Thomas F Baumert

Institut de Recherche contre les Cancers de l'Appareil Digestif, Strasburg, Alsace, France

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Publications (250)1870.7 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis B virus (HBV) infection is a major cause of chronic liver disease, including liver cirrhosis, liver failure and hepatocellular carcinoma (HCC)-the second leading and fastest rising cause of cancer death world-wide. While de novo infection can be efficiently prevented by vaccination and chronic infection can be controlled using antivirals targeting the viral polymerase, the development of efficient antiviral strategies to eliminate the virus and thus to cure infection remains a key unmet medical need. The recent progress in the development of robust infectious HBV cell culture models now enables the investigation of the full viral life cycle, including a more detailed study of the molecular mechanisms of virus-host interactions responsible for viral persistence. The understanding of these virus-host interactions will be instrumental for the development of curative treatments. Host-dependency factors have recently emerged as promising candidates to treat and prevent infection by various pathogens. This review focuses on the potential of host-targeting agents (HTAs) as novel antivirals to treat and cure HBV infection. These include HTAs that inhibit de novo and re-infection, synthesis and spread of cccDNA as well as development of immune-based approaches eliminating or curing infected hepatocytes, including the eradication of viral cccDNA. Copyright © 2015 Elsevier B.V. All rights reserved.
    08/2015; 14:41-46. DOI:10.1016/j.coviro.2015.07.009
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    Dataset: GPC5 screen
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    ABSTRACT: Lipoprotein components are crucial factors for hepatitis C virus (HCV) assembly and entry. As hepatoma cells producing cell culture-derived HCV particles (HCVcc) are impaired in some aspects of lipoprotein metabolism, it is of upmost interest to biochemically and functionally characterize the in vivo-produced viral particles, particularly regarding how lipoprotein components modulate HCV entry by lipid transfer receptors such as scavenger receptor BI (SR-BI). Sera from HCVcc-infected liver humanized FRG mice were separated by density gradients. Viral subpopulations, termed HCVfrg particles, were characterized for their physical properties, apolipoprotein association and infectivity. We demonstrate that in contrast to the widely-spread distribution of apolipoproteins across the different HCVcc subpopulations, the most infectious HCVfrg particles are highly enriched in ApoE, suggesting that such apolipoprotein enrichment plays a role for entry of in vivo-derived infectious particles, likely via usage of apolipoprotein receptors. Consistent with this salient feature, we further reveal previously undefined functionalities of SR-BI in promoting entry of in vivo-produced HCV. First, unlike HCVcc, SR-BI is a particularly limiting factor for entry of HCVfrg subpopulations of very low density. Second, HCVfrg entry involves SR-BI lipid transfer activity, but not its binding capacity to the viral glycoprotein E2. In conclusion, we demonstrate that composition and biophysical properties of the different subpopulations of in vivo-produced HCVfrg particles modulate their levels of infectivity and receptor usage, hereby featuring divergences with in vitro-produced HCVcc particles and highlighting the powerfulness of this in vivo model for the functional study of the interplay between HCV and liver components. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 07/2015; DOI:10.1074/jbc.M115.662999 · 4.57 Impact Factor
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    ABSTRACT: Chronic hepatitis B and D infections are major causes of liver disease and hepatocellular carcinoma worldwide. Efficient therapeutic approaches for cure are absent. Sharing the same envelope proteins, hepatitis B virus (HBV) and hepatitis D virus (HDV) use the sodium taurocholate co-transporting polypeptide (NTCP, a bile acid transporter) as a receptor to enter hepatocytes. However, the detailed mechanisms of the viral entry process are still poorly understood. Here, we established a high-throughput infectious cell culture model enabling functional genomics of HDV entry and infection. Using a targeted RNAi entry screen we identified glypican 5 (GPC5) as a common host cell entry factor for HBV and HDV. These findings advance our understanding of virus cell entry and open new avenues for curative therapies. Since glypicans have been shown to play a role in the control of cell division and growth regulation, virus-GPC5 interactions may also play a role in the pathogenesis of virus-induced liver disease and cancer. This article is protected by copyright. All rights reserved. © 2015 by the American Association for the Study of Liver Diseases.
    Hepatology 07/2015; DOI:10.1002/hep.28013 · 11.19 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) enters human hepatocytes through a multistep mechanism involving, among other host proteins, the virus receptor CD81. How CD81 governs HCV entry is poorly characterized, and CD81 protein interactions after virus binding remain elusive. We have developed a quantitative proteomics protocol to identify HCV-triggered CD81 interactions and found 26 dynamic binding partners. At least six of these proteins promote HCV infection, as indicated by RNAi. We further characterized serum response factor binding protein 1 (SRFBP1), which is recruited to CD81 during HCV uptake and supports HCV infection in hepatoma cells and primary human hepatocytes. SRFBP1 facilitates host cell penetration by all seven HCV genotypes, but not of vesicular stomatitis virus and human coronavirus. Thus, SRFBP1 is an HCV-specific, pan-genotypic host entry factor. These results demonstrate the use of quantitative proteomics to elucidate pathogen entry and underscore the importance of host protein-protein interactions during HCV invasion. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; DOI:10.1016/j.celrep.2015.06.063 · 8.36 Impact Factor
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  • Eloi R Verrier · Stefan Wieland · Thomas F Baumert
    Hepatology 06/2015; DOI:10.1002/hep.27935 · 11.19 Impact Factor
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    ABSTRACT: In our study, we characterized the effect on the Hepatitis C Virus (HCV) life cycle of Monensin, an ionophore that is known to raise the intracellular pH. We show that Monensin inhibits HCV entry in a pangenotypic and dose-dependent manner. Monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. Interestingly, we demonstrated that HCV cell-to-cell transmission is dependent on the vesicular pH. Under the selective pressure of Monensin, we selected a Monensin-resistant virus which has evolved to use a new entry route that is partially pH- and clathrin-independent. Characterization of this mutant led to the identification of two mutations in envelope proteins, Y297H in E1 and I399T in the hypervariable region 1 (HVR1) of E2, which confer resistance to Monensin and thus allow HCV to use a pH-independent entry route. Interestingly, the I399T mutation introduces a N-glycosylation site within HVR1, increases the density of virions and their sensitivity to neutralization with anti-apolipoprotein E (ApoE) antibodies, suggesting that this mutation likely induces conformational changes in HVR1 that in turn modulate the association with ApoE. Strikingly, the I399T mutation dramatically reduces HCV cell-to-cell spread. In conclusion, we identified a mutation in HVR1 that overcomes the vesicular pH-dependence, modifies the biophysical properties of particles and drastically reduces cell-to-cell transmission, indicating that the regulation by HVR1 of particle association with ApoE might control the pH-dependence of cell-free and cell-to-cell transmission. Thus, HVR1 and ApoE are critical regulators of HCV propagation. Although several cell surface proteins have been identified as entry factors for Hepatitis C Virus (HCV), precise mechanisms regulating its transmission into hepatic cells are still unclear. In our study, we used Monensin A, an ionophore that is known to raise the intracellular pH, and demonstrated that cell-free and cell-to-cell transmission are both pH-dependent processes. We generated Monensin-resistant viruses that displayed different entry routes and biophysical properties. Thanks to these mutants, we highlighted the importance of the hypervariable region 1 (HVR1) in E2 envelope protein for the association of particles with apolipoprotein E, which in turn might control the pH-dependency of cell-free and cell-to-cell transmission. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 06/2015; DOI:10.1128/JVI.00192-15 · 4.65 Impact Factor
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    Che C. Colpitts · Eloi R. Verrier · Thomas F. Baumert
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    ABSTRACT: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain major health problems worldwide, with 400-500 million chronically infected people worldwide. Chronic infection results in liver cirrhosis and hepatocellular carcinoma, the second leading cause of cancer death. Current treatments for HBV limit viral replication without efficiently curing infection. HCV treatment has markedly progressed with the licensing of direct-acting antivirals (DAAs) for HCV cure, yet limited access for the majority of patients is a major challenge. Preventative and curative treatment strategies, aimed at novel targets, are needed for both viruses. Viral entry represents one such target, although detailed knowledge of the entry mechanisms is a prerequisite. For HBV, the recent discovery of the NTCP cell entry factor enabled the establishment of an HBV cell culture model and showed that cyclosporin A and Myrcludex B are NTCP-targeting entry inhibitors. Advances in the understanding of HCV entry revealed it to be a complex process involving many factors, offering several antiviral targets. These include viral envelope proteins E1 and E2, virion-associated lipoprotein ApoE, and cellular factors CD81, SR-BI, EGFR, claudin-1, occludin, and the cholesterol transporter NPC1L1. Small molecules targeting SR-BI, EGFR and NPC1L1 have entered clinical trials, whereas other viral- and host-targeted small molecules, peptides and antibodies show promise in preclinical models. This review summarizes our current understanding of HBV and HCV entry, and describes novel antiviral targets and compounds in different stages of clinical development. Overall, proof-of-concept studies indicate that entry inhibitors are a promising class of antivirals to prevent and treat HBV and HCV infections.
    05/2015; DOI:10.1021/acsinfecdis.5b00039
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    ABSTRACT: Since their discovery, tremendous progress has been made in our understanding of the roles of claudins in tight junction physiology. In addition, interactions between claudins and other cellular proteins have highlighted their novel roles in cell physiology. Moreover, the importance of claudins is becoming apparent in the pathophysiology of several diseases, including viral infections. Notable is the discovery of CLDN1 as an essential host factor for hepatitis C virus (HCV) entry, which led to detailed characterization of CLDN1 and its association with tetraspanin CD81 for the initiation of HCV infection. CLDN1 has also been shown to facilitate dengue virus entry. Furthermore, owing to the roles of claudins in forming anatomical barriers, several viruses have been shown to alter claudin expression at the tight junction. This review summarizes the role of claudins in viral infection, with particular emphasis on HCV. Copyright © 2015. Published by Elsevier Ltd.
    Seminars in Cell and Developmental Biology 05/2015; DOI:10.1016/j.semcdb.2015.04.011 · 5.97 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) causes persistent infection in the majority of infected individuals. The mechanisms of persistence and clearance are only partially understood. Antibodies against host cell entry receptors have been shown to inhibit HCV infection in cell culture and animal models. In this study we aimed to investigate whether anti-receptor antibodies are induced during infection in humans in vivo and whether their presence is associated with outcome of infection. We established an ELISA using a recombinant CD81- claudin-1 (CLDN1) fusion protein to detect and quantify antibodies directed against extracellular epitopes of the HCV CD81-CLDN1 co-receptor complex. The presence of anti-receptor antibodies was studied in serum of patients from a well-defined cohort of a single-source HCV outbreak of pregnant women and several control groups including uninfected pregnant women, patients with chronic hepatitis B and D virus (HBV/HDV) infection and healthy individuals. The virus-neutralizing activity of antibodies was determined using recombinant cell culture-derived HCV (HCVcc). Our results demonstrate that HCV infected patients have statistically significantly higher anti-CD81/CLDN1 antibody titers during the early phase of infection than controls, the titers being significantly higher in resolvers compared to persisters. Functional studies using immunoadsorption and HCV cell culture models demonstrate that HCV-neutralizing anti-receptor antibodies are induced in early phase of HCV infection but not in control groups. The virus-neutralizing properties of these antibodies suggest a role for control of viral infection in conjunction with anti-viral responses. Characterization of these anti-receptor antibodies opens new avenues to prevent and treat HCV infection. This article is protected by copyright. All rights reserved. © 2015 by the American Association for the Study of Liver Diseases.
    Hepatology 05/2015; DOI:10.1002/hep.27906 · 11.19 Impact Factor
  • Medecine sciences: M/S 05/2015; 31(5):469-72. DOI:10.1051/medsci/20153105003 · 0.52 Impact Factor
  • Che C Colpitts · Mirjam B Zeisel · Thomas F Baumert
    Hepatology 04/2015; DOI:10.1002/hep.27876 · 11.19 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) infection relies on virus-host interactions with human hepatocytes, a context in which host cell kinases play critical roles in every step of the HCV life cycle. During viral entry, cellular kinases, including EGFR, EphA2 and PKA, regulate the localization of host HCV entry factors and induce receptor complex assembly. Following virion internalization, viral genomes replicate on endoplasmic reticulum-derived membranous webs. The formation of membranous webs depends on interactions between the HCV NS5a protein and PI4KIIIα. The phosphorylation status of NS5a, regulated by PI4KIIIα, CKI and other kinases, also acts as a molecular switch to virion assembly, which takes place on lipid droplets. The formation of lipid droplets is enhanced by HCV activation of IKKα. In view of the multiple crucial steps in the viral life cycle that are mediated by host cell kinases, these enzymes also represent complementary targets for antiviral therapy. This article is part of a Special Issue entitled:Inhibitors of Protein Kinases. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 04/2015; DOI:10.1016/j.bbapap.2015.04.011 · 4.66 Impact Factor
  • Journal of Hepatology 04/2015; 62:S196. DOI:10.1016/S0168-8278(15)30021-0 · 10.40 Impact Factor
  • Journal of Hepatology 04/2015; 62:S203-S204. DOI:10.1016/S0168-8278(15)30035-0 · 10.40 Impact Factor
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    ABSTRACT: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread. We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing. HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals. This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of Hepatology 04/2015; 62:S214. DOI:10.1016/S0168-8278(15)30058-1 · 10.40 Impact Factor
  • Journal of Hepatology 04/2015; 62:S576. DOI:10.1016/S0168-8278(15)30881-3 · 10.40 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer. Cell entry of HCV and other pathogens is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver-chimeric mouse model, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the number of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.
    Nature Biotechnology 03/2015; 33(5). DOI:10.1038/nbt.3179 · 39.08 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) infects the liver and hepatocytes are the major cell type supporting viral replication. Hepatocytes and cholangiocytes derive from a common hepatic progenitor cell that proliferates during inflammatory conditions, raising the possibility that cholangiocytes may support HCV replication and contribute to the hepatic reservoir. We screened cholangiocytes along with a panel of cholangiocarcinoma-derived cell lines for their ability to support HCV entry and replication. While primary cholangiocytes were refractory to infection and lacked expression of several entry factors, two cholangiocarcinoma lines, CC-LP-1 and Sk-ChA-1, supported efficient HCV entry; furthermore, Sk-ChA-1 cells supported full virus replication. In vivo cholangiocarcinomas expressed all of the essential HCV entry factors; however, cholangiocytes adjacent to the tumor and in normal tissue showed a similar pattern of receptor expression to ex vivo isolated cholangiocytes, lacking SR-BI expression, explaining their inability to support infection. This study provides the first report that HCV can infect cholangiocarcinoma cells and suggests that these heterogeneous tumors may provide a reservoir for HCV replication in vivo.
    Journal of General Virology 02/2015; 96(Pt_6). DOI:10.1099/vir.0.000090 · 3.53 Impact Factor

Publication Stats

6k Citations
1,870.70 Total Impact Points


  • 2015
    • Institut de Recherche contre les Cancers de l'Appareil Digestif
      Strasburg, Alsace, France
  • 2008–2015
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2007–2015
    • University of Strasbourg
      • Laboratoire de BioVectorologie
      Strasburg, Alsace, France
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1998–2014
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2013
    • Imperial College London
      Londinium, England, United Kingdom
    • Institut de France
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States
  • 2010–2012
    • University of Birmingham
      • • School of Biosciences
      • • Institute for Biomedical Research
      Birmingham, England, United Kingdom
    • Stanford University
      • Department of Pathology
      Palo Alto, California, United States
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      • Department of Biology and Stem Cell Development
      Strasburg, Alsace, France
  • 2011
    • Cancer Research Center of Lyon
      Lyons, Rhône-Alpes, France
  • 2009
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2001–2009
    • University of Freiburg
      • • Faculty of Biology
      • • Department of Internal Medicine
      Freiburg, Baden-Württemberg, Germany
  • 2006–2007
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
    • Rensselaer Polytechnic Institute
      • Department of Chemical and Biological Engineering
      Troy, New York, United States
  • 2004
    • Technische Universität München
      München, Bavaria, Germany
  • 1998–2001
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Maryland, United States
  • 1996
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, Massachusetts, United States