according to the Scheuer scoring system.Demographic data,biochemical indexes,and FibroScan data were collected for statistical analysis.Results:EHBF levels decreased as the liver histological stages of inflammation and fibrosis increased(P<0.01).EHBF was significantly negatively associated with the levels of alanine aminotransferase,aspartate aminotransferase,gamma-glutamyl transpeptidase,alkaline phosphatase,aspartate aminotransferase-to-platelet ratio index,fibrosis index based on the four factors,and liver stiffness measurement(P<0.05).The EHBF levels of patients without liver inflammation(G0)were significantly higher than those of patients with liver inflammation(G1e4)(P<0.001).The area under the receiver operating characteristic curve(AUROC)value for discriminating patients without liver inflammation was 0.827,and the optimal cutoff value was 0.936 L/min.The EHBF levels of patients with severe liver inflammation(G4)were significantly lower than those of patients with G0e3 liver inflammation(P<0.001).The AUROC value for discriminating patients with severe liver inflammation was 0.792,and the optimal cutoff value was 0.552 L/min.The EHBF levels of patients without liver fibrosis(S0)were significantly higher than those of patients with liver fibrosis(S1e4)(P<0.001).The AUROC value for discriminating patients without liver fibrosis was 0.633,and the optimal cutoff value was 1.173 L/min.The EHBF levels of patients with liver cirrhosis(S4)were significantly lower than those of patients with S0e3 liver fibrosis(P<0.001).The AUROC value for discriminating patients with liver cirrhosis(S4)was 0.630,and the optimal cutoff value was 0.562 L/min.Conclusions:EHBF levels and liver pathology are significantly correlated.EHBF could effectively reflect liver inflammation and fibrosis in patients infected with HBV,especially for patients without liver inflammation or liver fibrosis.展开更多
Autophagy is a self-eating process,in which the damaged or excessed cell organelles and misfolded protein aggregates are removed from the cellular microenvironment.Autophagy is generally thought of as a pro-survival m...Autophagy is a self-eating process,in which the damaged or excessed cell organelles and misfolded protein aggregates are removed from the cellular microenvironment.Autophagy is generally thought of as a pro-survival mechanism which is not only important for balancing energy supply at times of nutrient deprivation but also in the removal of various stress stimuli to ensure homeostasis.In addition to the target materials of“self”origin,autophagy can also eliminate intracellular pathogens and acts as a defense mechanism to curb infections.In addition,autophagy is linked to the host cell's innate immune response.However,viruses have evolved various strategies to manipulate and overtake host cell machinery to establish productive replication and maintain infectious process.In fact,replication of many viruses has been found to be autophagy-dependent and suppression of autophagy can potentially affect the viral replication.Thus,autophagy can either serve as an anti-viral defense mechanism or a pro-viral process that supports viral replication.Hepatitis B virus(HBV)and hepatitis C virus(HCV)are known to co-opt cellular autophagy process as a pro-viral tool.Both viruses also induce mitophagy,which contributes to the establishment of chronic hepatitis.This review focuses on the roles of autophagy and mitophagy in the chronic liver disease pathogenesis associated with HBV and HCV infections.展开更多
Background and aim:Several effective antiviral drugs are now available;however,the risk of liver-related complications is still present.Low-level viremia(LLV),defined as a hepatitis B virus(HBV)deoxy-ribonucleic acid(...Background and aim:Several effective antiviral drugs are now available;however,the risk of liver-related complications is still present.Low-level viremia(LLV),defined as a hepatitis B virus(HBV)deoxy-ribonucleic acid(DNA)load lower than 2000 IU/mL,is one of the major factors responsible for these complications.It has been reported that 22.7e43.1%of patients with HBV experience LLV.Herein,we aimed to explore the risk factors for very LLV(VLLV)during antiviral treatment.Methods:We collected data of patients with chronic hepatitis B(CHB)who received nucleos(t)ide analog treatment from October 2016 to April 2021.VLLV was defined as an HBV DNA load of 9e20 IU/mL.A total of 139 patients with LLV were matched with 139 patients with a sustained virological response at a 1:1 ratio according to age and gender.Results:Seropositivity rates for hepatitis B e antigen(HBeAg)(45.3%vs.17.3%,P<0.001)and hepatitis B surface antigen(HBsAg,3.11±0.68 lg IU/mL vs.2.54±1.04 lg IU/mL,P<0.001)and alanine amino-transferase levels(30.34±15.08 U/L vs.26.15±16.66 U/L,P¼0.040)in the two groups were significantly different.The multivariate analysis showed that both HBeAg seropositivity(adjusted odd ratio(aOR),3.63;95% confidence interval(CI):1.98±6.64;P<0.001)and HBsAg levels(aOR,2.21;95% CI:1.53±3.20;P<0.001)are independent risk factors for VLLV.During the multivariate analysis in the subgroup of HBeAg-positive patients,male gender(aOR,3.68;95% CI:1.23±10.76;P=0.017)and high HBsAg(aOR,4.86;95%CI:1.73e13.64;P¼0.003)levels were significantly correlated with VLLV.However,this was not the case in HBeAg-negative patients(P>0.050).HBeAg seropositivity(aOR,5.08;95% CI:2.15±12.02;P<0.001 vs.aOR,2.78;95% CI:1.16±7.00;P=0.022)and HBsAg levels(aOR,2.75;95% CI:1.41e5.37;P=0.003 vs.aOR,2.10;95% CI:1.27±3.46;P=0.004)significantly increased the risk of VLLV,irrespective of the age group.Both HBsAg(area under the receiver operating characteristic curve(AUC),0.681;95% CI:0.623±0.736;P<0.001)and HBeAg(AUC,0.640;95% CI:0.581±0.697;P<0.001)had certain pre-dictive value for VLLV.Conclusion:HBeAg seropositivity and higher HBsAg levels were not only risk factors for VLLV but also predicted its occurrence.When a patient with CHB remains HBeAg seropositive with high HBsAg levels after antiviral treatment for 48 weeks,emphasis should be placed on the potential occurrence of VLLV,warranting the use of highly sensitive HBV DNA detection methods.展开更多
Hepatitis B virus(HBV) belongs to Hepadnaviridae family and mainly infects hepatocytes, which can cause acute or chronic hepatitis. Currently, two types of antiviral drugs are approved for chronic infection clinically...Hepatitis B virus(HBV) belongs to Hepadnaviridae family and mainly infects hepatocytes, which can cause acute or chronic hepatitis. Currently, two types of antiviral drugs are approved for chronic infection clinically: interferons and nucleos(t)ide analogues. However, the clinical cure for chronic infection is still rare, and it is a huge challenge for all researchers to develop high-efficiency, safe, non-tolerant, and low-toxicity anti-HBV drugs. Antazoline hydrochloride is a first-generation antihistamine with anticholinergic properties, and it is commonly used to relieve nasal congestion and in eye drops. Recently, an in vitro high-throughput evaluation system was constructed to screen nearly 800 compounds from the Food and Drug Administration(FDA)-approved Drug Library. We found that arbidol hydrochloride and antazoline hydrochloride can effectively reduce HBV DNA in the extracellular supernatant in a dose-dependent manner, with EC_(50) of4.321 lmol/L and 2.910 lmol/L in HepAD38 cells, respectively. Moreover, the antiviral effects and potential mechanism of action of antazoline hydrochloride were studied in different HBV replication systems. The results indicate that antazoline hydrochloride also has a significant inhibitory effect on HBV DNA in the extracellular supernatant of Huh7 cells,with an EC_(50) of 2.349 lmol/L. These findings provide new ideas for screening and research related to HBV agents.展开更多
基金supported by grants from the National Projects on Major Infectious Diseases,Ministry of Science and Technolog of China(No.2009ZX10004-903)and the Doctoral Fund of Ministry of Education of China(No.20100001110055)
文摘Objective To identify the difference and significance of dominant types of hepatitis B virus(HBV) pre-S mutation between liver tumor tissues and paired adjacent non-tumor tissues and to test if the mutations were tumor tissue specific.Methods HBV DNA isolated from 34 paired intratumoral and peritumoral tissues of Hepatocellular Carcinoma(HCC) patients were screened by PCR and direct sequencing. All patients carried HBV with genotype C, except for one B/C heterozygote. The expression,localization and excretion of LHBs mutant carrying pre-S deletions were characterized in vitro. The expression of endoplasmic reticulum(ER) GRP78 mRNA was assayed.Results Four patterns of pre-S mutations were identified: pre-S1 in-frame deletion involving the first start codon; pre-S2 in-frame deletion;pre-S2 start codon mutation with or without in-frame deletion; and S promoter in-frame deletion(ΔSP). The first two types were evenly found in both tumor and non-tumor tissues. They were rarely present as dominant strains. The last two types were frequently found in the dominant strains in tumor tissues. The overall prevalence of HBV carrying ΔSP was 17.64%(6/34) in tumor tissues, but none were dominant in non-tumor tissues. HBV carrying ΔSP was unable to produce S protein in vitro. Immunocytofluorescence assay showed that the ΔSP LHBs mutant aggregated in the cytoplasm, accumulating mainly in the ER. Transient transfection and expression of ΔSP mutant caused GRP78 up-regulation in vitro.Conclusion HBV S promoter deletion was found dominantly in HCC tumor tissue. The aggregation of mutant large surface proteins in the ER possibly involved in HBV-related HCC.
基金supported by grants from the National Projects on Major Infectious Diseases,Ministry of Science and Technolog of China(No.2009ZX10004-903)the Doctoral Fund of Ministry of Education of China(No.20100001110055)
文摘Objective To identify the difference and significance of dominant types of hepatitis B virus(HBV) pre-S mutation between liver tumor tissues and paired adjacent non-tumor tissues and to test if the mutations were tumor tissue specific.Methods HBV DNA isolated from 34 paired intratumoral and peritumoral tissues of Hepatocellular Carcinoma(HCC) patients were screened by PCR and direct sequencing. All patients carried HBV with genotype C, except for one B/C heterozygote. The expression, localization and excretion of LHBs mutant carrying pre-S deletions were characterized in vitro. The expression of endoplasmic reticulum(ER) GRP78 m RNA was assayed.Results Four patterns of pre-S mutations were identified: pre-S1 in-frame deletion involving the first start codon; pre-S2 in-frame deletion; pre-S2 start codon mutation with or without in-frame deletion; and S promoter in-frame deletion(ΔSP). The first two types were evenly found in both tumor and non-tumor tissues. They were rarely present as dominant strains. The last two types were frequently found in the dominant strains in tumor tissues. The overall prevalence of HBV carrying ΔSP was 17.64%(6/34) in tumor tissues, but none were dominant in non-tumor tissues. HBV carrying ΔSP was unable to produce S protein in vitro. Immunocytofluorescence assay showed that the ΔSP LHBs mutant aggregated in the cytoplasm, accumulating mainly in the ER. Transient transfection and expression of ΔSP mutant caused GRP78 up-regulation in vitro.Conclusion HBV S promoter deletion was found dominantly in HCC tumor tissue. The aggregation of mutant large surface proteins in the ER possibly involved in HBV-related HCC.
基金supported by the Deutsche Forschungsgemeinschaft(RTG1949/2)the National Natural Science Foundation of China(82202497).
文摘Hepatitis B virus(HBV)produces and releases various particle types,including complete virions,subviral particles with envelope proteins,and naked capsids.Recent studies demonstrate that HBV exploits distinct intracellular membrane trafficking pathways,including the endosomal vesicle trafficking and autophagy pathway,to assemble and release viral and subviral particles.Herein,we summarize the findings about the distinct roles of autophagy and endosomal membrane trafficking and the interaction of both pathways in HBV replication,assembly,and release.
基金supported by the National Natural Science Foundation of China (No.60878056)the Doctoral Foundation of Xi’an Jiaotong University (DFXJTU2004-12)
文摘Objective To explore the optimal primer ratio and concentration of asymmetric polymerase chain reaction (A-PCR) in producing hepatitis B virus (HBV) single-stranded DNA (ssDNA) for pyrosequencing. Methods A-PCR was carried out to generate HBV ssDNA with forward to reverse primers of different ratios (50∶1, 100∶1) and concentrations (13.0 pmol/25μL and 0.14 pmol/25μL, 19.5 pmol/25μL and 0.21 pmol/25μL), and the product yield and quality were compared respectively. Results The forward to reverse primer ratio of 50∶1 provided better yield and concentration of 19.5 pmol/25μL and 0.21 pmol//25μL generated a clearer band. Conclusion A simple and feasible method to produce HBV ssDNA for pyrosequencing in batch is established.
文摘Covalently closed circular(ccc)DNA of hepatitis B virus(HBV)existed in the nuclei of HBV infected hepatocytes with a half-life time of 14.3 years in a mathmatic model.Viral protein feedback regulation in HBV life cycle to maintain vital viral replication is an important mechanism.Interleukin-6,epithelial growth factor,heme oxygenase-1,histones,and hepatocyte nuclear factors are demonstrated as the key regulators for HBV life cycle.CpG island structure and methylation status are involved in the regulation of HBV DNA replication.Nucleos(t)ide analogues are widely used in the clinical practice for the treatment of chronic hepatitis B patients,although no evidence indicating a direct inhibiton of HBV cccDNA.In the future,along with the study of HBV life cycle,new drugs including RNA interference technique,will pave the way to eliminate the HBV cccDNA from infected hepatocytes resulting final cure of chronic hepatitis B.
文摘Reversible phosphorylation and dephosphorylation play important roles in cell function and cell signal transduction. PPP2R5A (protein phosphatase 2 regulatory subunit B’ alpha) is responsible for specifically regulating the catalytic function, substrate specificity and intracellular localization of the tumor suppressor phosphatase PP2A (serine/threonine protein phosphatase 2A). Therefore, the abnormal expression and function of PPP2R5A may be related to canceration. The aim of this study was to reveal its role in the occurrence and development of hepatocellular carcinoma (HCC). It is hoped that the results of this study can provide guidance for the prevention and treatment of HCC. The results showed that PPP2R5A inhibited the proliferation and metastasis of HCC cells, and acted as a tumor suppressor in HCC cells, but it had no significant effect on cell cycle. Further research found that PPP2R5A exerted tumor suppressor efficacy by inhibiting the MAPK/AKT/WNT signaling pathway. Combined with analysis of clinical tissue samples and TCGA database, it was found that the expression of PPP2R5A in tumor tissues of Chinese HCC patients was down-regulated and significantly correlated with the progression-free survival (PFS) of HCC patients. On the contrary, PPP2R5A showed an up-regulation trend in HCC cases in TCGA database although its effect on PFS was the same with that in Chinese HCC patients. Hepatitis B virus (HBV) infection is the main pathogenic factor of HCC in China. It was found that HBV infection reduced the content of PPP2R5A in cells. It was concluded that HBV inhibited the initiation of the protective mechanism mediated by PPP2R5A, making the occurrence and progress of HCC more “unimpeded”. This conclusion will further reveal the role of PPP2R5A in HBV-induced and HBV-unrelated HCC, therefore, providing clues for the prevention and treatment of the two types of HCC, respectively.
基金supported by the National Natural Science Foundation of China(No.82170605)the Guangdong Basic and Applied Basic Research Foundation(No.2021B1515120069)Shenzhen Science and Technology Program(JCYJ20210324123212033).
文摘Background and aims:Hepatitis B virus(HBV)infection is a major global health problem which progresses to liver cirrhosis(LC)and hepatocellular carcinoma(HCC).Early prediction of disease changes and intervention are essential to slow disease progression and protect liver function.This study aimed to analyze the clinical characteristics of patients with HBV-related LC and HCC at different serum alanine aminotransferase(ALT)levels and explore the risk factors of HBV infection progressing to LC/HCC.Methods:A total of 379 patients with HBV infection treated in The Third People's Hospital of Shenzhen between January 2014 and December 2016 without any antiviral drug therapy were enrolled.Patients were divided into the LC/HCC and non-LC/HCC groups based on clinical diagnosis,which was determined through imaging and expressions of pathological and laboratory test markers,and patients with LC/HCC were further divided into three groups according to the serum ALT levels.Differences in general information,clinical symptoms,and expression levels of serological indices of the above groups were compared and analyzed,logistic regression was used to analyze the risk factors for LC/HCC development,and the clinical diagnostic efficacy of indicators was judged by the receiver operator characteristic(ROC).Results:LC/HCC mainly occurred in the ALT normal and mildly elevated groups,with 70.83% of patients with HCC having an LC background.In the comparison of different ALT level groups,the moderately eseverely elevated group had the highest proportion of patients with skin jaundice,abdominal varices,rebound tenderness,higher white blood cell and neutrophil(NEUT)counts;and higher levels of aspartate aminotransferase,glutamyl transpeptidase,total bilirubin,and direct bilirubin.The LC/HCC group was older and had significantly higher proportions of male patients,alcohol consumption,and combined hypertension than the non-LC/HCC group(all P<0.05).Logistic regression analysis showed that age,combined hypertension,abdominal varicose veins,subcostal palpation,and NEUT count were risk factors for LC/HCC development;and the area under the curve for this model on the ROC analysis was 0.935(95%confidence interval 0.899e0.972)with specificity and sensitivity of 97.4%and 70.7%,respectively.
基金Publication of this article was supported by a Research to Prevent Blindness unrestricted core grant(Albert Einstein College of Medicine-Grant number:340844).
文摘Background:To evaluate the association between corneal central endothelial cell count(CECC)with reactivity for hepatitis B virus(HBV),hepatitis C virus(HCV),human immunodeficiency virus(HIV),human T-lymphotropic virus-1(HTLV1),and syphilis from an eye bank database.Methods:Eye bank data included 19,159 donors and 38,318 corneas screened for HBV,HCV,HIV,HTLV1,and syphilis from July 2007-May 2015.Linear and binary mixed effects models were used to determine the adjusted marginal effect a positive viral screening test had on CECC and morphology,respectively.The models were adjusted for age,race,gender,lens status,and death to preservation.Eyes with missing data were excluded from the analysis.Statistical significance was defined as P values<0.05.Results:A total of 18,097 donors and 35,136 corneas were included in the final analysis.Average CECC for eyes with negative viral screening was 2,597±436 while the average CECC for eyes screening positive for syphilis,HBV,HCV,HIV,and HTLV1 were 2,638±392(P=0.073),2,569±419(P=0.815),2,603±363(P=0.207),2,615±360(P=0.733),and 2,625±436(P=0.362)respectively.Conclusions:The presence of HBV,HCV,HIV,HTLV1,and syphilis display no association with a statistically significant difference in CECC when compared to normal non-diseased donors.
文摘Hepatitis B virus(HBV)is regarded as a stealth virus,invading and replicating efficiently in human liver undetected by host innate antiviral immunity.Here,we show that type I interferon(IFN)induction but not its downstream signaling is blocked by HBV replication in HepG2.2.15 cells.This effect may be partially due to HBV X protein(HBx),which impairs IFNβpromoter activation by both Sendai virus(SeV)and components implicated in signaling by viral sensors.As a deubiquitinating enzyme(DUB),HBx cleaves Lys63-linked polyubiquitin chains from many proteins except TANK-binding kinase 1(TBK1).It binds and deconjugates retinoic acid-inducible gene I(RIG I)and TNF receptor-associated factor 3(TRAF3),causing their dissociation from the downstream adaptor CARDIF or TBK1 kinase.In addition to RIG I and TRAF3,HBx also interacts with CARDIF,TRIF,NEMO,TBK1,inhibitor of kappa light polypeptide gene enhancer in B-cells,kinase epsilon(IKKi)and interferon regulatory factor 3(IRF3).Our data indicate that multiple points of signaling pathways can be targeted by HBx to negatively regulate production of type I IFN.
基金supported by the Key Project of Hubei Province Natural Science Foundation(2014CFA075)the National Natural Science Foundation of China(31400153)the Applied Basic Research Program(2015060101010033),Wuhan,China
文摘Chronic hepatitis B infection is caused by hepatitis B virus(HBV) and a total cure is yet to be achieved. The viral covalently closed circular DNA(ccc DNA) is the key to establish a persistent infection within hepatocytes. Current antiviral strategies have no effect on the pre-existing ccc DNA reservoir. Therefore, the study of the molecular mechanism of ccc DNA formation is becoming a major focus of HBV research. This review summarizes the current advances in ccc DNA molecular biology and the latest studies on the elimination or inactivation of ccc DNA, including three major areas:(1) epigenetic regulation of ccc DNA by HBV X protein,(2) immune-mediated degradation,and(3) genome-editing nucleases. All these aspects provide clues on how to finally attain a cure for chronic hepatitis B infection.
基金the National Natural Science Foundation of China(project no.81971936)Hubei Province's Outstanding Medical Academic Leader Program,Foundation for Innovative Research Groups of the Natural Science Foundation of Hubei(project no.2020CFA015)the Funda-mental Research Funds for the Central Universities(project no.2042022kf1215 and 2042021gf0013)and Basic and Clinical Medical Research Joint Fund of Zhongnan Hospital,Wuhan University.
文摘Commensal microbiota is closely related to Hepatitis B virus(HBV)infection.Gut bacteria maturation accelerates HBV immune clearance in hydrodynamic injection(HDI)HBV mouse model.However,the effect of gut bacteria on HBV replication in recombinant adeno-associated virus(AAV)-HBV mouse model with immune tolerance remains obscure.We aim to investigate its role on HBV replication in AAV-HBV mouse model.C57BL/6 mice were administrated with broad-spectrum antibiotic mixtures(ABX)to deplete gut bacteria and intravenously injected with AAV-HBV to establish persistent HBV replication.Gut microbiota community was analyzed by fecal qPCR assay and 16S ribosomal RNA(rRNA)gene sequencing.HBV replication markers in blood and liver were determined by ELISA,qPCR assay and Western blot at indicated time points.Immune response in AAV-HBV mouse model was activated through HDI of HBV plasmid or poly(I:C)and then detected by quantifying the percentage of IFN-γ^(+)/CD8^(+)T cells in the spleen via flow cytometry as well as the splenic IFN-γmRNA level via qPCR assay.We found that antibiotic exposure remarkably decreased gut bacteria abundance and diversity.Antibiotic treatment failed to alter the levels of serological HBV antigens,intrahepatic HBV RNA transcripts and HBc protein in AAV-HBV mouse model,but contributed to HBsAg increase after breaking of immune tolerance.Overall,our data uncovered that antibiotic-induced gut bacteria depletion has no effect on HBV replication in immune tolerant AAV-HBV mouse model,providing new thoughts for elucidating the correlation between gut bacteria dysbiosis by antibiotic abuse and clinical chronic HBV infection.
基金the National Natural Science Foundation of China(82172256,92169105,81861138044,and M-0060)the National Scientific and Technological Major Project of China(2017ZX10202203)the Sino-German Virtual Institute for Viral Immunology.
文摘Chronic hepatitis B virus(HBV)infection remains a major public health concern globally,and T cell responses are widely believed to play a pivotal role in mediating HBV clearance.Accordingly,research on the characteristics of HBV-specific T cell responses,from activation to exhaustion,has advanced rapidly.Here,we summarize recent developments in characterizing T cell immunity in HBV infection by reviewing basic and clinical research published in the last five years.We provide a comprehensive summary of the mechanisms that induce effective anti-HBV T cell immunity,as well as the latest developments in understanding T cell dysfunction in chronic HBV infection.Furthermore,we briefly discuss current novel treatment strategies aimed at restoring anti-HBV T cell responses.
基金the National Natural Science Foundation of China(81971921,81971931)the National base cultivation project(20DZ2210404)the Major science and technology project for the prevention and treatment of major infectious diseases(2018ZX10301208)。
文摘Hepatitis B virus(HBV)is a primary cause of chronic liver diseases in humans.HBV infection exhibits strict host and tissue tropism.HBV core promoter(Cp)drives transcription of pregenomic RNA(pg RNA)and plays a key role in the viral life cycle.Hepatocyte nuclear factor 4α(HNF4α)acts as a major transcriptional factor that stimulates Cp.In this work,we reported that BEL7404 cell line displayed a high efficiency of DNA transfection and high levels of HBV antigen expression after transfection of HBV replicons without prominent viral replication.The introduction of exogenous HNF4αand human sodium taurocholate cotransporting polypeptide(h NTCP)expression into BEL7404made it permissive for HBV replication and susceptible to HBV infection.BEL7404-derived cell lines with induced HBV permissiveness and susceptibility were constructed by stable co-transfection of h NTCP and Tet-inducible HNF4αfollowed by limiting dilution cloning.HBV replication in such cells was sensitive to inhibition by nucleotide analog tenofovir,while the infection was inhibited by HBV entry inhibitors.This cell culture system provides a new and additional tool for the study of HBV replication and infection as well as the characterization of antiviral agents.
基金This work was supported by funding from the National Natural Science Foundation of China(81672004 and 31270202)the Chinese Ministry of Science and Technology(2018ZX10302104-001-010)+3 种基金Science and Technology Department of Jilin Province(20160101044JC and 20190101003JH)Health Commission of Jilin Province(2016J065)the Key Laboratory of Molecular Virology,Jilin Province(20102209)Norman Bethune Program of Jilin University(2015331)to Baisong Zheng.
文摘Our recent study reported that ATP1B3 inhibits hepatitis B virus(HBV)replication via inducing NF-κB activation.However,ATP1B3 mutants which were defective in NF-κB activation still maintained the moderate degree of suppression on HBV replication,suggesting that another uncharacterized mechanism is also responsible for ATP1B3-mediated HBV suppression.Here,we demonstrated that ATP1B3 reduced the expression of HBV envelope proteins LHBs,MHBs and SHBs,but had no effect on intracellular HBV DNA,RNA levels as well as HBV promoter activities.Further investigation showed that proteasome inhibitor MG132 rescued ATP1B3-mediated envelope proteins degradation,demonstrating that proteasome-dependent pathway is involved in ATP1B3-induced degradation of envelope proteins.Co-IP showed that ATP1B3 interacts with LHBs and MHBs and induces LHBs and MHBs polyubiquitination.Immunofluorescence colocalization analysis confirmed LHBs and MHBs colocalized with ATP1B3 together.Our work provides important information for targeting ATP1B3 as a potential therapeutic molecule for HBV infection.
基金This work was supported by a scholarship from the Medical Faculty of University Duisburg-Essenthe Foundation for Innovative Research Groups of Hubei Provincial Natural Science Foundation(2018CFA031)+1 种基金Hubei Province’s Outstanding Medical Academic Leader Program,the National Natural Science Foundation of China(No.81974079)the Key R&D Program of Hunan province(No.2020SK30291)。
文摘Mammalian target of rapamycin(m TOR) is a conserved Ser/Thr kinase that includes m TOR complex(m TORC) 1 and m TORC2. The m TOR pathway is activated in viral hepatitis, including hepatitis B virus(HBV) infection-induced hepatitis.Currently, chronic HBV infection remains one of the most serious public health issues worldwide. The unavailability of effective therapeutic strategies for HBV suggests that clarification of the pathogenesis of HBV infection is urgently required. Increasing evidence has shown that HBV infection can activate the m TOR pathway, indicating that HBV utilizes or hijacks the m TOR pathway to benefit its own replication. Therefore, the m TOR signaling pathway might be a crucial target for controlling HBV infection. Here, we summarize and discuss the latest findings from model biology research regarding the interaction between the m TOR signaling pathway and HBV replication.
基金This work was supported by the Science and Technology Pro-gram of Guangzhou,China(No.202002030044).
文摘Background and aims:Effective hepatic blood flow(EHBF)decreases with liver disease progression,and identifying liver pathology is critical for patients with liver disease.This study was designed to elucidate the correlation between EHBF and liver pathology and explore the potential of EHBF for predicting the degree of liver pathology.Methods:In this study,207 patients with hepatitis B virus(HBV)who underwent liver biopsy and indocyanine green(ICG)clearance tests were enrolled.EHBF was measured using the ICG clearance test,and liver tissue was histologically analyzed to determine the pathological stage according to the Scheuer scoring system.Demographic data,biochemical indexes,and FibroScan data were collected for statistical analysis.Results:EHBF levels decreased as the liver histological stages of inflammation and fibrosis increased(P<0.01).EHBF was significantly negatively associated with the levels of alanine aminotransferase,aspartate aminotransferase,gamma-glutamyl transpeptidase,alkaline phosphatase,aspartate aminotransferase-to-platelet ratio index,fibrosis index based on the four factors,and liver stiffness measurement(P<0.05).The EHBF levels of patients without liver inflammation(G0)were significantly higher than those of patients with liver inflammation(G1e4)(P<0.001).The area under the receiver operating characteristic curve(AUROC)value for discriminating patients without liver inflammation was 0.827,and the optimal cutoff value was 0.936 L/min.The EHBF levels of patients with severe liver inflammation(G4)were significantly lower than those of patients with G0e3 liver inflammation(P<0.001).The AUROC value for discriminating patients with severe liver inflammation was 0.792,and the optimal cutoff value was 0.552 L/min.The EHBF levels of patients without liver fibrosis(S0)were significantly higher than those of patients with liver fibrosis(S1e4)(P<0.001).The AUROC value for discriminating patients without liver fibrosis was 0.633,and the optimal cutoff value was 1.173 L/min.The EHBF levels of patients with liver cirrhosis(S4)were significantly lower than those of patients with S0e3 liver fibrosis(P<0.001).The AUROC value for discriminating patients with liver cirrhosis(S4)was 0.630,and the optimal cutoff value was 0.562 L/min.Conclusions:EHBF levels and liver pathology are significantly correlated.EHBF could effectively reflect liver inflammation and fibrosis in patients infected with HBV,especially for patients without liver inflammation or liver fibrosis.
基金This work was supported by USA National Institutes of Health(NIH)grants AI125350,AI085087 and AI139234 to A.Siddiqui.
文摘Autophagy is a self-eating process,in which the damaged or excessed cell organelles and misfolded protein aggregates are removed from the cellular microenvironment.Autophagy is generally thought of as a pro-survival mechanism which is not only important for balancing energy supply at times of nutrient deprivation but also in the removal of various stress stimuli to ensure homeostasis.In addition to the target materials of“self”origin,autophagy can also eliminate intracellular pathogens and acts as a defense mechanism to curb infections.In addition,autophagy is linked to the host cell's innate immune response.However,viruses have evolved various strategies to manipulate and overtake host cell machinery to establish productive replication and maintain infectious process.In fact,replication of many viruses has been found to be autophagy-dependent and suppression of autophagy can potentially affect the viral replication.Thus,autophagy can either serve as an anti-viral defense mechanism or a pro-viral process that supports viral replication.Hepatitis B virus(HBV)and hepatitis C virus(HCV)are known to co-opt cellular autophagy process as a pro-viral tool.Both viruses also induce mitophagy,which contributes to the establishment of chronic hepatitis.This review focuses on the roles of autophagy and mitophagy in the chronic liver disease pathogenesis associated with HBV and HCV infections.
基金This work was supported by the grant from Zhuhai Medical and Health Technology Project(20181117E030074)the Department of Science and Technology of Guangdong Province of China(2021A1515010458).
文摘Background and aim:Several effective antiviral drugs are now available;however,the risk of liver-related complications is still present.Low-level viremia(LLV),defined as a hepatitis B virus(HBV)deoxy-ribonucleic acid(DNA)load lower than 2000 IU/mL,is one of the major factors responsible for these complications.It has been reported that 22.7e43.1%of patients with HBV experience LLV.Herein,we aimed to explore the risk factors for very LLV(VLLV)during antiviral treatment.Methods:We collected data of patients with chronic hepatitis B(CHB)who received nucleos(t)ide analog treatment from October 2016 to April 2021.VLLV was defined as an HBV DNA load of 9e20 IU/mL.A total of 139 patients with LLV were matched with 139 patients with a sustained virological response at a 1:1 ratio according to age and gender.Results:Seropositivity rates for hepatitis B e antigen(HBeAg)(45.3%vs.17.3%,P<0.001)and hepatitis B surface antigen(HBsAg,3.11±0.68 lg IU/mL vs.2.54±1.04 lg IU/mL,P<0.001)and alanine amino-transferase levels(30.34±15.08 U/L vs.26.15±16.66 U/L,P¼0.040)in the two groups were significantly different.The multivariate analysis showed that both HBeAg seropositivity(adjusted odd ratio(aOR),3.63;95% confidence interval(CI):1.98±6.64;P<0.001)and HBsAg levels(aOR,2.21;95% CI:1.53±3.20;P<0.001)are independent risk factors for VLLV.During the multivariate analysis in the subgroup of HBeAg-positive patients,male gender(aOR,3.68;95% CI:1.23±10.76;P=0.017)and high HBsAg(aOR,4.86;95%CI:1.73e13.64;P¼0.003)levels were significantly correlated with VLLV.However,this was not the case in HBeAg-negative patients(P>0.050).HBeAg seropositivity(aOR,5.08;95% CI:2.15±12.02;P<0.001 vs.aOR,2.78;95% CI:1.16±7.00;P=0.022)and HBsAg levels(aOR,2.75;95% CI:1.41e5.37;P=0.003 vs.aOR,2.10;95% CI:1.27±3.46;P=0.004)significantly increased the risk of VLLV,irrespective of the age group.Both HBsAg(area under the receiver operating characteristic curve(AUC),0.681;95% CI:0.623±0.736;P<0.001)and HBeAg(AUC,0.640;95% CI:0.581±0.697;P<0.001)had certain pre-dictive value for VLLV.Conclusion:HBeAg seropositivity and higher HBsAg levels were not only risk factors for VLLV but also predicted its occurrence.When a patient with CHB remains HBeAg seropositive with high HBsAg levels after antiviral treatment for 48 weeks,emphasis should be placed on the potential occurrence of VLLV,warranting the use of highly sensitive HBV DNA detection methods.
基金supported by grants from the National Nature Science Foundation of China (31770180)。
文摘Hepatitis B virus(HBV) belongs to Hepadnaviridae family and mainly infects hepatocytes, which can cause acute or chronic hepatitis. Currently, two types of antiviral drugs are approved for chronic infection clinically: interferons and nucleos(t)ide analogues. However, the clinical cure for chronic infection is still rare, and it is a huge challenge for all researchers to develop high-efficiency, safe, non-tolerant, and low-toxicity anti-HBV drugs. Antazoline hydrochloride is a first-generation antihistamine with anticholinergic properties, and it is commonly used to relieve nasal congestion and in eye drops. Recently, an in vitro high-throughput evaluation system was constructed to screen nearly 800 compounds from the Food and Drug Administration(FDA)-approved Drug Library. We found that arbidol hydrochloride and antazoline hydrochloride can effectively reduce HBV DNA in the extracellular supernatant in a dose-dependent manner, with EC_(50) of4.321 lmol/L and 2.910 lmol/L in HepAD38 cells, respectively. Moreover, the antiviral effects and potential mechanism of action of antazoline hydrochloride were studied in different HBV replication systems. The results indicate that antazoline hydrochloride also has a significant inhibitory effect on HBV DNA in the extracellular supernatant of Huh7 cells,with an EC_(50) of 2.349 lmol/L. These findings provide new ideas for screening and research related to HBV agents.
