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
Hepatitis B virus(HBV)establishes chronic infection through strategic manipulation of host metabolic networks,driving a spectrum of hepatic pathologies ranging from hepatitis to cirrhosis and hepatocellular carcinoma....Hepatitis B virus(HBV)establishes chronic infection through strategic manipulation of host metabolic networks,driving a spectrum of hepatic pathologies ranging from hepatitis to cirrhosis and hepatocellular carcinoma.Mechanistically,HBV reprograms core metabolic pathways,including glycolysis,tricarboxylic acid(TCA)cycle,oxidative phosphorylation,and lipid homeostasis,to fuel its replication machinery and evade immune surveillance.This review systematically synthesizes current evidence on HBV-induced glucose/lipid metabolic rewiring,with particular emphasis on how viral-host crosstalk at the metabolic interface sustains viral pathogenesis.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
AIM：To characterize the IFN-response and its modulation by the antiviral compound lamivudine in HBV- transfected HepG2.2.15 cells. METHODS： HepG2.2.15 and HepG2 cells were stimulated with various concentrations of I...AIM：To characterize the IFN-response and its modulation by the antiviral compound lamivudine in HBV- transfected HepG2.2.15 cells. METHODS： HepG2.2.15 and HepG2 cells were stimulated with various concentrations of IFN-α 2a in the presence or absence of lamivudine. Then, total RNA was extracted and analysed by customised cDNA arrays and northern blot for interferon-inducible genes （ISGs）. In addition, cellular proteins were extracted for EMSA and western blot. HBV replication was assessed by southern blot or ELISAs for HBsAg and HBeAg. RESULTS： Two genes （MxA, CigS） with completely abolished and 4 genes （IFITM1, -2, -3, and 6-16） with partially reduced IFN-responses were identified in HepG2.2.15 cells. In 2 genes （IFITM1, 6-16）, the response to IFN-α could be restored by treatment with lamivudine. This effect could not be explained by a direct modulation of the Jak/Stat signalling pathway since EMSA and western blot experiments revealed no suppression of Statl activation and ISGF3 formation after stimulation with IFN-α in HepG2.2.15 compared to HepG2 cells. CONCLUSION： These results are consistent with the assumption that chronic hepatitis B may specifically modulate the cellular response to IFN by a selective blockage of some ISGs. Antiviral treatment with lamivudine may partially restore ISG expressionby reducing HBV gene expression and replication.展开更多
Chronic hepatitis B virus(CHB) is currently treated with either interferon-based or nucleot(s)idebased antiviral therapies.However,treatment with pegylated interferon alpha results in a durable antiviral response in o...Chronic hepatitis B virus(CHB) is currently treated with either interferon-based or nucleot(s)idebased antiviral therapies.However,treatment with pegylated interferon alpha results in a durable antiviral response in only about 30%patients and is associated with side effects.Most patients receiving nucleot(s)ide analogue treatment do not establish long-term,durable control of Infection and have rebounding viremia after cessation of therapy.Thus,novel therapy strategies are necessary to achieve the induction of potent and durable antiviral immune responses of the patients which can maintain long-term control of viral replication.Therapeutic vaccination of HBV carriers is a promising strategy for the control of hepatitis B.Here the authors review new therapeutic vaccination strategies to treat chronic hepatitis B which may be introduced for patient treatment in the future.展开更多
Though efficient vaccines against hepatitis B virus(HBV) and antiviral therapies are available,chronic HBV infection is still a global health problem. The process of HBV infection and HBV life cycle are extensively st...Though efficient vaccines against hepatitis B virus(HBV) and antiviral therapies are available,chronic HBV infection is still a global health problem. The process of HBV infection and HBV life cycle are extensively studied in last decades, however, the mechanisms of HBV-induced alterations of host cell metabolisms and host factors involved in modulating of viral replication are not fully understood. Thus, it is an important issue to examine these specific HBV-host interactions for development of novel strategies for antiviral therapies. Recently, microRNAs(miRNAs), a class of post-transcriptional regulatory small RNA, seem to be the relevant fine tuning factors of various cellular activities and pathways, including cell growth, metabolism, and viral replication. In this review, we summarize the up to date knowledge concerning the virus-host interactions and emphasizing on the role of miRNAs in regulation of HBV replication and host cell metabolism.展开更多
As the open reading frames of hepatitis B virus(HBV)genomes are overlapping,resistance mutations(MTs)in HBV polymerase may result in stop codon MTs in hepatitis B surface proteins,which are usually detected as a mixed...As the open reading frames of hepatitis B virus(HBV)genomes are overlapping,resistance mutations(MTs)in HBV polymerase may result in stop codon MTs in hepatitis B surface proteins,which are usually detected as a mixed population with wild-type(WT)HBV.The question was raised how the coexistence of nucleos(t)ide analogs(NAs)resistance MTs and WT sequences affects HBV replication.In the present study,HBV genomes with frequently detected reverse transcriptase(RT)/surface truncation MTs,rtA181T/sW172^*,rtV191I/sW182^*and rtM204I/sW196^*,were phenotypically characterized alone or together with their WT counterparts in different ratios by transient transfection in the absence or presence of Nas.In the absence of Nas,RT/surface truncation MTs impaired the expression and secretion of HBV surface proteins,and had a dose-dependent negative effect on WT HBV virion secretion.However,in the presence of Nas,coexistence of MTs with WT maintained viral replication,and the presence of WT was able to rescue the production of MT HBV virions.Our findings reveal that complementation of WT and MT HBV genomes is highly effective under drug treatment.展开更多
A 62-year-old man had chronic hepatitis B virus （HBV） infection and was diagnosed with liver cirrhosis. At the time of diagnosis the patient＇s virologic markers were positive for hepatitis B surface antigen （HBsAg...A 62-year-old man had chronic hepatitis B virus （HBV） infection and was diagnosed with liver cirrhosis. At the time of diagnosis the patient＇s virologic markers were positive for hepatitis B surface antigen （HBsAg）, antibody to hepatitis B e antigen （anti-HBe） and antibody to hepatitis B core antigen （anti-HBc）, while antibody to hepatitis B surface antigen （anti-HBs） and HBV DNA were negative. Later the patient received chemotherapy for malignancy. However, this was interrupted due to elevated liver enzymes. At the same time HBV DNA became positive. Lamivudine （LMV） therapy was administered immediately. However, the levels of serum aminotransferase and total bilirubin （TB） were still rising. Finally the patient died of fulminant hepatic failure. A sequence revealed HBV genotype C （HBsAg subtype adw） with immune escape mutations, F8L, $34L, F41S, G44V, F93C, V96G, Lll0I, C149Y and F161Y. The high morbidity and mortality of this complication is one of the major obstacles to completing the standard treatment for malignancy in HBV carriers. Therefore, the relative risk of antiviral prophylactic failure should be further assessed and the optimal strategy for antiviral prophylaxis in HBsAg-positive patients with oncologic and hematologic malignancies undergoing chemotherapy should be revised.展开更多
Reverse transcription-polymerase chain reaction(RT-PCR)is an essential method for specific diagnosis of SARS-CoV-2 infection.Unfortunately,false negative test results are often reported.In this study,we attempted to d...Reverse transcription-polymerase chain reaction(RT-PCR)is an essential method for specific diagnosis of SARS-CoV-2 infection.Unfortunately,false negative test results are often reported.In this study,we attempted to determine the principal causes leading to false negative results of RT-PCR detection of SARS-CoV-2 RNAs in respiratory tract specimens.Multiple sputum and throat swab specimens from 161 confirmed COVID-19 patients were tested with a commercialfluorescent RT-PCR kit targeting the ORF1 ab and N regions of SARS-CoV-2 genome.The RNA level of a cellular housekeeping gene ribonuclease P/MRP subunit p30(RPP30)in these specimens was also assessed by RT-PCR.Data for a total of 1052 samples were retrospectively re-analyzed and a strong association between positive results in SARS-CoV-2 RNA tests and high level of RPP30 RNA in respiratory tract specimens was revealed.By using the ROC-AUC analysis,we identified Ct cutoff values for RPP30 RT-PCR which predicted false negative results for SARS-CoV-2 RT-PCR with high sensitivity(95.03%–95.26%)and specificity(83.72%–98.55%)for respective combination of specimen type and ampli-fication reaction.Using these Ct cutoff values,false negative results could be reliably identified.Therefore,the presence of cellular materials,likely infected host cells,are essential for correct SARS-CoV-2 RNA detection by RT-PCR in patient specimens.RPP30 could serve as an indicator for cellular content,or a surrogate indicator for specimen quality.In addition,our results demonstrated that false negativity accounted for a vast majority of contradicting results in SARS-CoV-2 RNA test by RT-PCR.展开更多
Hepatitis B virus(HBV) infection remains a major global health problem because current therapies rarely eliminate HBV infections to achieve a complete cure. A different treatment paradigm to effectively clear HBV infe...Hepatitis B virus(HBV) infection remains a major global health problem because current therapies rarely eliminate HBV infections to achieve a complete cure. A different treatment paradigm to effectively clear HBV infection and eradicate latent viral reservoirs is urgently required. In recent years, the development of a new RNA-guided gene-editing tool, the CRISPR/Cas9(clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) system, has greatly facilitated site-specific mutagenesis and represents a very promising potential therapeutic tool for diseases, including for eradication of invasive pathogens such as HBV. Here, we review recent advances in the use of CRISPR/Cas9, which is designed to target HBV specific DNA sequences to inhibit HBV replication and to induce viral genome mutation, in cell lines or animal models. Advantages, limitations and possible solutions, and proposed directions for future research are discussed to highlight the opportunities and challenges of CRISPR/Cas9 as a new, potentially curative therapy for chronic hepatitis B infection.展开更多
Severe fever with thrombocytopenia syndrome(SFTS)is an emerging infectious disease with high mortality(12%–30%).The mechanism by which the SFTS bunyavirus(SFTSV)causes severe illness remains unclear.To evaluate the p...Severe fever with thrombocytopenia syndrome(SFTS)is an emerging infectious disease with high mortality(12%–30%).The mechanism by which the SFTS bunyavirus(SFTSV)causes severe illness remains unclear.To evaluate the phenotypic and functional characteristics of the NK cell subsets in SFTS patients,twenty-nine SFTS patients were sequentially sampled from admission until recovery.Phenotypic and functional characteristics of NK cell subsets in circulating blood were analysed via flow cytometry.Then,correlations between NK cell subset frequencies and the SFTS index(SFTSI)were evaluated in all SFTS patients(15 mild,14 severe)upon admission.The frequencies of CD56dimCD16+NK cells were greatly decreased in early SFTSV infection and were negatively correlated with disease severity.Additionally,higher Ki-67 and granzyme B expression and relatively lower NKG2 A expression in CD56dimCD16+NK cells were observed in acute infection.Moreover,the effector function of CD56dimNK cells was increased in the acute phase compared with the recovery phase in nine severe SFTS patients.Additionally,interleukin(IL)-15,interferon(IFN)-a,IL-18 and IFN-c secretion was markedly increased during early infection.Collectively,despite depletion of CD56dimCD16+NK cells,activation and functional enhancement of CD56dimCD16+NK cells were still observed,suggesting their involvement in defence against early SFTSV infection.展开更多
Dear Editor,We report a case of HBV reactivation in an anti-HBs positive, anti-HBc positive non-Hodgkin’s lymphoma patient. Hepatitis B virus (HBV) reactivation is a well-recognized complication of patients undergoin...Dear Editor,We report a case of HBV reactivation in an anti-HBs positive, anti-HBc positive non-Hodgkin’s lymphoma patient. Hepatitis B virus (HBV) reactivation is a well-recognized complication of patients undergoing chemotherapy or immunosuppressive therapy for lymphomas. The presence of antibodies to the展开更多
The recent emergence and rapid global spread of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) pose an unprecedented medical and socioeconomic crisis, and the disease caused by it, Coronavirus disease...The recent emergence and rapid global spread of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) pose an unprecedented medical and socioeconomic crisis, and the disease caused by it, Coronavirus disease 2019(COVID-19),was declared a pandemic by the World Health Organization(WHO) on March 11, 2020. Chinese scientists and physicians rapidly identified the causative pathogen, which turned out to be a novel betacoronavirus with high sequence similarities to bat and pangolin coronaviruses. The scientific community has ignited tremendous efforts to unravel the biological underpinning of SARS-CoV-2, which constitutes the foundation for therapy and vaccine development strategies. Here, we summarize the current state of knowledge on the genome, structure, receptor, and origin of SARS-CoV-2.展开更多
Hepatitis B virus(HBV)infection is one of the most common causes for liver related morbidity and mortality worldwide.Liver fibrosis and cirrhosis occur in the course of chronic HBV infection,with the increasing risk t...Hepatitis B virus(HBV)infection is one of the most common causes for liver related morbidity and mortality worldwide.Liver fibrosis and cirrhosis occur in the course of chronic HBV infection,with the increasing risk to develop hepatocellular carcinoma.In about 95%of adults’acute hepatitis B virus infection is self-limited,whereas in 90%of young children HBV infection leads to chronic progression.It is likely that a fully developed immune system contributes to HBV clearance(Dandri and Locarnini 2012;Bertoletti and Kennedy 2015).展开更多
The mitogen activated protein kinases-extracellular signal regulated kinases （MAPK-ERK） pathway is involved in regulation of multiple cellular processes including the cell cycle. In the present study using a Huh7 ce...The mitogen activated protein kinases-extracellular signal regulated kinases （MAPK-ERK） pathway is involved in regulation of multiple cellular processes including the cell cycle. In the present study using a Huh7 cell line Conl with an HCV replicon, we have shown that the MAPK-ERK pathway plays a significant role in the modulation of HCV replication and protein expression and might influence IFN-a signalling. Epithelial growth factor （EGF） was able to stimulate ERK activation and decreased HCV RNA load while a MAPK-ERK pathway inhibitor U0126 led to an elevated HCV RNA load and higher NS5A protein amounts in Conl cells. It could be further demonstrated that the inhibition of the MAPK-ERK pathway facilitated the translation directed by the HCV internal ribosome entry site. Consistently, a U0126 treatment enhanced activity of the HCV reporter replicon in transient transfeetion assays. Thus, the MAPK-ERK pathway plays an important role in the regulation of HCV gene expression and replication. In addition, cyclin-dependent kinases （CDKs） downstream of ERK may also be involved in the modulation of HCV replication since roscovitine, an inhibitor of CDKs had a similar effect to that of U0126. Modulation of the cell cycle progression by cell cycle inhibitor or RNAi resulted consistently in changes of HCV RNA levels. Further, the replication of HCV replicon in Conl cells was inhibited by IFN-~z. The inhibitory effect of IFN-CZ could be partly reversed by pre-incubation of Con-1 cells with inhibitors of the MAPK-ERK pathway and CDKs. It could be shown that the MAPK-ERK inhibitors are able to partially modulate the expression of interferon-stimulated genes.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 the original version of Fig.41 and 4J,the cutoff lines were accidently shifted during figure layout.Figures 41 and 4J are re-drawn and provided below.
The WHO estimates that almost500 million people world-wide are chronically infected with hepatitis B and C viruses(HBV and HCV)and human immune deficiency virus(HIV).During the recent years,significant progress was ma...The WHO estimates that almost500 million people world-wide are chronically infected with hepatitis B and C viruses(HBV and HCV)and human immune deficiency virus(HIV).During the recent years,significant progress was made in treatment of chronic infection with HBV,HCV,and HIV,mainly based on directly antiviral agents.However,展开更多
A key question in the coronavirus disease 2019(COVID-19)pandemic is the duration of specific T cell responses against the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)post primary infection,which is diff...A key question in the coronavirus disease 2019(COVID-19)pandemic is the duration of specific T cell responses against the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)post primary infection,which is difficult to address due to the large-scale COVID-19 vaccination and re-exposure to the virus.Here,we conducted an analysis of the long-term SARS-CoV-2-specific T cell responses in a unique cohort of convalescent individuals(CIs)that were among the first to be infected worldwide and without any possible antigen re-exposure since then.The magnitude and breadth of SARS-CoV-2-specific T cell responses correlated inversely with the time that had elapsed from disease onset and the age of those CIs.The mean magnitude of SARS-CoV-2-specific CD4 and CD8 T cell responses decreased about 82%and 76%,respectively,over the time period of ten months after infection.Accordingly,the longitudinal analysis also demonstrated that SARS-CoV-2-specific T cell responses waned significantly in 75%of CIs during the follow-up.Collectively,we provide a comprehensive characterization of the long-term memory T cell response in CIs,suggesting that robust SARS-CoV-2-specific T cell immunity post primary infection may be less durable than previously expected.展开更多
The objective of this study was to characterize the genome structure of duck hepatitis B virus （DHBV） isolated from Hubei brown ducks. The natural carrier rate of DHBV in adult ducks from Hubei area was investigated...The objective of this study was to characterize the genome structure of duck hepatitis B virus （DHBV） isolated from Hubei brown ducks. The natural carrier rate of DHBV in adult ducks from Hubei area was investigated and the DHBV DNA-positive serum screened out. The complete genome of a DHBV strain was amplified by polymerase chain reaction （PCR） and cloned into T vector and sequenced. The results showed that the carrier rate of DHBV in Hubei brown ducks was 10 % This strain （GenBank accession number DQ276978） had a genome of 3024 nucleotides with three overlapping open reading frames encoding the surface, core and polymerase proteins respectively. Comparison of the strain with 17 DHBV strains registered in GenBank revealed a homology from 89.3 % to 93.5 % at the nucleotide level. The sequences of the structural and functional domains of these proteins were highly conserved. The strain was found to share more signature amino acids in the polymerase genes with the ＂Chinese＂ DHBV strains than those of the ＂Western＂ country strains. This finding was also corroborated by a phylogenetic tree analysis. Therefore, the DQ276978 might belong to a subtype of the Chinese DHBV strains.展开更多
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(82202497)the National Key R&D Program of China(2023YFC2306800)the Fundamental Research Funds for the Central Universities(226-2024-00129).
文摘Hepatitis B virus(HBV)establishes chronic infection through strategic manipulation of host metabolic networks,driving a spectrum of hepatic pathologies ranging from hepatitis to cirrhosis and hepatocellular carcinoma.Mechanistically,HBV reprograms core metabolic pathways,including glycolysis,tricarboxylic acid(TCA)cycle,oxidative phosphorylation,and lipid homeostasis,to fuel its replication machinery and evade immune surveillance.This review systematically synthesizes current evidence on HBV-induced glucose/lipid metabolic rewiring,with particular emphasis on how viral-host crosstalk at the metabolic interface sustains viral pathogenesis.
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Supported by grants from the Deutsche Forschungsgemeinschaft (DFG SCHL 377/2-2, LU 669/2-1 and GRK 1045/1)
文摘AIM：To characterize the IFN-response and its modulation by the antiviral compound lamivudine in HBV- transfected HepG2.2.15 cells. METHODS： HepG2.2.15 and HepG2 cells were stimulated with various concentrations of IFN-α 2a in the presence or absence of lamivudine. Then, total RNA was extracted and analysed by customised cDNA arrays and northern blot for interferon-inducible genes （ISGs）. In addition, cellular proteins were extracted for EMSA and western blot. HBV replication was assessed by southern blot or ELISAs for HBsAg and HBeAg. RESULTS： Two genes （MxA, CigS） with completely abolished and 4 genes （IFITM1, -2, -3, and 6-16） with partially reduced IFN-responses were identified in HepG2.2.15 cells. In 2 genes （IFITM1, 6-16）, the response to IFN-α could be restored by treatment with lamivudine. This effect could not be explained by a direct modulation of the Jak/Stat signalling pathway since EMSA and western blot experiments revealed no suppression of Statl activation and ISGF3 formation after stimulation with IFN-α in HepG2.2.15 compared to HepG2 cells. CONCLUSION： These results are consistent with the assumption that chronic hepatitis B may specifically modulate the cellular response to IFN by a selective blockage of some ISGs. Antiviral treatment with lamivudine may partially restore ISG expressionby reducing HBV gene expression and replication.
基金the Deutsche Forschungsgemeinschaft(TRR60 and GK 1045/2)National Major Science and Technology Project for Infectious Diseases of China(2008ZX10002-011,2012ZX10004503)+1 种基金the National Natural Science Foundation of China(No.30271170,30571646,81101248)the International Science&Technology CooperationProgram of China(2011DFA31030)for supporting some of the work in the review
文摘Chronic hepatitis B virus(CHB) is currently treated with either interferon-based or nucleot(s)idebased antiviral therapies.However,treatment with pegylated interferon alpha results in a durable antiviral response in only about 30%patients and is associated with side effects.Most patients receiving nucleot(s)ide analogue treatment do not establish long-term,durable control of Infection and have rebounding viremia after cessation of therapy.Thus,novel therapy strategies are necessary to achieve the induction of potent and durable antiviral immune responses of the patients which can maintain long-term control of viral replication.Therapeutic vaccination of HBV carriers is a promising strategy for the control of hepatitis B.Here the authors review new therapeutic vaccination strategies to treat chronic hepatitis B which may be introduced for patient treatment in the future.
文摘Though efficient vaccines against hepatitis B virus(HBV) and antiviral therapies are available,chronic HBV infection is still a global health problem. The process of HBV infection and HBV life cycle are extensively studied in last decades, however, the mechanisms of HBV-induced alterations of host cell metabolisms and host factors involved in modulating of viral replication are not fully understood. Thus, it is an important issue to examine these specific HBV-host interactions for development of novel strategies for antiviral therapies. Recently, microRNAs(miRNAs), a class of post-transcriptional regulatory small RNA, seem to be the relevant fine tuning factors of various cellular activities and pathways, including cell growth, metabolism, and viral replication. In this review, we summarize the up to date knowledge concerning the virus-host interactions and emphasizing on the role of miRNAs in regulation of HBV replication and host cell metabolism.
基金supported by the Deutsche Forschungsgemeinschaft (TRR60)the National Nature Science Foundation of China (31770180, 31621061)+1 种基金the Youth Innovation Promotion Association CAS (No. 2016303)the Youth Planning Project of Hubei Health Planning Commission (WJ2017Q027)
文摘As the open reading frames of hepatitis B virus(HBV)genomes are overlapping,resistance mutations(MTs)in HBV polymerase may result in stop codon MTs in hepatitis B surface proteins,which are usually detected as a mixed population with wild-type(WT)HBV.The question was raised how the coexistence of nucleos(t)ide analogs(NAs)resistance MTs and WT sequences affects HBV replication.In the present study,HBV genomes with frequently detected reverse transcriptase(RT)/surface truncation MTs,rtA181T/sW172^*,rtV191I/sW182^*and rtM204I/sW196^*,were phenotypically characterized alone or together with their WT counterparts in different ratios by transient transfection in the absence or presence of Nas.In the absence of Nas,RT/surface truncation MTs impaired the expression and secretion of HBV surface proteins,and had a dose-dependent negative effect on WT HBV virion secretion.However,in the presence of Nas,coexistence of MTs with WT maintained viral replication,and the presence of WT was able to rescue the production of MT HBV virions.Our findings reveal that complementation of WT and MT HBV genomes is highly effective under drug treatment.
基金National Basic Research Priorities Program of China(2011CB106303)The National Natural Science Foundation of China(31200699)The Fundamental Research Funds for the Central Universities(HUST:2012QN140)
文摘A 62-year-old man had chronic hepatitis B virus （HBV） infection and was diagnosed with liver cirrhosis. At the time of diagnosis the patient＇s virologic markers were positive for hepatitis B surface antigen （HBsAg）, antibody to hepatitis B e antigen （anti-HBe） and antibody to hepatitis B core antigen （anti-HBc）, while antibody to hepatitis B surface antigen （anti-HBs） and HBV DNA were negative. Later the patient received chemotherapy for malignancy. However, this was interrupted due to elevated liver enzymes. At the same time HBV DNA became positive. Lamivudine （LMV） therapy was administered immediately. However, the levels of serum aminotransferase and total bilirubin （TB） were still rising. Finally the patient died of fulminant hepatic failure. A sequence revealed HBV genotype C （HBsAg subtype adw） with immune escape mutations, F8L, $34L, F41S, G44V, F93C, V96G, Lll0I, C149Y and F161Y. The high morbidity and mortality of this complication is one of the major obstacles to completing the standard treatment for malignancy in HBV carriers. Therefore, the relative risk of antiviral prophylactic failure should be further assessed and the optimal strategy for antiviral prophylaxis in HBsAg-positive patients with oncologic and hematologic malignancies undergoing chemotherapy should be revised.
基金supported by the Natural Science Foundation of Anhui Province(Grant No.1608085MH162)。
文摘Reverse transcription-polymerase chain reaction(RT-PCR)is an essential method for specific diagnosis of SARS-CoV-2 infection.Unfortunately,false negative test results are often reported.In this study,we attempted to determine the principal causes leading to false negative results of RT-PCR detection of SARS-CoV-2 RNAs in respiratory tract specimens.Multiple sputum and throat swab specimens from 161 confirmed COVID-19 patients were tested with a commercialfluorescent RT-PCR kit targeting the ORF1 ab and N regions of SARS-CoV-2 genome.The RNA level of a cellular housekeeping gene ribonuclease P/MRP subunit p30(RPP30)in these specimens was also assessed by RT-PCR.Data for a total of 1052 samples were retrospectively re-analyzed and a strong association between positive results in SARS-CoV-2 RNA tests and high level of RPP30 RNA in respiratory tract specimens was revealed.By using the ROC-AUC analysis,we identified Ct cutoff values for RPP30 RT-PCR which predicted false negative results for SARS-CoV-2 RT-PCR with high sensitivity(95.03%–95.26%)and specificity(83.72%–98.55%)for respective combination of specimen type and ampli-fication reaction.Using these Ct cutoff values,false negative results could be reliably identified.Therefore,the presence of cellular materials,likely infected host cells,are essential for correct SARS-CoV-2 RNA detection by RT-PCR in patient specimens.RPP30 could serve as an indicator for cellular content,or a surrogate indicator for specimen quality.In addition,our results demonstrated that false negativity accounted for a vast majority of contradicting results in SARS-CoV-2 RNA test by RT-PCR.
基金supported by National Natural Science Foundation of China (NSFC8120232,NSFC81461130019)Transregio-SFB (TRR) of the Deutsche Forschungsgemeinschaft (DFG TRR60)
文摘Hepatitis B virus(HBV) infection remains a major global health problem because current therapies rarely eliminate HBV infections to achieve a complete cure. A different treatment paradigm to effectively clear HBV infection and eradicate latent viral reservoirs is urgently required. In recent years, the development of a new RNA-guided gene-editing tool, the CRISPR/Cas9(clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) system, has greatly facilitated site-specific mutagenesis and represents a very promising potential therapeutic tool for diseases, including for eradication of invasive pathogens such as HBV. Here, we review recent advances in the use of CRISPR/Cas9, which is designed to target HBV specific DNA sequences to inhibit HBV replication and to induce viral genome mutation, in cell lines or animal models. Advantages, limitations and possible solutions, and proposed directions for future research are discussed to highlight the opportunities and challenges of CRISPR/Cas9 as a new, potentially curative therapy for chronic hepatitis B infection.
基金supported by the National Natural Science Foundation of China(81271884)and of Hubei(2018CFB471)
文摘Severe fever with thrombocytopenia syndrome(SFTS)is an emerging infectious disease with high mortality(12%–30%).The mechanism by which the SFTS bunyavirus(SFTSV)causes severe illness remains unclear.To evaluate the phenotypic and functional characteristics of the NK cell subsets in SFTS patients,twenty-nine SFTS patients were sequentially sampled from admission until recovery.Phenotypic and functional characteristics of NK cell subsets in circulating blood were analysed via flow cytometry.Then,correlations between NK cell subset frequencies and the SFTS index(SFTSI)were evaluated in all SFTS patients(15 mild,14 severe)upon admission.The frequencies of CD56dimCD16+NK cells were greatly decreased in early SFTSV infection and were negatively correlated with disease severity.Additionally,higher Ki-67 and granzyme B expression and relatively lower NKG2 A expression in CD56dimCD16+NK cells were observed in acute infection.Moreover,the effector function of CD56dimNK cells was increased in the acute phase compared with the recovery phase in nine severe SFTS patients.Additionally,interleukin(IL)-15,interferon(IFN)-a,IL-18 and IFN-c secretion was markedly increased during early infection.Collectively,despite depletion of CD56dimCD16+NK cells,activation and functional enhancement of CD56dimCD16+NK cells were still observed,suggesting their involvement in defence against early SFTSV infection.
基金supported by the National Basic Research Priorities Program of China (2011CB106303)National Natural Science Foundation of China(31200699)the Fundamental Research Funds for the Central Universities (HUST: 2012QN140)
文摘Dear Editor,We report a case of HBV reactivation in an anti-HBs positive, anti-HBc positive non-Hodgkin’s lymphoma patient. Hepatitis B virus (HBV) reactivation is a well-recognized complication of patients undergoing chemotherapy or immunosuppressive therapy for lymphomas. The presence of antibodies to the
基金supported by the Fundamental Research Funds for the Central Universities (2020kfyXGYJ028)the National Natural Science Foundation of China (81861138044 and 91742114)+1 种基金the National Science and Technology Major Project (2017ZX10202203)the Medical Faculty of the University of Duisburg-Essen and Stiftung Universitaetsmedizin, University Hospital Essen, Germany。
文摘The recent emergence and rapid global spread of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) pose an unprecedented medical and socioeconomic crisis, and the disease caused by it, Coronavirus disease 2019(COVID-19),was declared a pandemic by the World Health Organization(WHO) on March 11, 2020. Chinese scientists and physicians rapidly identified the causative pathogen, which turned out to be a novel betacoronavirus with high sequence similarities to bat and pangolin coronaviruses. The scientific community has ignited tremendous efforts to unravel the biological underpinning of SARS-CoV-2, which constitutes the foundation for therapy and vaccine development strategies. Here, we summarize the current state of knowledge on the genome, structure, receptor, and origin of SARS-CoV-2.
文摘Hepatitis B virus(HBV)infection is one of the most common causes for liver related morbidity and mortality worldwide.Liver fibrosis and cirrhosis occur in the course of chronic HBV infection,with the increasing risk to develop hepatocellular carcinoma.In about 95%of adults’acute hepatitis B virus infection is self-limited,whereas in 90%of young children HBV infection leads to chronic progression.It is likely that a fully developed immune system contributes to HBV clearance(Dandri and Locarnini 2012;Bertoletti and Kennedy 2015).
基金supported by a joint grant of Chinese Academy of Science and Deutsche Akademische Austausch Dienstthe National Basic Research Priorities Program ofChina(2009CB522501,2005CB522901,2007CB512901)
文摘The mitogen activated protein kinases-extracellular signal regulated kinases （MAPK-ERK） pathway is involved in regulation of multiple cellular processes including the cell cycle. In the present study using a Huh7 cell line Conl with an HCV replicon, we have shown that the MAPK-ERK pathway plays a significant role in the modulation of HCV replication and protein expression and might influence IFN-a signalling. Epithelial growth factor （EGF） was able to stimulate ERK activation and decreased HCV RNA load while a MAPK-ERK pathway inhibitor U0126 led to an elevated HCV RNA load and higher NS5A protein amounts in Conl cells. It could be further demonstrated that the inhibition of the MAPK-ERK pathway facilitated the translation directed by the HCV internal ribosome entry site. Consistently, a U0126 treatment enhanced activity of the HCV reporter replicon in transient transfeetion assays. Thus, the MAPK-ERK pathway plays an important role in the regulation of HCV gene expression and replication. In addition, cyclin-dependent kinases （CDKs） downstream of ERK may also be involved in the modulation of HCV replication since roscovitine, an inhibitor of CDKs had a similar effect to that of U0126. Modulation of the cell cycle progression by cell cycle inhibitor or RNAi resulted consistently in changes of HCV RNA levels. Further, the replication of HCV replicon in Conl cells was inhibited by IFN-~z. The inhibitory effect of IFN-CZ could be partly reversed by pre-incubation of Con-1 cells with inhibitors of the MAPK-ERK pathway and CDKs. It could be shown that the MAPK-ERK inhibitors are able to partially modulate the expression of interferon-stimulated genes.
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 the original version of Fig.41 and 4J,the cutoff lines were accidently shifted during figure layout.Figures 41 and 4J are re-drawn and provided below.
文摘The WHO estimates that almost500 million people world-wide are chronically infected with hepatitis B and C viruses(HBV and HCV)and human immune deficiency virus(HIV).During the recent years,significant progress was made in treatment of chronic infection with HBV,HCV,and HIV,mainly based on directly antiviral agents.However,
基金supported by the National Natural Science Foundation of China (92169105,82172256,81861138044,91742114 and M-0060)the Fundamental Research Funds for the Central Universities (2020kfyXGYJ028,2020kfyXGYJ046 and 2020kfyXGYJ016)+2 种基金the National Science and Technology Major Project (2017ZX10202203-007-006,2017ZX10202202-001-009,2017ZX10202202-002-008,2017ZX10202201-002-003)the Deutsche Forschungsgemeinschaft (DI 714/22-1,ZE 893/2-1,and RTG1949/2)the Medical Faculty of the University of Duisburg-Essen and Stiftung Universiatsmedizin,University Hospital Essen,Germany,and the Tongji-Rongcheng Center for Biomedicine,Huazhong University of Science and Technology。
文摘A key question in the coronavirus disease 2019(COVID-19)pandemic is the duration of specific T cell responses against the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)post primary infection,which is difficult to address due to the large-scale COVID-19 vaccination and re-exposure to the virus.Here,we conducted an analysis of the long-term SARS-CoV-2-specific T cell responses in a unique cohort of convalescent individuals(CIs)that were among the first to be infected worldwide and without any possible antigen re-exposure since then.The magnitude and breadth of SARS-CoV-2-specific T cell responses correlated inversely with the time that had elapsed from disease onset and the age of those CIs.The mean magnitude of SARS-CoV-2-specific CD4 and CD8 T cell responses decreased about 82%and 76%,respectively,over the time period of ten months after infection.Accordingly,the longitudinal analysis also demonstrated that SARS-CoV-2-specific T cell responses waned significantly in 75%of CIs during the follow-up.Collectively,we provide a comprehensive characterization of the long-term memory T cell response in CIs,suggesting that robust SARS-CoV-2-specific T cell immunity post primary infection may be less durable than previously expected.
基金This project was supported by a grant from the National Key Science and Technology Program of the Tenth Five-years-Plan (No. 2001BA705B05) a grant from National Natural Sciences Foundation of China (No. 30271170).
文摘The objective of this study was to characterize the genome structure of duck hepatitis B virus （DHBV） isolated from Hubei brown ducks. The natural carrier rate of DHBV in adult ducks from Hubei area was investigated and the DHBV DNA-positive serum screened out. The complete genome of a DHBV strain was amplified by polymerase chain reaction （PCR） and cloned into T vector and sequenced. The results showed that the carrier rate of DHBV in Hubei brown ducks was 10 % This strain （GenBank accession number DQ276978） had a genome of 3024 nucleotides with three overlapping open reading frames encoding the surface, core and polymerase proteins respectively. Comparison of the strain with 17 DHBV strains registered in GenBank revealed a homology from 89.3 % to 93.5 % at the nucleotide level. The sequences of the structural and functional domains of these proteins were highly conserved. The strain was found to share more signature amino acids in the polymerase genes with the ＂Chinese＂ DHBV strains than those of the ＂Western＂ country strains. This finding was also corroborated by a phylogenetic tree analysis. Therefore, the DQ276978 might belong to a subtype of the Chinese DHBV strains.
