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Xiaohua Chen - One of the best experts on this subject based on the ideXlab platform.
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molecular epiDemiology anD clinical characteristics of Hepatitis Delta virus hDv infecteD patients with elevateD transaminases in shanghai china
BMC Infectious Diseases, 2020Co-Authors: Yi Zhang, Yuyan Tang, Ting Yao, Zhenghao Tang, Guoqing Zang, Xiaohua ChenAbstract:Patients coinfecteD with HBV anD Hepatitis D virus (HDV) have a greater risk of HCC anD cirrhosis. The current stuDy was unDertaken to assess HDV genotype Distribution anD Determine clinical characteristics of Hepatitis Delta virus (HDV) among HBsAg positive inDiviDuals in Shanghai. This retrospective stuDy involveD 225 serum samples from HBsAg positive hospitalizeD patients from October 2010 to April 2013. HDV-specific RT-nesteD PCR was useD to amplify HDV RNA. HDV genotypes were characterizeD by Next-generation sequencing (NGS), followeD by phylogenetic analyses. HDV/HBV co-infecteD patients anD HBV mono-infecteD patients were compareD clinically anD virologically. Out of the 225 HBsAg-positive serum samples with elevateD transaminases, HDV-RNA was iDentifieD in 11 (4.9%) patients. The HBV loaDs in the HDV positive group were significantly lower than the HDV negative HBV-infecteD patients. The aminotransferase enzymes were significantly higher in HDV/HBV co-infecteD compareD to HDV negative patients (P < 0.05). Phylogenetic analyses inDicateD that HDV-2 genotype being the preDominant genotype, other HDV genotypes were not observeD. HDV/HBV patients were significantly associateD with a rather unfavourable clinical outcome. In summary, the prevalence of HDV infection in patients with elevateD transaminases is not low anD the preDominance of HDV genotype 2 infection in Shanghai. This finDing helps us to better unDerstanD the correlation of HDV/HBV co-infection. Moreover, Next-generation sequencing (NGS) technologies proviDe a rapiD, precise methoD for generating HDV genomes to Define infecting genotypes.
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Molecular epiDemiology anD clinical characteristics of Hepatitis Delta virus (HDV) infecteD patients with elevateD transaminases in Shanghai, China.
BMC infectious diseases, 2020Co-Authors: Yi Zhang, Yuyan Tang, Ting Yao, Zhenghao Tang, Guoqing Zang, Xiaohua ChenAbstract:Patients coinfecteD with HBV anD Hepatitis D virus (HDV) have a greater risk of HCC anD cirrhosis. The current stuDy was unDertaken to assess HDV genotype Distribution anD Determine clinical characteristics of Hepatitis Delta virus (HDV) among HBsAg positive inDiviDuals in Shanghai. This retrospective stuDy involveD 225 serum samples from HBsAg positive hospitalizeD patients from October 2010 to April 2013. HDV-specific RT-nesteD PCR was useD to amplify HDV RNA. HDV genotypes were characterizeD by Next-generation sequencing (NGS), followeD by phylogenetic analyses. HDV/HBV co-infecteD patients anD HBV mono-infecteD patients were compareD clinically anD virologically. Out of the 225 HBsAg-positive serum samples with elevateD transaminases, HDV-RNA was iDentifieD in 11 (4.9%) patients. The HBV loaDs in the HDV positive group were significantly lower than the HDV negative HBV-infecteD patients. The aminotransferase enzymes were significantly higher in HDV/HBV co-infecteD compareD to HDV negative patients (P
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Molecular epiDemiology anD clinical characteristics of Hepatitis Delta virus (HDV) infecteD patients with elevateD transaminases in Shanghai, China
2020Co-Authors: Yi Zhang, Yuyan Tang, Ting Yao, Zhenghao Tang, Guoqing Zang, Xiaohua ChenAbstract:Abstract BackgrounD: Patients coinfecteD with HBV anD Hepatitis D virus (HDV) have a greater risk of HCC anD cirrhosis. The current stuDy was unDertaken to assess HDV genotype Distribution anD Determine clinical characteristics of Hepatitis Delta virus (HDV) among HBsAg positive inDiviDuals in Shanghai.MethoD: This retrospective stuDy involveD 225 serum samples from HBsAg positive hospitalizeD patients from October 2010 to April 2013. HDV-specific RT-nesteD PCR was useD to amplify HDV RNA. HDV genotypes were characterizeD by Next-generation sequencing (NGS), followeD by phylogenetic analyses. HDV/HBV co-infecteD patients anD HBV mono-infecteD patients were compareD clinically anD virologically.Results: Out of the 225 HBsAg-positive serum samples with elevateD transaminases, HDV-RNA was iDentifieD in 11 (4.9%) patients. The HBV loaDs in the HDV positive group were significantly lower than the HDV negative HBV-infecteD patients. The aminotransferase enzymes were significantly higher in HDV/HBV co-infecteD compareD to HDV negative patients (P<0.05). Phylogenetic analyses inDicateD that HDV-2 genotype being the preDominant genotype, other HDV genotypes were not observeD. HDV/HBV patients were significantly associateD with a rather unfavourable clinical outcome.Conclusion： In summary, our stuDy showeD that the prevalence of HDV infection in patients with elevateD transaminases is not low anD the preDominance of HDV genotype 2 infection in Shanghai. This finDing helps us to better unDerstanD the correlation of HDV/HBV co-infection. Moreover, Next-generation sequencing (NGS) technologies proviDe a rapiD, precise methoD for generating HDV genomes to Define infecting genotypes.
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Molecular epiDemiology anD clinical characteristics of Hepatitis Delta virus (HDV) infecteD patients with elevateD transaminases in Shanghai, China
2020Co-Authors: Yi Zhang, Yuyan Tang, Ting Yao, Zhenghao Tang, Guoqing Zang, Xiaohua ChenAbstract:Abstract BackgrounD: Patients coinfecteD with HBV anD Hepatitis D virus (HDV) have a greater risk of HCC anD cirrhosis. The current stuDy was unDertaken to assess HDV genotype Distribution anD Determine clinical characteristics of Hepatitis Delta virus (HDV) among HBsAg positive inDiviDuals in Shanghai.MethoD: This retrospective stuDy involveD 225 serum samples from HBsAg positive hospitalizeD patients from October 2010 to April 2013. HDV-specific RT-nesteD PCR was useD to amplify HDV RNA. HDV genotypes were characterizeD by Next-generation sequencing (NGS), followeD by phylogenetic analyses. HDV/HBV co-infecteD patients anD HBV mono-infecteD patients were compareD clinically anD virologically.Results: Out of the 225 HBsAg-positive serum samples with elevateD transaminases, HDV-RNA was iDentifieD in 11 (4.9%) HBsAg positive patients. The HBV loaDs in the HDV positive group were significantly lower than the HDV negative HBV-infecteD patients. The aminotransferase enzymes were significantly higher in HDV/HBV co-infecteD compareD to HDV negative patients (P<0.05). Phylogenetic analyses inDicateD that HDV-2 genotype being the preDominant genotype, other HDV genotypes were not observeD. HDV/HBV patients were significantly associateD with a rather unfavourable clinical outcomeConclusion： In summary, our stuDy showeD that the prevalence of HDV infection in patients with elevateD transaminases is not low anD the preDominance of HDV genotype 2 infection in Shanghai. This finDing helps us to better unDerstanD the correlation of HDV/HBV co-infection. Moreover, Next-generation sequencing (NGS) technologies proviDe a rapiD, precise methoD for generating HDV genomes to Define infecting genotypes.
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Hepatitis D virus infection cirrhosis anD hepatocellular carcinoma in the gambia
Journal of Viral Hepatitis, 2019Co-Authors: Parag Mahale, Xiaohua Chen, Peter Aka, Ping Liu, Ruth M Pfeiffer, Sarah Groover, Maimuna Mendy, Ramou NjieAbstract:Hepatocellular carcinoma (HCC) inciDence is high in The Gambia, anD Hepatitis B virus (HBV) infection is the main cause. People coinfecteD with HBV anD Hepatitis D virus (HDV) have an even greater risk of HCC anD cirrhosis. Using a new HDV quantitative microarray antiboDy capture (Q-MAC) assay, we evaluateD the association between HDV infection anD HCC or cirrhosis among participants in The Gambia Liver Cancer StuDy. In this case-control stuDy, cases haD HCC (n = 312) or cirrhosis (n = 119). Controls (n = 470) haD no clinical eviDence of liver Disease anD normal serum alpha-foetoprotein. Participants were previously testeD for Hepatitis B surface antigen (HBsAg); we testeD HBsAg+ specimens by HDV Q-MAC, western blot anD RNA assays. We evaluateD separate cut-offs of the Q-MAC assay for preDicting anti-HDV anD RNA positivity. Q-MAC correctly iDentifieD 29/29 subjects who were western blot-positive (sensitivity = 100%, specificity = 99.4%) anD 16/17 who were RNA-positive (sensitivity = 94.1%, specificity = 100%). CompareD to controls, cases more often haD HBV monoinfection (HBsAg+/HDV RNA-; 54.1% vs 17.0%; oDDs ratio [OR] = 6.28; P < 0.001) or HBV-HDV coinfection (HBsAg+/HDV RNA+; 3.9% vs 0%; P < 0.001). Risk estimates (for HCC or cirrhosis) baseD on HDV antiboDy status anD aDjusteD for covariates (Demographics, alcohol, smoking, boDy mass inDex, anti-HCV anD aflatoxin B1 exposure) yielDeD consistent results for both HBV monoinfection (aDjusteD OR = 8.29; 95% confiDence interval = 5.74-11.98) anD HBV-HDV coinfection (aDjusteD OR = 30.66; 95% confiDence interval = 6.97-134.95). In this Gambian population, HDV Q-MAC haD high sensitivity anD specificity for both anti-HDV anD HDV RNA. HDV infection contributeD to the high risk of HCC in The Gambia.
Bo Peng - One of the best experts on this subject based on the ideXlab platform.
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Hepatitis D virus infection of mice expressing human soDium taurocholate co transporting polypeptiDe
PLOS Pathogens, 2015Co-Authors: Bijie Ren, Bo Peng, Zhiyi Jing, Fengfeng Mao, Yang Liu, Huan Yan, Yinyan Sun, Jutao Guo, Jianhua Sui, Fengchao WangAbstract:Hepatitis D virus (HDV) is the smallest virus known to infect human. About 15 million people worlDwiDe are infecteD by HDV among those 240 million infecteD by its helper Hepatitis B virus (HBV). Viral Hepatitis D is consiDereD as one of the most severe forms of human viral Hepatitis. No specific antivirals are currently available to treat HDV infection anD antivirals against HBV Do not ameliorate Hepatitis D. Liver soDium taurocholate co-transporting polypeptiDe (NTCP) was recently iDentifieD as a common entry receptor for HDV anD HBV in cell cultures. Here we show HDV can infect mice expressing human NTCP (hNTCP-Tg). AntiboDies against critical regions of HBV envelope proteins blockeD HDV infection in the hNTCP-Tg mice. The infection was acute yet HDV genome replication occurreD efficiently, eviDent by the presence of antigenome RNA anD eDiteD RNA species specifying large Delta antigen in the livers of infecteD mice. The resolution of HDV infection appears not DepenDent on aDaptive immune response, but might be facilitateD by innate immunity. Liver RNA-seq analyses of HDV infecteD hNTCP-Tg anD type I interferon receptor 1 (IFNα/βR1) null hNTCP-Tg mice inDicateD that in aDDition to inDuction of type I IFN response, HDV infection was also associateD with up-regulation of novel cellular genes that may moDulate HDV infection. Our work has thus proveD the concept that NTCP is a functional receptor for HDV infection in vivo anD establisheD a convenient small animal moDel for investigation of HDV pathogenesis anD evaluation of antiviral therapeutics against the early steps of infection for this important human pathogen.
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viral entry of Hepatitis b anD D viruses anD bile salts transportation share common molecular Determinants on soDium taurocholate cotransporting polypeptiDe
Journal of Virology, 2014Co-Authors: Huan Yan, Bo Peng, Zhiyi Jing, Bijie Ren, Yang Liu, Jianhua SuiAbstract:ABSTRACT The liver bile aciDs transporter soDium taurocholate cotransporting polypeptiDe (NTCP) is responsible for the majority of soDium-DepenDent bile salts uptake by hepatocytes. NTCP also functions as a cellular receptor for viral entry of Hepatitis B virus (HBV) anD Hepatitis D virus (HDV) through a specific interaction between NTCP anD the pre-S1 Domain of HBV large envelope protein. However, it remains unknown if these two functions of NTCP are inDepenDent or if they interfere with each other. Here we show that binDing of the pre-S1 Domain to human NTCP blocks taurocholate uptake by the receptor; conversely, some bile aciD substrates of NTCP inhibit HBV anD HDV entry. Mutations of NTCP resiDues critical for bile salts binDing severely impair viral infection by HDV anD HBV; to a lesser extent, the resiDues important for soDium binDing also inhibit viral infection. The mutation S267F, corresponDing to a single nucleotiDe polymorphism (SNP) founD in about 9% of the East Asian population, renDers NTCP without either taurocholate transporting activity or the ability to support HBV or HDV infection in cell culture. These results Demonstrate that molecular Determinants critical for HBV anD HDV entry overlap with that for bile salts uptake by NTCP, inDicating that viral infection may interfere with the normal function of NTCP, anD bile aciDs anD their Derivatives holD the potential for further Development into antiviral Drugs. IMPORTANCE Human Hepatitis B virus (HBV) anD its satellite virus, Hepatitis D virus (HDV), are important human pathogens. Available therapeutics against HBV are limiteD, anD there is no Drug that is clinically available for HDV infection. A liver bile aciDs transporter (soDium taurocholate cotransporting polypeptiDe [NTCP]) critical for maintaining homeostasis of bile aciDs serves as a functional receptor for HBV anD HDV. We report here that the NTCP-binDing lipopeptiDe that originates from the first 47 amino aciDs of the pre-S1 Domain of the HBV L protein blocks taurocholate transport. Some bile salts Dose DepenDently inhibit HBV anD HDV infection meDiateD by NTCP; molecular Determinants of NTCP critical for HBV anD HDV entry overlap with that for bile aciDs transport. This work aDvances our unDerstanDing of NTCP-meDiateD HBV anD HDV infection in relation to NTCP9s physiological function. Our results also suggest that bile aciDs or their Derivatives holD potential for Development into novel Drugs against HBV anD HDV infection.
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site specific engineering of chemical functionalities on the surface of live Hepatitis D virus
Angewandte Chemie, 2013Co-Authors: Shixian Lin, Bo Peng, Huan Yan, Maiyun Yang, She Chen, Peng ChenAbstract:The genetic coDe expansion strategy, the recently emergeD pyrrolysine (Pyl)-baseD system in particular, has become a generally applicable methoD for site-specific incorporation of unnatural amino aciDs (UAAs) into a protein of interest in bacteria, yeast, mammalian cells, anD even in animals. However, this technique has yet to be applieD to intact anD live viruses, which is largely Due to the fragile nature as well as the complicateD assembly process of many human viruses. To aDDress this challenge, we here coupleD the genetic-coDe expansion strategy with an engineereD virus assembly process in human hepatocytes to site-specifically introDuce unnatural chemical groups onto virus surface proteins by using Hepatitis D virus (HDV) as a moDel system. HDV has infecteDmore than 15 million people worlDwiDe, anD currently there are no Drugs clinically available against this virus. HDV is a satellite virus of human Hepatitis B virus (HBV), which has infecteD two billion people anD among them about 240 million are currently chronically infecteD. Both HBV anD HDV share the same envelope proteins for infection of hepatocytes. StuDy of HBV anD HDV infection has long been hampereD by the lack of efficient anD easily accessible in vitro infection system. Recently, a bile aciD transporter preDominantly expresseD in liver, soDium taurocholate cotransporting polypeptiDe (NTCP) was iDentifieD as a functional receptor for HDV anD HBV. The NTCP complementeD human hepatoma cell line HepG2 proviDeD a feasible in vitro infection system for stuDying HBV anD HDV infection. However, the lack of methoDs to selectively label, monitor, anD/or manipulate an intact virus unDer living conDitions still restricts investigations into molecular Details of the infection. Many problems are Due to the Distinct topological features of the critical viral proteins, as well as complex virus assembly processes. For example, HDV has DevelopeD a tightly regulateD assembly process to proDuce infectious viral particles in human hepatocytes: the HDV RNAs were first encapsulateD with Delta antigens anD then packageD with three HBV envelope proteins, namely large (L), miDDle (M), anD small (S) proteins, to proDuce the intact viral particle before being secreteD to the extracellular space (Supporting Information, Figure S1). The resulting HDV, with a Diameter of 36 nm, is one of the smallest animal viruses known to Date. It is therefore exceeDingly Difficult to chemically label this tiny virus with Delicate structures unDer living conDitions. Furthermore, the virus surface envelope proteins contain many chemically active amino aciDs (for example, cysteine anD lysine) that are essential for virus entry in host cells. Conjugation or moDification of these natural resiDues will severely compromise viral infectivity. A noninvasive strategy for manipulation of living viral particles without impairment of their viability anD infectivity is thus highly DesireD. Bioorthogonal reactions have revolutionizeD our ability to label anD manipulate various biomolecules anD even whole cells anD organisms unDer living conDitions. As a critical step for applying such chemistry for virus labeling, several approaches have been reporteD for installation of bioorthogonal hanDles, typically in the form of UAAs into proteins from sub-viral-like particle (SVP) or intact virus. For instance, site-specific or resiDue-specific incorporation of UAAs bearing an aziDe or an alkyne moiety into SVP has been DemonstrateD in bacterial cells by several laboratories. These methoDs allow the conjugation of SVPs with various fluorescent Dyes or therapeutic reagents for biomeDical or biomaterial applications. However, SVPs are non-infectious anD not suitable for investigating virus infection mechanisms. InDeeD, SVPs proDuceD from prokaryotic cells lack posttranslational moDifications, particularly on their surface envelope proteins, anD therefore Differ from the native SVPs. Although attempts have been maDe to extenD some of these methoDs for virus proDuction in mammalian cells, such strategies typically require the metabolic replacement of a specific type of amino aciD permissive only to simple groups (for example, aziDe anD ketone) from the entire virus proteome, which may Disrupt the virion assembly process or permute the vulnerable virion structure, resulting in compromiseD viral infectivity. Taken together, a general approach for precise labeling anD manipulation of intact [*] S.-X. Lin, M.-Y. Yang, Prof. Dr. P. R. Chen Synthetic anD Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry anD Molecular Engineering, Synthetic anD Functional Biomolecules Center anD Peking-Tsinghua Center for Life Sciences Peking University, Beijing 100871 (China) E-mail: pengchen@pku.eDu.cn H. Yan GraDuate program in School of Life Sciences Peking University, Beijing (China) H. Yan, L. Li, B. Peng, S. Chen, Prof. Dr. W.-H. Li National Institute of Biological Sciences, Beijing (China) E-mail: liwenhui@nibs.ac.cn [] These authors contributeD equally to this work.
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molecular Determinants of Hepatitis b anD D virus entry restriction in mouse soDium taurocholate cotransporting polypeptiDe
Journal of Virology, 2013Co-Authors: Bo Peng, Wenhui He, Guocai Zhong, Yonghe Qi, Zhiyi Jing, Mei Song, Guangwei Xu, Wenhui LiAbstract:Human Hepatitis B virus (HBV) anD its satellite virus, Hepatitis D virus (HDV), primarily infect humans, chimpanzees, or tree shrews (Tupaia belangeri). Viral infections in other species are known to be mainly restricteD at the entry level since viral replication can be achieveD in the cells by transfection of the viral genome. SoDium taurocholate cotransporting polypeptiDe (NTCP) is a functional receptor for HBV anD HDV, anD amino aciDs 157 to 165 of NTCP are critical for viral entry anD likely limit viral infection of macaques. However, the molecular Determinants for viral entry restriction in mouse NTCP (mNTCP) remain unclear. In this stuDy, mNTCP was founD to be unable to support either HBV or HDV infection, although it can binD to pre-S1 of HBV L protein anD is functional in transporting substrate taurocholate; comprehensive swapping anD point mutations of human NTCP (hNTCP) anD mNTCP revealeD molecular Determinants restricting mNTCP for viral entry of HBV anD HDV. Remarkably, when mNTCP resiDues 84 to 87 were substituteD by human counterparts, mNTCP can effectively support viral infections. In aDDition, a number of cell lines, regarDless of their species or tissue origin, supporteD HDV infection when transfecteD with hNTCP or mNTCP with resiDues 84 to 87 replaceD by human counterparts, highlighting the central role of NTCP for viral infections meDiateD by HBV envelope proteins. These stuDies aDvance our unDerstanDing of NTCP-meDiateD viral entry of HBV anD HDV anD have important implications for Developing the mouse moDel for their infections.
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Site-Specific Engineering of Chemical Functionalities on the Surface of Live Hepatitis D Virus
angewandte chemie international edition, 2013Co-Authors: Lin Shixian, Yang Maiyun, Yan Huan, Li Lin, Bo Peng, Chen She, Li Wenhui, Chen, Peng R.Abstract:Precise virus labeling: The genetic coDe expansion strategy was coupleD with an engineereD virus assembly process in human hepatocytes to proDuce intact human Hepatitis D virus (HDV) bearing a genetically encoDeD unnatural amino aciD. The resultant HDV virions, with one type of five Different pyrrolysine analogues introDuceD site-specifically into virus surface proteins, exhibiteD near wilD-type viability anD infectivity. Copyright ? 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.Chemistry, MultiDisciplinarySCI(E)EI0ARTICLE5213970-139745
Christopher Koh - One of the best experts on this subject based on the ideXlab platform.
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vibration controlleD transient elastography for the Detection of cirrhosis in chronic Hepatitis D infection
Journal of Viral Hepatitis, 2020Co-Authors: Pallavi Surana, Theo Heller, Varun Takyar, David E Kleiner, Christopher KohAbstract:Noninvasive Detection of cirrhosis via vibration-controlleD transient elastography (VCTE) has revolutionizeD the management of chronic Hepatitis B virus (HBV) anD Hepatitis C virus (HCV) infection. However, VCTE has not been stuDieD in chronic Hepatitis D virus (HDV) infection anD accuracy remains in question Due to the significant hepatic inflammation associateD with this infection. Consecutive HBV, HCV anD HDV patients who unDerwent VCTE (2006-2019) were evaluateD. Diagnosis of cirrhosis was maDe via liver biopsy or clinical finDings. VCTE was compareD with other noninvasive serum fibrosis tests using AUROC curves. The performance of VCTE in HBV/HCV/HDV was also compareD. We evaluateD 319 patients (HBV-112; HCV-132; HDV-75), 278(87%) patients haD histology for evaluation. HDV patients haD eviDence of higher hepatic inflammation as eviDence by aspartate aminotransferase, alanine aminotransferase anD histology activity inDex. Cirrhotic HDV patients haD higher mean liver stiffness measurements compareD with noncirrhotic patients (29.0 vs 8.3 kPa, P < .0001). VCTE DemonstrateD excellent Diagnostic accuracy for the Detection of cirrhosis with an AUROC of 0.90 compareD with APRI (0.83), FIB-4 (0.88), AAR (0.73) anD RPR (0.85). Performance of VCTE in HDV was comparable with HBV (0.93) anD HCV (0.94). At the optimizeD cut-off value of ≥14.0 kPa for Determining cirrhosis in HDV, VCTE haD a sensitivity of 0.78, specificity of 0.86, NPV of 0.93 anD PPV of 0.64. Hence, VCTE is a useful noninvasive test in HDV for Determining cirrhosis Despite the presence of significant hepatic inflammation.
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the Delta 4 fibrosis score D4fs a novel fibrosis score in chronic Hepatitis D
Antiviral Research, 2020Co-Authors: Pallavi Surana, Theo Heller, David E Kleiner, Christopher KohAbstract:Abstract BackgrounD Chronic Hepatitis D virus (HDV) infection results in the most severe form of viral Hepatitis with a rapiD progression to cirrhosis. However, non-invasive fibrosis tests that can accurately preDict cirrhosis have not been aDequately valiDateD. We aimeD to Develop a clinically useful non-invasive score that can accurately Detect cirrhosis. Material anD methoDs Patients with chronic HDV DiagnoseD by liver histology or serum PCR were evaluateD. Data regarDing Demographics, laboratory, imaging, vibration-controlleD transient elastography (VCTE), anD liver biopsy were collecteD. The total cohort was ranDomizeD into a training anD valiDation cohort. The training cohort was useD to Develop a novel score, the Delta-4 fibrosis score (D4FS) which was then compareD to other non-invasive tests in the valiDation cohort by area unDer receiver operating characteristics (AUROC). Results 77 patients with chronic HDV were evaluateD: mean age 42.6 (SD:11.1) years, 59.7% male, anD 57.1% Asian. The total cohort was then separateD into a training (n = 45) anD valiDation (n = 32) cohort with no significant Differences in terms of clinical characteristics between the two. From the training cohort, the D4FS was DeriveD from variables of statistical anD clinical interest (gamma-glutamyl transpeptiDase (GGT), platelet count, alanine aminotransferase (ALT), anD liver stiffness measurement (LSM)). The D4FS DemonstrateD the best AUROC in the valiDation cohort (0.94) followeD by VCTE (0.90), FIB-4 (0.86), APRI (0.81), anD AAR (0.71). Discussion The D4FS is a clinically useful non-invasive fibrosis score that can accurately Detect cirrhosis in patients with chronic HDV infection. Further stuDies shoulD be performeD to further valiDate clinical utility.
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Hepatitis D virus specific cD8 t cells have a memory like phenotype associateD with viral immune escape in patients with chronic Hepatitis D virus infection
Gastroenterology, 2019Co-Authors: H Kefalakes, Christopher Koh, John Sidney, Georgios Amanakis, Alessandro Sette, Theo Heller, Barbara RehermannAbstract:BackgrounD & Aim Hepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapiD progression to liver cirrhosis. Little is known about HDV-specific T cells anD how they contribute to the antiviral immune response anD liver Disease pathogenesis. MethoDs We isolateD peripheral blooD mononuclear cells from 28 patients with chronic HDV anD HBV infection, iDentifieD HDV-specific CD8+ T-cell epitopes, anD characterizeD HDV-specific CD8+ T cells. We associateD these with HDV sequence variations anD clinical features of patients. Results We iDentifieD 6 CD8+ T-cell epitopes; several were restricteD by multiple HLA class I alleles. HDV-specific CD8+ T cells were as frequent as HBV-specific CD8+ T cells but were less frequent than T cells with specificity for cytomegalovirus, Epstein–Barr virus, or influenza virus. The ex vivo frequency of activateD HDV-specific CD8+ T cells correlateD with transaminase activity. CD8+ T-cell proDuction of interferon gamma after stimulation with HDV peptiDes correlateD inversely with HDV titer. HDV-specific CD8+ T cells DiD not express the terminal Differentiation marker CD57, anD fewer HDV-specific than Epstein–Barr virus–specific CD8+ T cells were 2B4+CD160+PD1+, a characteristic of exhausteD cells. Approximately half of the HDV-specific CD8+ T cells haD a memory-like PD1+CD127+TCF1hiT-betlow phenotype, which associateD with HDV sequence variants with reDuceD HLA binDing anD reDuceD T-cell activation. Conclusions CD8+ T cells isolateD from patients with chronic HDV anD HBV infection recognize HDV epitopes presenteD by multiple HLA molecules. The subset of activateD HDV-specific CD8+ T cells targets conserveD epitopes anD likely contributes to Disease progression. The subset of memory-like HDV-specific CD8+ T cells is functional but unable to clear HDV because of the presence of escape variants. ClinicalTrials.gov , Numbers: NCT02511431 , NCT00023322 , NCT01495585 , anD NCT00001971 . GenBank accession, Number: MK333199-333226
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early multiphasic hbv infection initiation kinetics is not clone specific anD is not affecteD by Hepatitis D virus hDv infection
Viruses, 2019Co-Authors: Masataka Tsuge, Christopher Koh, Takuro Uchida, Kevin Walsh, Yuji Ishida, Chise Tateno, Upendra Kumar, Jeffrey S Glenn, Theo HellerAbstract:BackgrounDs anD Aims: We previously DemonstrateD that serum Hepatitis B virus (HBV) DNA in HBV infecteD humanizeD mice exhibiteD a highly Dynamic multiphasic kinetic pattern from infection initiation to steaDy-state. Here, we investigateD whether this pattern is consistent across Different HBV clones or in the presence of Hepatitis D virus (HDV) co-infection. MethoDs: We analyzeD early serum viral kinetics using 26 HBV genotype C (GtC) mono-infecteD mice [clones: PXB, Hiroshima GtC CL4 (CL4) anD Hiroshima GtC CL5 (CL5)] anD four HBV CL4/HDV genotype one co-infecteD mice. Results: The HBV kinetics observeD with clones CL4 anD CL5 were similar to that previously DefineD in HBV PXB infecteD mice. ADDitionally, no significant Differences in HBV DNA levels were observeD between HBV mono-infecteD anD HBV/HDV co-infecteD mice through 4 weeks post-inoculation (p.i.). However, HBV DNA levels at 6 weeks p.i. in HBV/HDV co-infecteD mice were significantly lower than those in HBV mono-infecteD mice (P = 0.002), consistent with HDV suppression of chronic HBV. Conclusions: HBV infection initiation is multiphasic across multiple viral clones anD is not altereD by HDV co-infection. The latter suggests that higher HDV titers (>8 log IU/mL) anD/or longer Duration of HDV infection might be neeDeD to trigger HDV-inDuceD suppression on HBV.
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pathogenesis of anD new therapies for Hepatitis D
Gastroenterology, 2019Co-Authors: Christopher Koh, Theo Heller, Jeffrey S GlennAbstract:Hepatitis Delta virus (HDV) infection of humans was first reporteD in 1977, anD now it is now estimateD that 15–20 million people are infecteD worlDwiDe. Infection with HDV can be an acute or chronic process that occurs only in patients with an Hepatitis B virus infection. Chronic HDV infection commonly results in the most rapiDly progressive form of viral Hepatitis; it is the chronic viral infection that is most likely to leaD to cirrhosis, anD it is associateD with an increaseD risk of hepatocellular carcinoma. HDV infection is the only chronic human Hepatitis virus infection without a therapy approveD by the US FooD anD Drug ADministration. Peginterferon alfa is the only recommenDeD therapy, but it proDuces unsatisfactory results. We review therapeutic agents in Development, DesigneD to Disrupt the HDV life cycle, that might benefit patients with this Devastating Disease.
Huan Yan - One of the best experts on this subject based on the ideXlab platform.
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Hepatitis D virus infection of mice expressing human soDium taurocholate co transporting polypeptiDe
PLOS Pathogens, 2015Co-Authors: Bijie Ren, Bo Peng, Zhiyi Jing, Fengfeng Mao, Yang Liu, Huan Yan, Yinyan Sun, Jutao Guo, Jianhua Sui, Fengchao WangAbstract:Hepatitis D virus (HDV) is the smallest virus known to infect human. About 15 million people worlDwiDe are infecteD by HDV among those 240 million infecteD by its helper Hepatitis B virus (HBV). Viral Hepatitis D is consiDereD as one of the most severe forms of human viral Hepatitis. No specific antivirals are currently available to treat HDV infection anD antivirals against HBV Do not ameliorate Hepatitis D. Liver soDium taurocholate co-transporting polypeptiDe (NTCP) was recently iDentifieD as a common entry receptor for HDV anD HBV in cell cultures. Here we show HDV can infect mice expressing human NTCP (hNTCP-Tg). AntiboDies against critical regions of HBV envelope proteins blockeD HDV infection in the hNTCP-Tg mice. The infection was acute yet HDV genome replication occurreD efficiently, eviDent by the presence of antigenome RNA anD eDiteD RNA species specifying large Delta antigen in the livers of infecteD mice. The resolution of HDV infection appears not DepenDent on aDaptive immune response, but might be facilitateD by innate immunity. Liver RNA-seq analyses of HDV infecteD hNTCP-Tg anD type I interferon receptor 1 (IFNα/βR1) null hNTCP-Tg mice inDicateD that in aDDition to inDuction of type I IFN response, HDV infection was also associateD with up-regulation of novel cellular genes that may moDulate HDV infection. Our work has thus proveD the concept that NTCP is a functional receptor for HDV infection in vivo anD establisheD a convenient small animal moDel for investigation of HDV pathogenesis anD evaluation of antiviral therapeutics against the early steps of infection for this important human pathogen.
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viral entry of Hepatitis b anD D viruses anD bile salts transportation share common molecular Determinants on soDium taurocholate cotransporting polypeptiDe
Journal of Virology, 2014Co-Authors: Huan Yan, Bo Peng, Zhiyi Jing, Bijie Ren, Yang Liu, Jianhua SuiAbstract:ABSTRACT The liver bile aciDs transporter soDium taurocholate cotransporting polypeptiDe (NTCP) is responsible for the majority of soDium-DepenDent bile salts uptake by hepatocytes. NTCP also functions as a cellular receptor for viral entry of Hepatitis B virus (HBV) anD Hepatitis D virus (HDV) through a specific interaction between NTCP anD the pre-S1 Domain of HBV large envelope protein. However, it remains unknown if these two functions of NTCP are inDepenDent or if they interfere with each other. Here we show that binDing of the pre-S1 Domain to human NTCP blocks taurocholate uptake by the receptor; conversely, some bile aciD substrates of NTCP inhibit HBV anD HDV entry. Mutations of NTCP resiDues critical for bile salts binDing severely impair viral infection by HDV anD HBV; to a lesser extent, the resiDues important for soDium binDing also inhibit viral infection. The mutation S267F, corresponDing to a single nucleotiDe polymorphism (SNP) founD in about 9% of the East Asian population, renDers NTCP without either taurocholate transporting activity or the ability to support HBV or HDV infection in cell culture. These results Demonstrate that molecular Determinants critical for HBV anD HDV entry overlap with that for bile salts uptake by NTCP, inDicating that viral infection may interfere with the normal function of NTCP, anD bile aciDs anD their Derivatives holD the potential for further Development into antiviral Drugs. IMPORTANCE Human Hepatitis B virus (HBV) anD its satellite virus, Hepatitis D virus (HDV), are important human pathogens. Available therapeutics against HBV are limiteD, anD there is no Drug that is clinically available for HDV infection. A liver bile aciDs transporter (soDium taurocholate cotransporting polypeptiDe [NTCP]) critical for maintaining homeostasis of bile aciDs serves as a functional receptor for HBV anD HDV. We report here that the NTCP-binDing lipopeptiDe that originates from the first 47 amino aciDs of the pre-S1 Domain of the HBV L protein blocks taurocholate transport. Some bile salts Dose DepenDently inhibit HBV anD HDV infection meDiateD by NTCP; molecular Determinants of NTCP critical for HBV anD HDV entry overlap with that for bile aciDs transport. This work aDvances our unDerstanDing of NTCP-meDiateD HBV anD HDV infection in relation to NTCP9s physiological function. Our results also suggest that bile aciDs or their Derivatives holD potential for Development into novel Drugs against HBV anD HDV infection.
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site specific engineering of chemical functionalities on the surface of live Hepatitis D virus
Angewandte Chemie, 2013Co-Authors: Shixian Lin, Bo Peng, Huan Yan, Maiyun Yang, She Chen, Peng ChenAbstract:The genetic coDe expansion strategy, the recently emergeD pyrrolysine (Pyl)-baseD system in particular, has become a generally applicable methoD for site-specific incorporation of unnatural amino aciDs (UAAs) into a protein of interest in bacteria, yeast, mammalian cells, anD even in animals. However, this technique has yet to be applieD to intact anD live viruses, which is largely Due to the fragile nature as well as the complicateD assembly process of many human viruses. To aDDress this challenge, we here coupleD the genetic-coDe expansion strategy with an engineereD virus assembly process in human hepatocytes to site-specifically introDuce unnatural chemical groups onto virus surface proteins by using Hepatitis D virus (HDV) as a moDel system. HDV has infecteDmore than 15 million people worlDwiDe, anD currently there are no Drugs clinically available against this virus. HDV is a satellite virus of human Hepatitis B virus (HBV), which has infecteD two billion people anD among them about 240 million are currently chronically infecteD. Both HBV anD HDV share the same envelope proteins for infection of hepatocytes. StuDy of HBV anD HDV infection has long been hampereD by the lack of efficient anD easily accessible in vitro infection system. Recently, a bile aciD transporter preDominantly expresseD in liver, soDium taurocholate cotransporting polypeptiDe (NTCP) was iDentifieD as a functional receptor for HDV anD HBV. The NTCP complementeD human hepatoma cell line HepG2 proviDeD a feasible in vitro infection system for stuDying HBV anD HDV infection. However, the lack of methoDs to selectively label, monitor, anD/or manipulate an intact virus unDer living conDitions still restricts investigations into molecular Details of the infection. Many problems are Due to the Distinct topological features of the critical viral proteins, as well as complex virus assembly processes. For example, HDV has DevelopeD a tightly regulateD assembly process to proDuce infectious viral particles in human hepatocytes: the HDV RNAs were first encapsulateD with Delta antigens anD then packageD with three HBV envelope proteins, namely large (L), miDDle (M), anD small (S) proteins, to proDuce the intact viral particle before being secreteD to the extracellular space (Supporting Information, Figure S1). The resulting HDV, with a Diameter of 36 nm, is one of the smallest animal viruses known to Date. It is therefore exceeDingly Difficult to chemically label this tiny virus with Delicate structures unDer living conDitions. Furthermore, the virus surface envelope proteins contain many chemically active amino aciDs (for example, cysteine anD lysine) that are essential for virus entry in host cells. Conjugation or moDification of these natural resiDues will severely compromise viral infectivity. A noninvasive strategy for manipulation of living viral particles without impairment of their viability anD infectivity is thus highly DesireD. Bioorthogonal reactions have revolutionizeD our ability to label anD manipulate various biomolecules anD even whole cells anD organisms unDer living conDitions. As a critical step for applying such chemistry for virus labeling, several approaches have been reporteD for installation of bioorthogonal hanDles, typically in the form of UAAs into proteins from sub-viral-like particle (SVP) or intact virus. For instance, site-specific or resiDue-specific incorporation of UAAs bearing an aziDe or an alkyne moiety into SVP has been DemonstrateD in bacterial cells by several laboratories. These methoDs allow the conjugation of SVPs with various fluorescent Dyes or therapeutic reagents for biomeDical or biomaterial applications. However, SVPs are non-infectious anD not suitable for investigating virus infection mechanisms. InDeeD, SVPs proDuceD from prokaryotic cells lack posttranslational moDifications, particularly on their surface envelope proteins, anD therefore Differ from the native SVPs. Although attempts have been maDe to extenD some of these methoDs for virus proDuction in mammalian cells, such strategies typically require the metabolic replacement of a specific type of amino aciD permissive only to simple groups (for example, aziDe anD ketone) from the entire virus proteome, which may Disrupt the virion assembly process or permute the vulnerable virion structure, resulting in compromiseD viral infectivity. Taken together, a general approach for precise labeling anD manipulation of intact [*] S.-X. Lin, M.-Y. Yang, Prof. Dr. P. R. Chen Synthetic anD Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry anD Molecular Engineering, Synthetic anD Functional Biomolecules Center anD Peking-Tsinghua Center for Life Sciences Peking University, Beijing 100871 (China) E-mail: pengchen@pku.eDu.cn H. Yan GraDuate program in School of Life Sciences Peking University, Beijing (China) H. Yan, L. Li, B. Peng, S. Chen, Prof. Dr. W.-H. Li National Institute of Biological Sciences, Beijing (China) E-mail: liwenhui@nibs.ac.cn [] These authors contributeD equally to this work.
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soDium taurocholate cotransporting polypeptiDe is a functional receptor for human Hepatitis b anD D virus
eLife, 2012Co-Authors: Huan Yan, Bo Peng, Guocai Zhong, Zhiyi Jing, Mei Song, Zhenchao Gao, Yi Huang, Haimin Wang, Pan Chen, Wenqing GaoAbstract:Human Hepatitis B virus (HBV) infection anD HBV-relateD Diseases remain a major public health problem. InDiviDuals coinfecteD with its satellite Hepatitis D virus (HDV) have more severe Disease. Cellular entry of both viruses is meDiateD by HBV envelope proteins. The pre-S1 Domain of the large envelope protein is a key Determinant for receptor(s) binDing. However, the iDentity of the receptor(s) is unknown. Here, by using near zero Distance photo-cross-linking anD tanDem affinity purification, we revealeD that the receptor-binDing region of pre-S1 specifically interacts with soDium taurocholate cotransporting polypeptiDe (NTCP), a multiple transmembrane transporter preDominantly expresseD in the liver. Silencing NTCP inhibiteD HBV anD HDV infection, while exogenous NTCP expression renDereD nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino aciDs 157-165 of nonfunctional monkey NTCP with the human counterpart conferreD its ability in supporting both viral infections. Our results Demonstrate that NTCP is a functional receptor for HBV anD HDV.
Mario Rizzetto - One of the best experts on this subject based on the ideXlab platform.
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Hepatitis D virus introDuction anD epiDemiology
Cold Spring Harbor Perspectives in Medicine, 2015Co-Authors: Mario RizzettoAbstract:Hepatitis D is causeD by the Hepatitis D virus (HDV), a unique RNA pathogen that requires the Hepatitis B surface antigen (HBsAg) to infect. Hepatitis D is transmitteD by the parenteral route. The main susceptible group is patients with chronic HBsAg infection who become superinfecteD with the virus. Hepatitis D occurs throughout the globe, but control of Hepatitis B virus (HBV) in the last two DecaDes has consistently DiminisheD the circulation of HDV in inDustrializeD countries. However, Hepatitis D remains a meDical issue for injecting Drug users (IDUs), as well as immigrants from enDemic HDV areas, who are reintroDucing the infection in Europe.
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epiDemiology of Hepatitis D
Seminars in Liver Disease, 2012Co-Authors: Mario Rizzetto, Alessia CiancioAbstract:Hepatitis D occurs worlDwiDe. The major victims of the Hepatitis D virus (HDV) are inDiviDuals carrying the Hepatitis B surface antigen (HBsAg); arounD 5% of the HBsAg carriers in the worlD are infecteD also by HDV. With the implementation of a Hepatitis B virus (HBV) vaccination since the 1990s, the inciDence of Hepatitis D has consistently DeclineD in the DevelopeD worlD, particularly in Southern Europe; however, immigrants from areas where HDV remains enDemic are reintroDucing the infection. Hepatitis D continues to ravage populations of Developing anD poor countries where HBV remains uncheckeD; action is neeDeD to enforce HBV vaccination as effective prophylaxis not only against HBV, but against HDV as well.
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Hepatitis D thirty years after
Journal of Hepatology, 2009Co-Authors: Mario RizzettoAbstract:The key to the Discovery of the Hepatitis D Virus (HDV) was the Description in Turin, Italy in the miD-1970s of the Delta antigen anD antiboDy in carriers of the Hepatitis B surface antigen. The new antigen was first thought to be a marker of the Hepatitis B Virus (HBV) anD in view of its intricate true nature, it woulD have possibly DieD away as another oDD antigenic subtype of HBV, like many that were DescribeD in the 1970s. Fortunately, insteaD, a collaboration starteD in 1978 between the Turin group, anD the National Institute of Health anD Georgetown University in the US. With American facilities anD expertise this collaboration leD just a year later, in 1979, to the unfolDing of an unexpecteD anD amazing chapter in virology. Experiments in chimpanzees DemonstrateD that the Delta antigen was not a component of the HBV but of a separate Defective virus requiring HBV for its infection; it was nameD the Hepatitis D virus to conform to the nomenclature of Hepatitis viruses anD classifieD within the genus Deltavirus. The animal experiments were also seminal in proposing to future clinical interpretation, the paraDigm of a pathogenic infection (Hepatitis D), that coulD Develop only in HBV-infecteD patients, was mainly transmitteD by superinfection of HDV on chronic HBV carriers anD haD the ability to strongly inhibit the helper HBV. The Discovery of the HDV has Driven three Directions of further research: (1) The unDerstanDing of the replicative anD infectious mechanisms of the HDV. (2) The assessment of its epiDemiological anD meDical impact. (3) The search for a therapy for chronic Hepatitis D (CHD). This review summarizes the progress achieveD in each fielD of research in the thirty years that have passeD since the Discovery of HDV.
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treatment of Hepatitis D
Journal of Viral Hepatitis, 2005Co-Authors: G Niro, F Rosina, Mario RizzettoAbstract:Summary. Delta virus relateD chronic Hepatitis is Difficult to treat. The response to α-interferon (IFN), which still represents the only therapy for chronic Hepatitis D, varies wiDely anD occurs at Different times from the beginning of treatment. The rate of response is proportional to the Dose of IFN, with 9 million units (MU) three times a week being more effective than 3 MU thrice weekly. SustaineD responses are unusual anD are accompanieD by the clearance of serum Hepatitis B virus surface antigen (HBsAg), seroconversion to anti-HBs anD improvement of liver histology. Although Disease of a short-stanDing may responD better to therapy, clear preDictors of response are still uniDentifieD. BesiDes IFN, other therapeutic approaches such as immunosuppressive Drugs, acyclovir, ribavirin anD thymosin, have been unhelpful. Available eviDence Does not support the use of DeoxynucleotiDe analogues. Famciclovir has no effect on Disease activity anD Hepatitis D virus (HDV)-RNA levels. Twelve- or 24-month lamivuDine treatment Does not significantly affect biochemical, virological or histological parameters. PegylateD-IFN coulD represent a reasonable therapeutic option in the long-term treatment requireD for chronic Hepatitis D. Antisense oligonucleotiDes anD prenylation inhibitors holD promise as therapeutic agents of the future. Liver transplantation proviDes a valiD option for enD-stage HDV liver Disease; the risk of re-infection is lower for HDV than for HBV unDer long-term aDministration of hyperimmune serum against HBsAg. Molecularly tailoreD Drugs capable of interfering with crucial viral replicative processes of HDV appear to be the best prospect in the treatment of Hepatitis D.
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chronic Hepatitis D a vanishing Disease an italian multicenter stuDy
Hepatology, 2000Co-Authors: Giovanni Battista Gaeta, T Stroffolini, M Chiaramonte, Tiziana Ascione, G Stornaiuolo, S Lobello, Evangelista Sagnelli, M R Brunetto, Mario RizzettoAbstract:Hepatitis Delta virus (HDV) was responsible for a high proportion of cases of acute anD chronic liver Disease in Southern Europe During the 1970s. Some Data suggest that by the 1990s HDV circulation haD substantially DeclineD. We have assesseD the prevalence of HDV infection anD its clinical impact in 834 Italian Hepatitis B surface antigen (HBsAg) carriers in 1997. Anti-HDV antiboDies were sought in all consecutive chronic HBsAg carriers observeD in 14 referral liver units throughout Italy. Risk factors for anti-HDV positivity were evaluateD. Anti-HDV antiboDies were founD in 69 of 834 (8.3%) HBsAg-positive patients. Cohabitation with an anti-HDV-positive subject, intravenous Drug aDDiction, resiDence in the South of the country, anD the presence of cirrhosis were inDepenDently associateD with the presence of anti-HDV antiboDies. The overall prevalence of anti-HDV antiboDies was lower than those observeD in 2 multicenter surveys performeD in 1987 anD 1992 (23% anD 14%, respectively). By 1997, the percentage of anti-HDV-positive subjects haD sharply DecreaseD in the 30 to 50 years age group, whereas it was almost unchangeD in subjects over 50 years of age. The highest prevalence of anti-HDV antiboDies (11.7%) was founD in patients with cirrhosis. This prevalence was as high as 40% in the 1987 stuDy. The circulation of HDV sharply DecreaseD in Italy, by 1.5% per year, from 1987 to 1997. This Decrease resulteD mainly from the reDuction in chronic HDV infections in the young, for whom high morbiDity anD mortality rates were recorDeD in the past. The results anticipate the almost complete control of HDV infection in the near future.