Induction of broadly neutralizing monoclonal antibodies(bNAbs)that bind to the viral envelope glycoproteins is a major goal of hepatitis C virus(HCV)vaccine research.The study of bNAbs arising in natural infection is ...Induction of broadly neutralizing monoclonal antibodies(bNAbs)that bind to the viral envelope glycoproteins is a major goal of hepatitis C virus(HCV)vaccine research.The study of bNAbs arising in natural infection is essential in this endeavor.We generated a human antibody,8D6,recognizing the E2 protein of HCV isolated from a chronic hepatitis C patient.This antibody shows broadly neutralizing activity,which covers a pan-genotypic panel of cell culture-derived HCV virions(HCVcc).Functional and epitope analyses demonstrated that 8D6 can block the interaction between E2 and CD81 by targeting a highly conserved epitope on E2.We describe how the 8D6 lineage evolved via somatic hypermutation to achieve broad neutralization.We found that the V(D)J recombination-generated junctional and somatic hypermutation-induced disulfide bridge(C-C)motif in the CDRH3 is critical for the broad neutralization and binding activity of 8D6.This motif is conserved among a series of broadly neutralizing HCV antibodies,indicating a common binding model.Next,the 8D6 inferred germline(iGL)was reconstructed and tested for its binding affinity and neutralization activity.Interestingly,8D6 iGL-mediated relatively strong inhibition of the 1b genotype PR79L9 strain,suggesting that PR79L9 may serve as a potential natural viral strain that provides E2 sequences that induce bNAbs.Overall,our detailed epitope mapping and genetic studies of the HCV E2-specific mAb 8D6 have allowed for further refinement of antigenic sites on E2 and reveal a new mechanism to generate a functional CDRH3,while its iGL can serve as a probe to identify potential HCV vaccine strains.展开更多
Hepatitis B virus(HBV)represents the commonest etiologic agent of acute-on-chronic liver failure(ACLF)in most Asian countries.Nucleos(t)ide analogs(NAs)are effective in the treatment of chronic HBV infections,but may ...Hepatitis B virus(HBV)represents the commonest etiologic agent of acute-on-chronic liver failure(ACLF)in most Asian countries.Nucleos(t)ide analogs(NAs)are effective in the treatment of chronic HBV infections,but may also exacerbate the disease and stimulate its development into HBV-associated ACLF if not used appropriately.The current study aimed to assess the prevalence and severity of HBV-associated ACLF as a result from irregular medication of NAs(IMNA).A total of 1134 individuals with HBV-associated ACLF in nine hospitals in Heilongjiang Province were enrolled in this study between 2005 and 2015.Among these,777 chronic hepatitis B(CHB)and 357 HBV-associated liver cirrhosis cases were classified based on various predisposing factors,including IMNA,HBV reactivation(HBVR),infections,treatment drugs,alcohol use and others(hepatitis C virus,hepatitis E virus,gastrointestinal bleeding and unknown reasons).The percentage and improvement rate were examined.Among individuals with HBV-associated ACLF and CHB,IMNA was found in 9.01%,HBVR in 46.20%,infections in 9.52%,treatment drugs in 14.67%,alcohol in 11.71%,and others in 24.58%as predisposing factors.Improvement rates in cases with IMNA,HBVR,infections,treatment drugs,alcohol and others were 41.43%,58.50%,58.11%,56.14%,53.85%,and 65.97%,respectively.Multivariable analysis showed that IMNA,others,infections,hepatic encephalopathy and hepatorenal syndrome were associated with prognosis.Only IMNA independently predicted HBV-associated ACLF prognosis.Overall,our study demonstrated that the percentage of IMNAinduced HBV-associated ACLF was 12.61%,and worse disease conditions resulted from IMNA compared with other factors.Thus,the suitability of treatment with NAs should be thoroughly evaluated.展开更多
基金supported by grants from the Chinese National 973 Program(2015CB554302)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19000000)to B.S.+4 种基金the Chinese National 973 Program(2015CB554300)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29010205)to M.the National Natural Science Foundation of China(31670172)Shanghai Science and Technology Innovation Action(16DZ1910100)to B.S.Nanjing Galaxy Biopharma C.O.
文摘Induction of broadly neutralizing monoclonal antibodies(bNAbs)that bind to the viral envelope glycoproteins is a major goal of hepatitis C virus(HCV)vaccine research.The study of bNAbs arising in natural infection is essential in this endeavor.We generated a human antibody,8D6,recognizing the E2 protein of HCV isolated from a chronic hepatitis C patient.This antibody shows broadly neutralizing activity,which covers a pan-genotypic panel of cell culture-derived HCV virions(HCVcc).Functional and epitope analyses demonstrated that 8D6 can block the interaction between E2 and CD81 by targeting a highly conserved epitope on E2.We describe how the 8D6 lineage evolved via somatic hypermutation to achieve broad neutralization.We found that the V(D)J recombination-generated junctional and somatic hypermutation-induced disulfide bridge(C-C)motif in the CDRH3 is critical for the broad neutralization and binding activity of 8D6.This motif is conserved among a series of broadly neutralizing HCV antibodies,indicating a common binding model.Next,the 8D6 inferred germline(iGL)was reconstructed and tested for its binding affinity and neutralization activity.Interestingly,8D6 iGL-mediated relatively strong inhibition of the 1b genotype PR79L9 strain,suggesting that PR79L9 may serve as a potential natural viral strain that provides E2 sequences that induce bNAbs.Overall,our detailed epitope mapping and genetic studies of the HCV E2-specific mAb 8D6 have allowed for further refinement of antigenic sites on E2 and reveal a new mechanism to generate a functional CDRH3,while its iGL can serve as a probe to identify potential HCV vaccine strains.
基金This work was supported by the National Science and Technology Major Project(2017ZX10202203-007-007,2017ZX10202203-008-007).
文摘Hepatitis B virus(HBV)represents the commonest etiologic agent of acute-on-chronic liver failure(ACLF)in most Asian countries.Nucleos(t)ide analogs(NAs)are effective in the treatment of chronic HBV infections,but may also exacerbate the disease and stimulate its development into HBV-associated ACLF if not used appropriately.The current study aimed to assess the prevalence and severity of HBV-associated ACLF as a result from irregular medication of NAs(IMNA).A total of 1134 individuals with HBV-associated ACLF in nine hospitals in Heilongjiang Province were enrolled in this study between 2005 and 2015.Among these,777 chronic hepatitis B(CHB)and 357 HBV-associated liver cirrhosis cases were classified based on various predisposing factors,including IMNA,HBV reactivation(HBVR),infections,treatment drugs,alcohol use and others(hepatitis C virus,hepatitis E virus,gastrointestinal bleeding and unknown reasons).The percentage and improvement rate were examined.Among individuals with HBV-associated ACLF and CHB,IMNA was found in 9.01%,HBVR in 46.20%,infections in 9.52%,treatment drugs in 14.67%,alcohol in 11.71%,and others in 24.58%as predisposing factors.Improvement rates in cases with IMNA,HBVR,infections,treatment drugs,alcohol and others were 41.43%,58.50%,58.11%,56.14%,53.85%,and 65.97%,respectively.Multivariable analysis showed that IMNA,others,infections,hepatic encephalopathy and hepatorenal syndrome were associated with prognosis.Only IMNA independently predicted HBV-associated ACLF prognosis.Overall,our study demonstrated that the percentage of IMNAinduced HBV-associated ACLF was 12.61%,and worse disease conditions resulted from IMNA compared with other factors.Thus,the suitability of treatment with NAs should be thoroughly evaluated.