In this paper,we study a mathematical model of Hepatitis C Virus(HCV)infection.We present a compartmental mathematical model involving healthy hepatocytes,infected hepatocytes,non-activated dendritic cells,activated d...In this paper,we study a mathematical model of Hepatitis C Virus(HCV)infection.We present a compartmental mathematical model involving healthy hepatocytes,infected hepatocytes,non-activated dendritic cells,activated dendritic cells and cytotoxic T lymphocytes.The derivative used is of non-local fractional order and with non-singular kernel.The existence and uniqueness of the system is proven and its stability is analyzed.Then,by applying the Laplace Adomian decomposition method for the fractional derivative,we present the semi-analytical solution of the model.Finally,some numerical simulations are performed for concrete values of the parameters and several graphs are plotted to reveal the qualitative properties of the solutions.展开更多
Objective:To explore the application value of magnetic particle chemiluminescence method in the detection of hepatitis C virus(HCV)IgM,IgG and other antibody indicators in mice.Methods:A total of 90 mice with HCV were...Objective:To explore the application value of magnetic particle chemiluminescence method in the detection of hepatitis C virus(HCV)IgM,IgG and other antibody indicators in mice.Methods:A total of 90 mice with HCV were selected as the research objects.All the mice were tested for HCV IgM and IgA antibody,and then their venous blood samples were taken to detect the antibody index by enzyme-linked immunosorbent assay,magnetic particle chemiluminescence method and indirect agglutination method,and the results and positive rates of the three groups were compared.Results:There was no significant difference in the positive rate among the three groups(P>0.05).The specificity,accuracy and sensitivity of indirect agglutination test for IgM were 90.79%,80.00%and 30.00%,respectively.The specificity,accuracy and sensitivity of magnetic particle chemiluminescence assay were 97.44%,93.33%and80.00%,respectively.The specificity,accuracy and sensitivity of indirect agglutination assay were significantly lower than those of magnetic particle chemiluminescence assay(P<0.05).For IgA,the specificity,accuracy and sensitivity of indirect agglutination assay were 90.67%,78.66%and 20.00%,respectively.The specificity,accuracy and sensitivity of magnetic particle chemiluminescence assay were 96.25%,92.35%and80.00%,respectively.The specificity,accuracy and sensitivity of indirect agglutination assay were lower than those of magnetic particle chemiluminescence assay,and the difference was statistically significant(P<0.05).Conclusion:The magnetic particle chemiluminescence method is more effective in the detection of IgM,IgG and other antibodies in mice with HCV.展开更多
Objective To investigate the biological function of NS5ABP37 and to look for proteins interacting with NS5ABP37 protein in hepatocytes.Methods We constructed bait plasmid expressing NS5ABP37 protein of hepatitis C vir...Objective To investigate the biological function of NS5ABP37 and to look for proteins interacting with NS5ABP37 protein in hepatocytes.Methods We constructed bait plasmid expressing NS5ABP37 protein of hepatitis C virus(HCV)by cloning the gene of NS5ABP37 protein into pGBKT7,then the recombinant plasmid DNA was transformed into yeast AH109(α type).The transformed yeast AH109 was mated with yeast Y187(α type)containing liver cDNA library plasmid in 2×YPDA medium.Diploid yeast was plated on synthetic dropout nutrient medium(SD/-Trp-Leu-His-Ade)containing X-α-gal for selection and screening.After extracting and sequencing of plasmids from positive(blue)colonies,we made a sequence analysis by bioinformatics.Results We screened twenty-five proteins binding to NS5ABP37,including Homo sapiens cyclin I(CCNI)gene,Homo sapiens matrix metallopeptidase 25(MMP25)and Homo sapiens talin 1.Conclusion The yeast-two hybrid system is an effective method for identifying hepatocyte proteins interacting with NS5ABP37 of HCV.And the biological function of NS5ABP37 may be associated with glycometabolism,lipid metabolism and apoptosis.展开更多
Although direct-acting antivirals(DAAs)have notably increased the sustained virological response(SVR)rates in hepatitis C virus(HCV)-infected adolescent patients,the efficacy and safety for young children under 3 year...Although direct-acting antivirals(DAAs)have notably increased the sustained virological response(SVR)rates in hepatitis C virus(HCV)-infected adolescent patients,the efficacy and safety for young children under 3 years old remain unclear.Currently,no guidelines recommend DAA therapy for this situation worldwide.Furthermore,the China National Medical Products Administration has not approved any DAA for treating children below 12 years old.Here,we described the characteristics of two children approximately 2 years old,who were infected by HCV genotype 1b and had significant clinical symptoms.Both received 12 weeks of ledipasvir/sofosbuvir(Case 1:45.00 mg/200 mg per day,weight 17 kg;Case 2:33.75 mg/150 mg per day,weight 12 kg).They achieved SVR at 12 weeks after treatment completion without obvious treatment-related adverse effects.Therefore,the safety and benefits of ledipasvir/sofosbuvir treatment in children under 3 years old seem to be confirmed.Our findings require further evaluation.展开更多
RNAi interference(RNAi)is an evolutionarily conserved post-transcriptional gene silencing mechanism and has been well recognized as an important antiviral immunity in eukaryotes.Numerous viruses have been shown to enc...RNAi interference(RNAi)is an evolutionarily conserved post-transcriptional gene silencing mechanism and has been well recognized as an important antiviral immunity in eukaryotes.Numerous viruses have been shown to encode viral suppressors of RNAi(VSRs)to antagonize antiviral RNAi.Hepatitis C virus(HCV)is a medically important human pathogen that causes acute and chronic hepatitis.In this study,we screened all the nonstructural proteins of HCV and found that HCV NS2 could suppress RNAi induced either by small hairpin RNAs(shRNAs)or small interfering RNAs(siRNAs)in mammalian cells.Moreover,we demonstrated that NS2 could suppress RNAi via its direct interaction with doublestranded RNAs(dsRNAs)and siRNAs,and further identified that the cysteine 184 of NS2 is required for the RNAi suppression activity through a serial of point mutation analyses.Together,our findings uncovered that HCV NS2 can act as a VSR in vitro,thereby providing novel insights into the life cycle and virus-host interactions of HCV.展开更多
Hepatitis C virus(HCV) infects approximately 180 million people worldwide. Significant progress has been made since the establishment of in vitro HCV infection models in cells. However, the replication of HCV is compl...Hepatitis C virus(HCV) infects approximately 180 million people worldwide. Significant progress has been made since the establishment of in vitro HCV infection models in cells. However, the replication of HCV is complex and not completely understood. Here, we found that the expression of host prion protein(Pr P) was induced in an HCV replication cell model. We then showed that increased Pr P expression facilitated HCV genomic replication. Finally, we demonstrated that the KKRPK motif on the N-terminus of Pr P bound nucleic acids and facilitated HCV genomic replication. Our results provided important insights into how viruses may harness cellular protein to achieve propagation.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 aims:To investigate the safety and efficacy of direct-acting antiviral(DAA)regimens in a cohort of Chinese patients with chronic hepatitis C virus(HCV)infection.Methods:A total of 222 adult Chinese pati...Background and aims:To investigate the safety and efficacy of direct-acting antiviral(DAA)regimens in a cohort of Chinese patients with chronic hepatitis C virus(HCV)infection.Methods:A total of 222 adult Chinese patients were enrolled and treated via DAA regimens in accor-dance with HCV management guidelines.Treatment responses were evaluated 4 weeks after treatment,at the end of treatment(EOT)and 12 weeks post-treatment.Virological responses,biochemical re-sponses,model for end-stage liver disease(MELD)and Child-Pugh(CP)scores were recorded.Results:A total of 218 patients(98.2%)achieved sustained virological response 12 weeks post-treatment and 4 patients relapsed.The combined number of rapid virological responses for all six regimens was 170/222(76.6%),and 221/222(99.6%)had achieved virological responses by the end of treatment.In decompensated cirrhosis patients the baseline mean CP score was 6.8±1.3 and the mean MELD score was 10.1±3.3.Compared with the mean CP score at baseline,the mean score is significantly lower at the end of treatment(5.7±1.3)and 12 weeks post-treatment(5.6±1.0).Estimated glomerular filtration rates did not differ significantly from baseline during the treatment or 12 weeks post-treatment.The incidence of adverse events in patients with chronic hepatitis C and compensated cirrhosis was 42/172(24.4%),and in patients with decompensated cirrhosis it was 8/22(36.4%).The most frequently reported adverse events were elevated indirect bilirubin,fatigue and rash.There were no cases of serious adverse events,death or treatment discontinuation because of adverse events.Conclusion:DAA regimens were highly effective and well tolerated irrespective of HCV genotype,cirrhosis,liver or kidney transplantation,hepatocellular carcinoma,HCV/hepatitis B virus co-infection,or renal failure.展开更多
Background and Aims:Genotype(GT)1 remains the predominant hepatitis c virus(HCV)GT in Chinese patients.Over 80%of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860,which is favorable ...Background and Aims:Genotype(GT)1 remains the predominant hepatitis c virus(HCV)GT in Chinese patients.Over 80%of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860,which is favorable for interferon-based treatment regimens.This phaseⅢclinical trial aimed to evaluate the efficacy and safety of the ritonavirboosted danoprevir plus pegylated-interferonα-2a and ribavirin regimen for 12 weeks in treatment-na(i)ve mainland Chinese patients infected with HCV GT1 without cirrhosis.Methods:One hundred and forty-one treatment-na(i)ve,non-cirrhotic HCV GT1 Chinese patients(age≥18 years)were enrolled for this single-arm,multicenter,phaseⅢMANASA study(NCT03020082).Patients received a combination of ritonavir-boosted danoprevir(100 mg/100 mg)twice a day plus subcutaneous injection of weekly pegylated-interferonα-2a(180μg)and oral ribavirin(1000/1200 mg/day body weight<75/≥75 kg)for 12 weeks.The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment.The secondary end-points were safety outcomes,tolerability,virologic response over time and relapse rate.Results:All enrolled patients were HCV GT1-infected,and most among them(97.9%,123/141)had the HCV GT1b subtype.Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype(87.2%,123/141).Overall,140 patients completed the 12-week treatment,and 97.1%(136/140)patients achieved sustained virologic response at 12 weeks(per protocol population group,95%confidence interval:92.9-99.2%).Only drug-related serious adverse event occurred.Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction.One patient discontinued treatment because of severe head injury in a car accident.Conclusions:The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferonα-2a and ribavirin produced a sustained virologic response rate of 97.1%after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients,and was safe and well tolerated.展开更多
Hepatitis B virus(HBV)/Hepatitis C virus(HCV)coinfection is frequently observed because of the common infection routine.Despite the reciprocal inhibition exerted by HBV and HCV genomes,the coinfection of HBV and HCV i...Hepatitis B virus(HBV)/Hepatitis C virus(HCV)coinfection is frequently observed because of the common infection routine.Despite the reciprocal inhibition exerted by HBV and HCV genomes,the coinfection of HBV and HCV is associated with more severe forms of liver diseases.However,the complexity of viral interference and underlying pathological mechanism is still unclarified.With the demonstration of absence of direct viral interplay,some in vitro studies suggest the indirect effects of viral-host interaction on viral dominance outcome.Here,we comprehensively investigated the viral replication and host immune responses which might mediate the interference between viruses in HBV/HCV coinfected Huh7-NTCP cells and immunocompetent HCV human receptors transgenic ICR mice.We found that presence of HCV significantly inhibited HBV replication in vitro and in vivo irrespective of the coinfection order,while HBV did not affect HCV replication.Pathological alteration was coincidently reproduced in coinfected mice.In addition to the participation of innate immune response,an involvement of HCV in up-regulating HBV-specific immune responses was described to facilitate HBV clearance.Our systems partially recapitulate HBV/HCV coinfection and unveil the uncharacterized adaptive anti-viral immune responses during coinfection,which renews the knowledge on the nature of indirect viral interaction during HBV/HCV coinfection.展开更多
In clinical practice,many cirrhosis scores based on alanine aminotransferase(ALT)levels exist.Although the most recent direct acting antivirals(DAAs)reduce fibrosis and ALT levels,the Hepatitis C virus(HCV)is not alwa...In clinical practice,many cirrhosis scores based on alanine aminotransferase(ALT)levels exist.Although the most recent direct acting antivirals(DAAs)reduce fibrosis and ALT levels,the Hepatitis C virus(HCV)is not always removed.In this paper,we study a mathematical model of the HCV virus,which takes into account the role of the immune system,to investigate the ALT behavior during therapy.We find five equilibrium points and analyze their stability.A sufficient condition for global asymptotical stability of the infeetion-free equilibrium is obtained and local asymptotical stability conditions are given for the immune-free infection and cytotoxic T lymphocytes(CTL)response equilibria.The stability of the infection equilibrium with the full immune response is numerically performed.展开更多
Background and aim:Hepatitis C virus(HCV)infection is one of the major global health challenges,leading to a significant increase in rates of hepatic fibrosis,cirrhosis and hepatocellular carcinoma.A comprehensive nat...Background and aim:Hepatitis C virus(HCV)infection is one of the major global health challenges,leading to a significant increase in rates of hepatic fibrosis,cirrhosis and hepatocellular carcinoma.A comprehensive nationwide survey of trends in prevalence and associated factors could facilitate pre-ventive behavioral interventions.Herein,we sought to determine prevalence,diagnosis,treatment,and risk factors for HCV infection in the general United States(US)population.Methods:This was a secondary analysis of the publicly available data from the US National Health and Nutrition Examination Survey(NHANES).The prevalence of HCV-RNA-positive(HCV-RNAþ)was weighted using patient serum sample data collected from 1999 to 2018.A propensity score matching model was used due to the imbalance in the number of HCV-RNAþand HCV-RNA-negative(HCV-RNA?)patients.Matched variables included gender,age,educational level,marital status,language,household size,alcohol consumption,smoking,number of family members and family income to poverty ratio.Results:The weighted prevalence of HCV-RNAþwas 1.11%(95%confidence interval(CI):1.02e1.20),1.58%(95%CI:1.42e1.74)for men and 0.67%(95%CI:0.57e0.77)for women aged 20 years or older in the US from 1999 to 2018.The weighted prevalence of HCV-RNAþincreased from 0.87%(95%CI:0.62e1.12)in 2013e2014,0.95%(95%CI:0.68e1.22)in 2015e2016 to 1.00%(95%CI:0.72e1.28)in 2017e2018,respectively.In propensity-matched analysis,patients with HCV-RNAþwere more likely to be non-Hispanic black,and have had drug use and blood transfusions.Meanwhile,the weighted diagnostic and treatment rates were 56.27%(95%CI:50.90e61.64)and 35.40%(95%CI:27.64e43.16)from 1999 to 2018,respectively.Conclusions:Active HCV infection rate increased between 2013 and 2018,varied by demographic and risk variables.In the direct-acting antiviral era,affordable treatment and universal screening have the potential to improve overall national health.展开更多
As the most abundant liver-specific microRNA,mi-croRNA-122(miR-122)is involved in various physio-logical processes in hepatic function as well as in liver pathology.There is now compelling evidence that miR-122,as a r...As the most abundant liver-specific microRNA,mi-croRNA-122(miR-122)is involved in various physio-logical processes in hepatic function as well as in liver pathology.There is now compelling evidence that miR-122,as a regulator of gene networks and pathways in hepatocytes,plays a central role in diverse aspects of hepatic function and in the progress of liver diseases.This liver-enriched transcription factors-regulated miRNA promotes differentiation of hepatocytes and regulates lipid metabolism.With regard to liver diseases,miR-122 was shown to stimulate hepatitis C virus(HCV)replication through a unique and unusual interaction with two binding sites in the 5′-UTR of HCV genome to mediate the stability of the viral RNA,whereas inhibit the expression and replication of hepatitis B virus(HBV)by a miR-122-cylin G1/p53-HBV enhancer regulatory pathway.In addition,miR-122 acts as a suppressor of cell prolif-eration and malignant transformation of hepatocytes with remarkable tumor inhibition activity.Notably,a clinical trial targeting miR-122 with the anti-miR-122 oli-gonucleotides miravirsen,the first miRNA targeted drug,has been initiated for treatment of HCV infection.With further understanding of the comprehensive roles of miR-122 in hepatic functions and the mechanisms in-volved in miR-122 down-regulation in chronic hepatitis or hepatocellular carcinoma,miR-122 appears to be a promising candidate for effective therapeutic ap-proaches against tumor and infectious diseases.展开更多
Hepatocellular carcinoma(HCC)is one of the most common malignant tumors with a low survival rate.The identification of mechanisms underlying the development of HCC helps uncover cellular and mo-lecular targets for the...Hepatocellular carcinoma(HCC)is one of the most common malignant tumors with a low survival rate.The identification of mechanisms underlying the development of HCC helps uncover cellular and mo-lecular targets for the diagnosis,prevention,and treatment of HCC.Golgi protein 73(GP73)level is up-regulated in HCC patients and potentially can be a therapeutic target.Despite many studies devoted to GP73 as a marker for HCC early diagnosis,there is little discussion about the function of GP73 in HCC tumorigenesis.Given the poor response to currently available HCC therapies,a better understanding of the role of GP73 in HCC may provide a new therapeutic target for HCC.The current paper summarizes the role of GP73 as a diagnostic marker as well as its roles in liver carcinogenesis.Its roles in other types of cancer are also discussed.展开更多
Macroautophagy(hereafter autophagy)is a catabolic process by which autophagosomes arising from an isolation membrane fuse with lysosomes to degrade components in the cytoplasm.Autophagosomelysosome fusion step is one ...Macroautophagy(hereafter autophagy)is a catabolic process by which autophagosomes arising from an isolation membrane fuse with lysosomes to degrade components in the cytoplasm.Autophagosomelysosome fusion step is one of the key steps during the process of macroautophagy.The step is extremely complicated and its detailed mechanisms remain unclear.It consists of two phases:first phase is autophagosome migration phase and second phase is fusion of autophagosomes and lysosomes phase.Recently,various molecules have been reported to be involved in each phase.In the first phase,microtubules and actin remodeling mechanism are involved.In the second phase,soluble N-ethylmaleimide-sensitive factor attachment protein receptor(SNARE)proteins,Rab family proteins,phosphoinositide 3-kinase(PI3K)complex and Rubicon are involved.In the present review,we introduce recent findings related to autophagosome-lysosome fusion step and discuss liver diseases possibly associated with autophagosome-lysosome fusion dysfunction.展开更多
基金supported by the Agencia Estatal de Investigacin(AEI)of Spain,co-financed by the European Fund for Regional Development(FEDER)corresponding to the 2014-2020 multiyear financial framework,project PID2020-113275GB-I00Instituto de Salud Carlos II,grant COV20/00617Xunta de Galicia under grant ED431C 2019/02.
文摘In this paper,we study a mathematical model of Hepatitis C Virus(HCV)infection.We present a compartmental mathematical model involving healthy hepatocytes,infected hepatocytes,non-activated dendritic cells,activated dendritic cells and cytotoxic T lymphocytes.The derivative used is of non-local fractional order and with non-singular kernel.The existence and uniqueness of the system is proven and its stability is analyzed.Then,by applying the Laplace Adomian decomposition method for the fractional derivative,we present the semi-analytical solution of the model.Finally,some numerical simulations are performed for concrete values of the parameters and several graphs are plotted to reveal the qualitative properties of the solutions.
文摘Objective:To explore the application value of magnetic particle chemiluminescence method in the detection of hepatitis C virus(HCV)IgM,IgG and other antibody indicators in mice.Methods:A total of 90 mice with HCV were selected as the research objects.All the mice were tested for HCV IgM and IgA antibody,and then their venous blood samples were taken to detect the antibody index by enzyme-linked immunosorbent assay,magnetic particle chemiluminescence method and indirect agglutination method,and the results and positive rates of the three groups were compared.Results:There was no significant difference in the positive rate among the three groups(P>0.05).The specificity,accuracy and sensitivity of indirect agglutination test for IgM were 90.79%,80.00%and 30.00%,respectively.The specificity,accuracy and sensitivity of magnetic particle chemiluminescence assay were 97.44%,93.33%and80.00%,respectively.The specificity,accuracy and sensitivity of indirect agglutination assay were significantly lower than those of magnetic particle chemiluminescence assay(P<0.05).For IgA,the specificity,accuracy and sensitivity of indirect agglutination assay were 90.67%,78.66%and 20.00%,respectively.The specificity,accuracy and sensitivity of magnetic particle chemiluminescence assay were 96.25%,92.35%and80.00%,respectively.The specificity,accuracy and sensitivity of indirect agglutination assay were lower than those of magnetic particle chemiluminescence assay,and the difference was statistically significant(P<0.05).Conclusion:The magnetic particle chemiluminescence method is more effective in the detection of IgM,IgG and other antibodies in mice with HCV.
文摘Objective To investigate the biological function of NS5ABP37 and to look for proteins interacting with NS5ABP37 protein in hepatocytes.Methods We constructed bait plasmid expressing NS5ABP37 protein of hepatitis C virus(HCV)by cloning the gene of NS5ABP37 protein into pGBKT7,then the recombinant plasmid DNA was transformed into yeast AH109(α type).The transformed yeast AH109 was mated with yeast Y187(α type)containing liver cDNA library plasmid in 2×YPDA medium.Diploid yeast was plated on synthetic dropout nutrient medium(SD/-Trp-Leu-His-Ade)containing X-α-gal for selection and screening.After extracting and sequencing of plasmids from positive(blue)colonies,we made a sequence analysis by bioinformatics.Results We screened twenty-five proteins binding to NS5ABP37,including Homo sapiens cyclin I(CCNI)gene,Homo sapiens matrix metallopeptidase 25(MMP25)and Homo sapiens talin 1.Conclusion The yeast-two hybrid system is an effective method for identifying hepatocyte proteins interacting with NS5ABP37 of HCV.And the biological function of NS5ABP37 may be associated with glycometabolism,lipid metabolism and apoptosis.
基金the Special Project of Guangdong Rural Science and Technology Commissioner of China(KTPYJ2021014)。
文摘Although direct-acting antivirals(DAAs)have notably increased the sustained virological response(SVR)rates in hepatitis C virus(HCV)-infected adolescent patients,the efficacy and safety for young children under 3 years old remain unclear.Currently,no guidelines recommend DAA therapy for this situation worldwide.Furthermore,the China National Medical Products Administration has not approved any DAA for treating children below 12 years old.Here,we described the characteristics of two children approximately 2 years old,who were infected by HCV genotype 1b and had significant clinical symptoms.Both received 12 weeks of ledipasvir/sofosbuvir(Case 1:45.00 mg/200 mg per day,weight 17 kg;Case 2:33.75 mg/150 mg per day,weight 12 kg).They achieved SVR at 12 weeks after treatment completion without obvious treatment-related adverse effects.Therefore,the safety and benefits of ledipasvir/sofosbuvir treatment in children under 3 years old seem to be confirmed.Our findings require further evaluation.
基金supported by the Strategic Priority Research Program of Chinese Academy of Sciences(XDB29010300 to X.Z.)the National Natural Science Foundation of China(81873964 to Y.Q.,31670161 to X.Z.and 31800140 to J.M.)+2 种基金the Science and Technology Bureau of Wuhan(2018060401011309 to X.Z.)the Advanced Customer Cultivation Project of Wuhan National Biosafety Laboratory(2018ACCP-MS11 to Y.Q.)supported by the Newton Advanced Fellowship from the Academy of Medical Sciences,UK(NAF005\1002)。
文摘RNAi interference(RNAi)is an evolutionarily conserved post-transcriptional gene silencing mechanism and has been well recognized as an important antiviral immunity in eukaryotes.Numerous viruses have been shown to encode viral suppressors of RNAi(VSRs)to antagonize antiviral RNAi.Hepatitis C virus(HCV)is a medically important human pathogen that causes acute and chronic hepatitis.In this study,we screened all the nonstructural proteins of HCV and found that HCV NS2 could suppress RNAi induced either by small hairpin RNAs(shRNAs)or small interfering RNAs(siRNAs)in mammalian cells.Moreover,we demonstrated that NS2 could suppress RNAi via its direct interaction with doublestranded RNAs(dsRNAs)and siRNAs,and further identified that the cysteine 184 of NS2 is required for the RNAi suppression activity through a serial of point mutation analyses.Together,our findings uncovered that HCV NS2 can act as a VSR in vitro,thereby providing novel insights into the life cycle and virus-host interactions of HCV.
基金supported by the Strategic Priority Research Program A of the Chinese Academy of Sciences(XDA12010309)the National Science Foundation of China(31670170)+1 种基金the Nature Science Foundation of Hubei Province(2015CFA087)the National Basic Research Priorities Program of China(2013CB911102)
文摘Hepatitis C virus(HCV) infects approximately 180 million people worldwide. Significant progress has been made since the establishment of in vitro HCV infection models in cells. However, the replication of HCV is complex and not completely understood. Here, we found that the expression of host prion protein(Pr P) was induced in an HCV replication cell model. We then showed that increased Pr P expression facilitated HCV genomic replication. Finally, we demonstrated that the KKRPK motif on the N-terminus of Pr P bound nucleic acids and facilitated HCV genomic replication. Our results provided important insights into how viruses may harness cellular protein to achieve propagation.
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 Science and Technology Plan-ning Project of Guangdong Province Grant(2014B020212025).
文摘Background and aims:To investigate the safety and efficacy of direct-acting antiviral(DAA)regimens in a cohort of Chinese patients with chronic hepatitis C virus(HCV)infection.Methods:A total of 222 adult Chinese patients were enrolled and treated via DAA regimens in accor-dance with HCV management guidelines.Treatment responses were evaluated 4 weeks after treatment,at the end of treatment(EOT)and 12 weeks post-treatment.Virological responses,biochemical re-sponses,model for end-stage liver disease(MELD)and Child-Pugh(CP)scores were recorded.Results:A total of 218 patients(98.2%)achieved sustained virological response 12 weeks post-treatment and 4 patients relapsed.The combined number of rapid virological responses for all six regimens was 170/222(76.6%),and 221/222(99.6%)had achieved virological responses by the end of treatment.In decompensated cirrhosis patients the baseline mean CP score was 6.8±1.3 and the mean MELD score was 10.1±3.3.Compared with the mean CP score at baseline,the mean score is significantly lower at the end of treatment(5.7±1.3)and 12 weeks post-treatment(5.6±1.0).Estimated glomerular filtration rates did not differ significantly from baseline during the treatment or 12 weeks post-treatment.The incidence of adverse events in patients with chronic hepatitis C and compensated cirrhosis was 42/172(24.4%),and in patients with decompensated cirrhosis it was 8/22(36.4%).The most frequently reported adverse events were elevated indirect bilirubin,fatigue and rash.There were no cases of serious adverse events,death or treatment discontinuation because of adverse events.Conclusion:DAA regimens were highly effective and well tolerated irrespective of HCV genotype,cirrhosis,liver or kidney transplantation,hepatocellular carcinoma,HCV/hepatitis B virus co-infection,or renal failure.
基金Ascletis Pharmaceuticals Co.,Ltd.provided financial support for this study(MANASA)
文摘Background and Aims:Genotype(GT)1 remains the predominant hepatitis c virus(HCV)GT in Chinese patients.Over 80%of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860,which is favorable for interferon-based treatment regimens.This phaseⅢclinical trial aimed to evaluate the efficacy and safety of the ritonavirboosted danoprevir plus pegylated-interferonα-2a and ribavirin regimen for 12 weeks in treatment-na(i)ve mainland Chinese patients infected with HCV GT1 without cirrhosis.Methods:One hundred and forty-one treatment-na(i)ve,non-cirrhotic HCV GT1 Chinese patients(age≥18 years)were enrolled for this single-arm,multicenter,phaseⅢMANASA study(NCT03020082).Patients received a combination of ritonavir-boosted danoprevir(100 mg/100 mg)twice a day plus subcutaneous injection of weekly pegylated-interferonα-2a(180μg)and oral ribavirin(1000/1200 mg/day body weight<75/≥75 kg)for 12 weeks.The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment.The secondary end-points were safety outcomes,tolerability,virologic response over time and relapse rate.Results:All enrolled patients were HCV GT1-infected,and most among them(97.9%,123/141)had the HCV GT1b subtype.Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype(87.2%,123/141).Overall,140 patients completed the 12-week treatment,and 97.1%(136/140)patients achieved sustained virologic response at 12 weeks(per protocol population group,95%confidence interval:92.9-99.2%).Only drug-related serious adverse event occurred.Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction.One patient discontinued treatment because of severe head injury in a car accident.Conclusions:The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferonα-2a and ribavirin produced a sustained virologic response rate of 97.1%after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients,and was safe and well tolerated.
基金supported by National Key Research and Development Program of China(2018YFA0507201 to X.C)the grants from the National Natural Science Foundation of China(81672021 to R.P,31770180 to C.W)。
文摘Hepatitis B virus(HBV)/Hepatitis C virus(HCV)coinfection is frequently observed because of the common infection routine.Despite the reciprocal inhibition exerted by HBV and HCV genomes,the coinfection of HBV and HCV is associated with more severe forms of liver diseases.However,the complexity of viral interference and underlying pathological mechanism is still unclarified.With the demonstration of absence of direct viral interplay,some in vitro studies suggest the indirect effects of viral-host interaction on viral dominance outcome.Here,we comprehensively investigated the viral replication and host immune responses which might mediate the interference between viruses in HBV/HCV coinfected Huh7-NTCP cells and immunocompetent HCV human receptors transgenic ICR mice.We found that presence of HCV significantly inhibited HBV replication in vitro and in vivo irrespective of the coinfection order,while HBV did not affect HCV replication.Pathological alteration was coincidently reproduced in coinfected mice.In addition to the participation of innate immune response,an involvement of HCV in up-regulating HBV-specific immune responses was described to facilitate HBV clearance.Our systems partially recapitulate HBV/HCV coinfection and unveil the uncharacterized adaptive anti-viral immune responses during coinfection,which renews the knowledge on the nature of indirect viral interaction during HBV/HCV coinfection.
文摘In clinical practice,many cirrhosis scores based on alanine aminotransferase(ALT)levels exist.Although the most recent direct acting antivirals(DAAs)reduce fibrosis and ALT levels,the Hepatitis C virus(HCV)is not always removed.In this paper,we study a mathematical model of the HCV virus,which takes into account the role of the immune system,to investigate the ALT behavior during therapy.We find five equilibrium points and analyze their stability.A sufficient condition for global asymptotical stability of the infeetion-free equilibrium is obtained and local asymptotical stability conditions are given for the immune-free infection and cytotoxic T lymphocytes(CTL)response equilibria.The stability of the infection equilibrium with the full immune response is numerically performed.
基金This work was supported by grants from Natural Science Foundation of Guangdong Province (2021A1515010458) of China.
文摘Background and aim:Hepatitis C virus(HCV)infection is one of the major global health challenges,leading to a significant increase in rates of hepatic fibrosis,cirrhosis and hepatocellular carcinoma.A comprehensive nationwide survey of trends in prevalence and associated factors could facilitate pre-ventive behavioral interventions.Herein,we sought to determine prevalence,diagnosis,treatment,and risk factors for HCV infection in the general United States(US)population.Methods:This was a secondary analysis of the publicly available data from the US National Health and Nutrition Examination Survey(NHANES).The prevalence of HCV-RNA-positive(HCV-RNAþ)was weighted using patient serum sample data collected from 1999 to 2018.A propensity score matching model was used due to the imbalance in the number of HCV-RNAþand HCV-RNA-negative(HCV-RNA?)patients.Matched variables included gender,age,educational level,marital status,language,household size,alcohol consumption,smoking,number of family members and family income to poverty ratio.Results:The weighted prevalence of HCV-RNAþwas 1.11%(95%confidence interval(CI):1.02e1.20),1.58%(95%CI:1.42e1.74)for men and 0.67%(95%CI:0.57e0.77)for women aged 20 years or older in the US from 1999 to 2018.The weighted prevalence of HCV-RNAþincreased from 0.87%(95%CI:0.62e1.12)in 2013e2014,0.95%(95%CI:0.68e1.22)in 2015e2016 to 1.00%(95%CI:0.72e1.28)in 2017e2018,respectively.In propensity-matched analysis,patients with HCV-RNAþwere more likely to be non-Hispanic black,and have had drug use and blood transfusions.Meanwhile,the weighted diagnostic and treatment rates were 56.27%(95%CI:50.90e61.64)and 35.40%(95%CI:27.64e43.16)from 1999 to 2018,respectively.Conclusions:Active HCV infection rate increased between 2013 and 2018,varied by demographic and risk variables.In the direct-acting antiviral era,affordable treatment and universal screening have the potential to improve overall national health.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.30970146,91029724,and 81021003).
文摘As the most abundant liver-specific microRNA,mi-croRNA-122(miR-122)is involved in various physio-logical processes in hepatic function as well as in liver pathology.There is now compelling evidence that miR-122,as a regulator of gene networks and pathways in hepatocytes,plays a central role in diverse aspects of hepatic function and in the progress of liver diseases.This liver-enriched transcription factors-regulated miRNA promotes differentiation of hepatocytes and regulates lipid metabolism.With regard to liver diseases,miR-122 was shown to stimulate hepatitis C virus(HCV)replication through a unique and unusual interaction with two binding sites in the 5′-UTR of HCV genome to mediate the stability of the viral RNA,whereas inhibit the expression and replication of hepatitis B virus(HBV)by a miR-122-cylin G1/p53-HBV enhancer regulatory pathway.In addition,miR-122 acts as a suppressor of cell prolif-eration and malignant transformation of hepatocytes with remarkable tumor inhibition activity.Notably,a clinical trial targeting miR-122 with the anti-miR-122 oli-gonucleotides miravirsen,the first miRNA targeted drug,has been initiated for treatment of HCV infection.With further understanding of the comprehensive roles of miR-122 in hepatic functions and the mechanisms in-volved in miR-122 down-regulation in chronic hepatitis or hepatocellular carcinoma,miR-122 appears to be a promising candidate for effective therapeutic ap-proaches against tumor and infectious diseases.
基金This study was supported bygrants funded by the USA National Institutes of Health(NIH)R01CA222490 to Y.-J.Y.Wanalong with grants from the National Natural Science Foundation of China Project number 81602456financial sup-port from the China Scholarship Council(CSC)to Y.Wang.
文摘Hepatocellular carcinoma(HCC)is one of the most common malignant tumors with a low survival rate.The identification of mechanisms underlying the development of HCC helps uncover cellular and mo-lecular targets for the diagnosis,prevention,and treatment of HCC.Golgi protein 73(GP73)level is up-regulated in HCC patients and potentially can be a therapeutic target.Despite many studies devoted to GP73 as a marker for HCC early diagnosis,there is little discussion about the function of GP73 in HCC tumorigenesis.Given the poor response to currently available HCC therapies,a better understanding of the role of GP73 in HCC may provide a new therapeutic target for HCC.The current paper summarizes the role of GP73 as a diagnostic marker as well as its roles in liver carcinogenesis.Its roles in other types of cancer are also discussed.
基金This study is partially supported by Japan MEXT KAKENHI to T.Takehara(18H02795)and by The Japanese Society of Gastroenterology to H.Hikita.
文摘Macroautophagy(hereafter autophagy)is a catabolic process by which autophagosomes arising from an isolation membrane fuse with lysosomes to degrade components in the cytoplasm.Autophagosomelysosome fusion step is one of the key steps during the process of macroautophagy.The step is extremely complicated and its detailed mechanisms remain unclear.It consists of two phases:first phase is autophagosome migration phase and second phase is fusion of autophagosomes and lysosomes phase.Recently,various molecules have been reported to be involved in each phase.In the first phase,microtubules and actin remodeling mechanism are involved.In the second phase,soluble N-ethylmaleimide-sensitive factor attachment protein receptor(SNARE)proteins,Rab family proteins,phosphoinositide 3-kinase(PI3K)complex and Rubicon are involved.In the present review,we introduce recent findings related to autophagosome-lysosome fusion step and discuss liver diseases possibly associated with autophagosome-lysosome fusion dysfunction.
