Chronic viral hepatitis

Chronic viral hepatitis

Hepatitis B and C virus-host interaction (Prof. Dr. Ulrike Protzer)

The human hepatitis B virus (HBV) is a small, enveloped DNA viruses (family hepadnaviridae) whereas the hepatitis C virus is an enveloped plus-strand RNA virus (family flaviviridae). Although the viruses are rather diverse, both cause acute and chronic liver infections in humans. With about 350 million chronic HBV and about 170 million chronic HCV carriers worldwide who are at high risk of developing liver cirrhosis and hepatocellular carcinoma, chronic viral hepatitis is a major public health threat. Since strategies to eradicate the viruses and treatments for virus-induced liver disease and hepatocellular carcinoma are still very limited, novel therapeutic strategies are urgently needed. As a prerequisite for developing these, we established infection systems that allow studying (and interfering with) all steps of virus replication.

The main focus of our group is to understand in molecular detail the interaction of HBV with its host and its host cell, the hepatocyte. Hereby, we investigate which cellular pathways are involved in the control of HBV replication, which viral proteins may counteract them and how HBV is activated or inactivated by immune mediators and metabolites. In addition, we use the advanced understanding of HBV molecular biology for developing targeted antiviral strategies. Based on thorough analyses of immune responses, we design novel immunotherapies, test them in the preclinical mouse models we have established and promote preclinical development of the most promising ones.

Since hepatitis C virus infected individuals often develop type II diabetes, we investigate how the virus may interfere with insulin signaling. We also want to contribute to the molecular understanding of hepatocarcinogenesis, which develops on the basis of chronic hepatitis B or C virus infection.

Research focus

Our scientific interest is to better understand the interaction of hepatitis B (HBV) and C (HCV) virus with their host and to develop new therapeutic strategies to treat chronic viral hepatitis and hepatocellular carcinoma.

The majority of the team is currently concentrating on the question, how HBV is controlled by cellular defense mechanisms, innate immunity and by the systemic immune response, and how HBV manages to escape this immune control. To be able to study this, we have developed new animal and cell culture models of HBV infection, have established primary cell cultures and cellular infection models for HBV and HCV, respectively, and use molecular and immunological diagnostics to follow the human situation. In addition, we have established two HBV-transgenic mouse lines as models for vertical transmission of HBV, and have developed mouse models of self-limited as well as chronic hepatitis B. These models we use to develop novel antiviral therapies.

 

Research topics

Our scientific interest is to better understand the interaction of hepatitis B (HBV) and C (HCV) virus with their host and to develop new therapeutic strategies to treat chronic viral hepatitis and hepatocellular carcinoma.

The majority of the team is currently concentrating on the question, how HBV is controlled by cellular defense mechanisms, innate immunity and by the systemic immune response, and how HBV manages to escape this immune control. To be able to study this, we have developed new animal and cell culture models of HBV infection, have established primary cell cultures and cellular infection models for HBV and HCV, respectively, and use molecular and immunological diagnostics to follow the human situation. In addition, we have established two HBV-transgenic mouse lines as models for vertical transmission of HBV, and have developed mouse model of self-limited as well as chronic hepatitis B. These models we use to develop novel antiviral therapies.

Research topics

1. Control of HBV infection at the cellular level

HBV replication is strictly non-cytopathic and is hardly recognized by the infected cell. Thus, hepatitis B viruses avoid harming their hosts. Since they are optimized to persist life long, these viruses established a well-controlled replication strategy and an intimate cross talk with their host cells. Therefore, genome replication and gene expression of HBV greatly vary in response to extra cellular stimuli such as cytokines or hormones, and in response to the state of the host cell, e.g. cellular differentiation (reviewed in: Protzer 2012).

To study this, we established preparation and culture of primary hepatocytes from animal and human liver tissue (Schulze-Bergkamen 2003) as well as the infectable cell line HepaRG (Lucifora 2011) and the novel cell line HepG2-H1.3 (Jost 2007), which allow us to study the effect of antivirals and interferons on the persistence form of HBV, the nuclear covalently closed circular (ccc) DNA (Protzer 2007, Quasdorff 2008). Hereby we currently focus on intracellular pathways activated by interferon and lymphotoxin, that help to eliminate the virus.

Analysing the molecular biology of HBV in detail, we found that we can manipulate it to generate HBV-based vectors (Protzer 1999, Schulze-Bergkamen 2003, Untergasser 2004, Untergasser 2006), which we proved to be well tolerated in a chimpanzee (Shin 2005). Since the HBx protein proofed essential to establish and maintain HBV infection (Lucifora 2011), we no study how HBx controls transcription from HBV cccDNA.

HBV is recognized by liver macrophages (Kupffer cells) leading to the secretion of proinflammatory cytokines such as IL-6 (Hösel 2009). IL-6 was able to block HBV replication at the level of transcription by depleting HNF1a and HNF4a, two essential transcription factors (Quasdorff 2008, Quasdorff 2010). IL6 in addition helps to prevent apoptosis of the infected hepatocyte, which is deadly for the virus (Arzberger 2010), and activates STAT3, which we propose to be involved in HBV-induced hepatocarcinogenesis.

2. Interference of HCV with insulin signaling pathways

HCV infected patients have a more than 60% increased risk to develop insulin resistance and type 2 diabetes mellitus if compared to healthy controls and also if compared to patients with HBV infection. Insulin resistance in HCV infected patients is associated with increased liver fibrosis and reduced responsiveness to antiviral therapy. How HCV infection causes insulin resistance is so far unknown.
Hepatic endoplasmic reticulum (ER)-stress is known to induce IR via the activation of JNK. We recently showed that counteracting ER stress in hepatocytes is sufficient to normalize blood glucose levels (Bailly-Maitre 2010). HCV translates a large polyprotein into the ER membrane and several groups describe ER-stress in models with subgenomic HCV replicons. Our aim is to investigate whether ER-stress can explain for IR in HCV infection using the model of full-length HCV replicons and HCV infection of Huh7.5 cells.

3. Control of HBV infection by innate and adaptive immune responses

HBV only infects humans and chimpanzees. Systemic studies on the immune control of infection using HBV in a convenient, well characterized animal model are therefore limited. To overcome the species barrier, we have established adenoviral vectors that transfer replication competent HBV genomes (AdHBV) into a broad range of cultured cells and in vivo into animals (Sprinzl 2001, Sprinzl 2004). Following infection of mice with AdHBV, the mice either replicate HBV for 2-3 weeks and develop a T-cell immune response against HBV as well as neutralizing antibodies (Isogawa 2005, John von Freyend 2010) or develop chronic infection (Huang 2012). This system now allows for the first time to follow onset and clearance of HBV infection and will help to dissect cellular and molecular mechanisms essential for HBV clearance. Close immune monitoring of patient samples shall confirm and extend the findings in the human situation.

4. Therapeutic vaccination for chronic hepatitis B

To break tolerance in chronic HBV infection, CD4+ as well as CD8+ effector T cells need to be induced. Additionally neutralizing anti-HBs antibody responses are desired to block virus spread and tolerizing effects of HBsAg. We aim at establishing vaccination schemes able to achieve both (Kutscher 2012). HBV transgenic mice proofed to be a suitable model to study this, since they only start to express HBV antigens after birth and therefore allow breaking tolerance against HBV envelop and core proteins (Quasdorff, submitted).
Using these mice, we showed that DC based vaccines (Farag 2012) as well a as properly formulated, particulate HBV vaccine (collaboration Rheinbiothech/Dynavax Europe) can induce anti-HBs seroconversion as well as a CD8+ effector T cell response (Buchmann 2013). To achieve even more powerfull responses, we now exploit adenovirus- and MVA-based vaccination schemes.

5. HBV drug resistance and novel antivirals

To be able to study anti-HBV therapies, we use HBV replicating cell lines after transient or stable transfection of replication competent HBV genomes, the cell line HepaRG, which can be infected with HBV and supports the complete replication cycle, and HBV transgenic mouse models for in vivo testing.
We established medium-throughput, infection- and transfection-based HBV assays that allow phenotypic testing of HBV variants isolated from patient material as well as antiviral screening. The assay determines viral fitness as well as sensitivity or resistance to a given drug. Using these assays, we identified a series of antivirally active peptides, cytokines and shRNAs (Krepastakies 2012, Lucifora 2012).
In addition, we have designed bifunctional siRNAs, which besides gene silencing trigger the cytosolic pattern recognition receptor Rig I and control HBV very efficiently and long-lasting (Ebert 2011). By site directed mutagenesis we generated a series of HBV variants with all known resistance mutations now available for testing (Zhang, submitted). Since interferon type I (Klöcker 2000, Dumortier 2005) as well as lymphotoxin very efficiently block HBV replication, we started more detailed studies on the mode of action.  

6. Development of T cell based therapeutic strategies for viral hepatitis and hepatocellular carcinoma

An efficient T cell response is essential to control and finally clear HBV infection. We therefore exploit T cell therapy strategies to eliminate HBV.
On the other hand, we cloned graft T cell receptors (TCR) from patients with resolved HBV infection and use them to graft T cells to retarget them against HBV infected cells. Alternatively, we use chimeric antigen receptors (CAR), which are composed of intracellular TCR signaling domains and „single chain” antibody fragments (scFv) directed against HBV envelope proteins recognizing these HBV proteins on infected cells independent of peptide presentation on MHC (Bohne 2008). We recently showed that this strategy is also promising in vivo (Krebs, in revision) and further develop this approach for clinical use.

Group

 

Head of the group

Ulrike Protzer studied medicine and finished trainings as a specialist for Internal Medicine with a focus on hepatology and infectious diseases and as a specialist for in Medical Microbiology, Virology and Infection Epidemiology working with Karl-Hermann zum Büschenfelde, Guido Gerken, Georg Kräusslich and Martin Krönke. She did her scientific postdoctoral training with Heinz Schaller at the Center for Molecular Biology Heidelberg (ZMBH, Molecular Biology of Hepatitis B Viruses), where she also passed her “habilitation”. At the University of Cologne she was appointed as a junior group leader before she became chair of virology at the Technische Universität München heading the Institute of Virology there and at the Helmholtz Zentrum München. Currently, she serves in the executive board of the German Center for Infection Research

Short CV:

*2.11.1962, married, two children
1982-1988    Medical School, University of Erlangen
1989-1996    Internships in Frankfurt and Mainz, Hepatology / Infectious Diseases
1996            Specialist for Internal Medicine (board exam)
1996-2000    Postdoctoral fellow at the Center for Molecular Biology, University of Heidelberg
2000-2002    Research group leader, Institute of Virology, University of Heidelberg, Germany
2002-2007    Assistant professor for “Molecular Infectiology”, University of Cologne, Germany
2005            Specialist for Medical Microbiology and Virology (board exam)
since 2007   Full professor (W3), Chair for Virology and Director of the Institutes of Virology, Technische Universität München and Helmholtz Zentrum München

Fellowships:

1982-1988    Scholarship for highly talented students from the state of Bavaria
1996-1997    Postdoctoral fellowship
1997-2000    Stipend for the promotion of university teachers

Honors:

since 2006   Member of the organizing committee of the Int. Meeting on Hepatitis B Virus
2006-2012    Member of the advisory board of the German Association of Virology
2005-2007    Steering committee of the SFB 670, University of Cologne
since 2007   Co-coordinator of the German Guidelines for Diagnosis, Prevention and Treatment of Hepatitis B and C Virus Infection
since 2009   Member of the advisory board of the Heinrich Pette Institute for Experimental Virology, Hamburg
since 2010   Member of the advisory board for health research serving the German Federal Ministry of Education and Research
since 2012   Vice speaker and member of the executive board of the German Center for Infection research (DZIF)

Members of the group

     

  • Postdocs
  •  

       

    • Christian Bach
    •  

    • Felix Bohne
    •  

    • Knud Esser
    •  

    • Karin Krebs
    •  

    • Julie Lucifora#
    •  

    • Martin Mück-Häusl
    •  

    • Beate Schittl
    •  

    • Kathrin Singethan

     

  • PhD Students
  •  

       

    • Nina Böttinger
    •  

    • Xiaoming Cheng*
    •  

    • Christina Dargel**
    •  

    • Hanaa Gaber°
    •  

    • Julia Graf
    •  

    • Clemens Jäger
    •  

    • Yuchen Xia*
    •  

    • Ke Zhang
    •  

     

*supported by stipends from *Chinese Science Council, **Konrad Adenauer foundation, DAAD° and #DZIF.

     

  • Technicians
  •  

       

    • Theresa Asen
    •  

    • Kathrin Kappes
    •  

    • Natalie Röder
    •  

     

Selected publications, patents

Bohne, F., Londoño, M.C., Benítez, C., Miquel, R., Martínez-Llordella, M., Russo, C., Ortiz, C., Bonaccorsi-Riani, E., Brander, C., Bauer, T., Protzer, U., Jaeckel, E., Taubert, R., Forns, X., Navasa, M., Berenguer, M., Rimola, A., Lozano, J.J., Sánchez-Fueyo, A. HCV-induced immune responses influence the development of operational tolerance after liver transplantation in humans. Sci. Transl. Med. 6:242ra81 (2014)

Heikenwälder, M., Protzer, U. LINE(1)s of evidence in HBV-driven liver cancer. Cell Host Microbe 15, 249-250 (2014)

Hösel, M., Lucifora, J., Michler, T., Holz, G., Gruffaz, M., Stahnke, S., Zoulim, F., Durantel, D., Heikenwälder, M., Nierhoff, D., Millet, R., Salvetti, A., Protzer, U., Buning, H. Hepatitis B virus infection enhances susceptibility towards adeno-associated viral vector transduction in vitro and in vivo. Hepatology 59, 2110-2120 (2014)

Lucifora, J., Xia, Y., Reisinger, F., Stadler, D., Heikenwälder, M., Protzer, U. Dégradation spécifique de l´ADN nucléaire responsable de la persistance du virus de l´hépatite B. Med. Sci. (Paris) 30, 724-726 (2014)

Lucifora, J., Xia, Y., Reisinger, F., Zhang, K., Stadler, D., Cheng, X., Sprinzl, M.F., Koppensteiner, H., Makowska, Z., Volz, T., Remouchamps, C., Chou, W.-M., Thasler, W.E., Hüser, N., Durantel, D., Liang, T.J., Münk, C., Heim, M.H., Browning, J.L., Dejardin, E., Dandri, M., Schindler, M., Heikenwälder, M., Protzer, U. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 343, 1221-1228 (2014)

Protzer, U., Böhm, F., Longerich, T., Seebach, J., Heidary Navid, M., Friemel, J., Marques-Maggio, E., Bawohl, M., Heikenwälder, M., Schirmacher, P., Dutkowski, P., Clavien, P.A., Schemmer, P., Schnitzler, P., Gotthardt, D., Müllhaupt, B., Weber, A. Molecular detection of Hepatitis E Virus (HEV) in liver biopsies after liver transplantation. Mod. Pathol., DOI: 10.1038/modpathol.2014.147 (2014)

Ringelhan, M., Protzer, U., O'Connor, T., Heikenwälder, M. The direct and indirect role of HBV in liver cancer: Prospective markers for HCC-screening and potential therapeutic targets. J. Pathol. 235, 355-367 (2015) [published online 2014]

Sprinzl, M.F., Puschnik, A., Schlitter, A.M., Schad, A., Ackermann, K., Esposito, I., Lang, H., Galle, P.R., Weinmann, A., Heikenwälder, M., Protzer, U. Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion. J. Hepatol., DOI: 10.1016/j.jhep.2014.11.011 (2014)

Wisskirchen, K., Lucifora, J., Michler, T., Protzer, U. New pharmacological strategies to fight enveloped viruses. Trends Pharmacol. Sci. 35, 470-478 (2014)

Wolf, M.J., Adili, A., Piotrowitz, K., Abdullah, Z., Boege, Y., Stemmer, K., Ringelhan, M., Simonavicius, N., Egger, M., Wohlleber, D., Lorentzen, A.R., Einer, C., Schulz, S., Clavel, T., Protzer, U., Thiele, C., Zischka, H., Moch, H., Tschöp, M.H., Tumanov, A.V., Haller, D., Unger, K., Karin, M., Kopf, M., Knolle, P., Weber, A., Heikenwälder, M. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549-564 (2014)

Wuestenberg, A., Kah, J., Singethan, K., Sirma, H., Keller, A.D., Rosal, S.R., Schrader, J., Loscher, C., Volz, T., Bartenschlager, R., Lohmann, V., Protzer, U., Dandri, M., Lohse, A.W., Tiegs, G., Sass, G. Matrix conditions and KLF2-dependent induction of heme oxygenase-1 modulate inhibition of HCV replication by fluvastatin. PLoS ONE 9:e96533 (2014)

Xia, Y., Lucifora, J., Reisinger, F., Heikenwälder, M., Protzer, U. Response to comment on "Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA". Science 344:1237 (2014)

Sprinzl MF, Reisinger F, Puschnik A, Ringelhan M, Ackermann K, Hartmann D, Schiemann M, Weinmann A, Galle PR, Schuchmann M, Friess H, Otto G, Heikenwalder M and Protzer U. Sorafenib perpetuates cellular anti-cancer effector functions by modulating the cross talk between macrophages and natural killer cellsHepatology 2013, accepted for publication.

Benhenda S, Ducroux A, Riviere L, Sobhian B, Ward M, Dion S, Hantz O, Protzer U, Michel ML, Benkirane M, Semmes J, Buendia MA and Neuveut C. The PRMT1 methyltransferase is a binding partner of HBx and a negative regulator of hepatitis B virus transcriptionJournal of Virology 2013, accepted for publication.

Buchmann P, Dembek C, Kuklick L, Jäger C, Tedjokusumo R, John von Freyend M, Drebber U, Janowicz Z, Melber K and Protzer U.
A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus transgenic mice.  Vaccine 2013, in press.

Lucifora J., Esser K. and Protzer U. Ezetimibe blocks HBV infection after virus uptake into hepatocytes. Antiviral Research 2012, 97: 195-197.

Zhang Dake, Dong Peiling, Zhang Ke, Deng Libin, Bach Christian, Chen Wei, Li Feifei, Protzer Ulrike, Ding Huiguo, Zeng Changqin. Whole genome HBV deletion profiles and the accumulation of preS deletion mutant during antiviral treatment. BMC Microbiology 2012, 12: 307.

Schneider M, Ackermann K, Protzer U, Schätzl HM and Gilch S. SARS-CoV replication is severely impaired by MG132 due to proteasome-independent inhibition of calpain. Journal of Virology 2012, 86(18):10112-22.

Wohlleber D, Kashkar H, Gärtner K, Frings MK, Odenthal M, Hegenbarth S, Börner C, Arnold B, Hämmerling G, Nieswandt B, van Rooijen N, Limmer A, Cederbrant K, Heikenwalder M, Pasparakis M, Protzer U, Dienes HP, Kurts C, Krönke M, Knolle PA.
A novel non-canonical CTL effector function mediated by TNF. Cell Reports 2012, 27; 2:478-87

Farag MMS, Tedjokusumo R, Flechtenmacher C, Asen T, Stremmel W, Müller M, Protzer U, Weigand K. Immune tolerance against HBV can be overcome in HBV transgenic mice by immunization with dendritic cells pulsed by HBVsvp. Vaccine 2012, 30(42):6034-9.

Dembek CJ, Kutscher S, Allgayer S, Bauer T, Hoffmann D, Goebel FD, Bogner JR, Erfle V, Protzer U and Cosma A. Longitudinal changes in HIV-1 specific T-cell quality associated with viral load dynamic. Journal of Clinical Virology 2012, 55(2):114-20.

Stross L, Günther J, Gasteiger G, Asen T, Aichler M, Esposito I, Busch DH, Knolle PA, Sparwasser T, Protzer UFoxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute, experimental hepatitis B virus infection. Hepatology 2012, 56(3):873-83.

Krepstakies M, Lucifora J, Nagel CH, Zeisel MB, Holstermann B, Hohenberg H, Kowalski I, Gutsmann T, Baumert TF, Brandenburg K, Hauber J and Protzer U. Targeting Virus Attachment and Entry by a New Class of Synthetic Cross-Species Peptide Inhibitors. Journal of Infectious Diseases 2012, 205(11):1654-64.

Huang LR, Gäbel YA, Arzberger S, Kurts C, Heikenwalder  M, Knolle PA, Protzer ULow-dose adenoviral HBV genome transfer establishes persistent infection in immune competent miceGastroenterology 2012, 205(11):1654-64.

Hoffmann D, Hutzenthaler M, Seebach J, Panning M, Umgelter A, Menzel H, Protzer U, Metzler D. Norovirus GII.4 and GII.7 Capsid Sequences Undergo Positive Selection in Chronically Infected Patients. Infection, Genetics and Evolution, 2012, 12:461-6.

Hösel M, Broxtermann M, Janicki H, Esser K, Arzberger S, Hartmann P, Gillen S, Kleeff J, Stabenow D, Odenthal M, Knolle PA, Hallek M, Protzer U, Büning H. TLR2-mediated innate immune response in human non-parenchymal liver cells towards adeno-associated viral (AAV) vectors. Hepatology 2012, Jan;55(1):287-97.

Vincent IE, Zannetti C, Lucifora J, Norder H, Protzer U, Hainaut P, Zoulim F, Tommasino M, Trepo C, Hasan U, Chemin I.
Hepatitis B Virus Impairs TLR9 Expression and Function in Plasmacytoid Dendritic Cells. PLOS One 2011, 6 (10): e26315.

Ebert G, Poek H, Lucifora J, Barschuk N, Esser K, Esposito I, Hartmann G, Protzer U. siRNAs designed to activate retinoic acid–inducible protein I control hepatitis B virus in primary human hepatocytes and in mice. Gastroenterology 2011, accepted for publication.

Lucifora J, Arzberger  S, Durantel D, Belloni L, Strubin M, Levrero M, Zoulim F, Hantz O and Protzer U. Hepatitis B Virus X protein is essential to initiate and maintain virus replication after infection. J Hepatology 2011, Mar 1. [Epub ahead of print].

John von Freyend M, Untergasser A, Arzberger S, Oberwinkler S, Drebber U, Schirmacher P and Protzer U. Sequential control of hepatitis B virus in a mouse model of acute, self-resolving hepatitis B. Journal of Viral Hepatitis 2011, 18(3):216-26.

Arzberger S, Hösel M, Protzer U. Apoptosis of hepatitis B virus infected hepatocytes prevents release of infectious virus. Journal of Virology 2010, 84(22):11994-2001.

Marquardt JU, Quasdorff M, Varnholt H, Curth HM, Mesghenna S, Protzer U, Goeser T, Nierhoff D. Neighbor of Punc E11, a novel onco-fetal marker for hepatocellular carcinoma. Int J of Cancer 2010, July 23 [Epub ahead of print].

Dembek CJ, Kutscher S, Heltai S, Allgayer S, Biswas P, Ghezzi S, Vicenzi E, Hoffmann D, Reitmeir P, Tambussi G, Bogner JR, Lusso P, Stellbrink HJ, Santagostino E, Vollbrecht T, Goebel FD, Protzer U, Draenert R, Tinelli M, Poli G, Erfle V, Malnati M, Cosma A.
Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma are associated with nonprogressive HIV-1 infection. AIDS Res Ther. 2010, 7(1):20.

Arzberger S, Hösel M, Protzer UApoptosis of hepatitis B virus infected hepatocytes prevents release of infectious virus. Journal of Virology 2010, 84(22):11994-2001.

Lucifora J, Vincent JE, Berthillon P, Dupinay T, Michelet M, Protzer U, Zoulim F, Durantel D, Trepo C and Chemin I.HBV replication in primary macaque hepatocytes: crossing the species barrier towards a new small primate model. Hepatoloy 2010, 2010 Jun;51(6):1954-60.

Kutscher S, Allgayer S, Dembek CJ, Bogner JR, Protzer U, Goebel FD, Erfle V, Cosma A. MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays. Gene Therapy 2010, in press.

Stabenow D, Frings M, Trück C, Gärtner K, Förster I, Kurts C, Tüting T, Odenthal M, Dienes HP, Cederbrand K, Protzer U and Knolle PA. Bioluminescence imaging allows measuring CD8 T cell function 1 in the liver. Hepatology 2010, 51: 1430-37.

Hoffmann D, Seebach J, Foley BT, Frösner G, Nadas K, Protzer U, Schätzl HM. Isolated norovirus GII.7 strain within an extended GII.4 outbreak. J Med Virol. 2010, 82:1058-64.

Sarrazin C, Berg T, Ross RS, Schirmacher P, Wedemeyer H, Neumann U, Schmidt HH, Spengler U, Wirth S, Kessler HH, Peck-Radosavljevic M, Ferenci P, Vogel W, Moradpour D, Heim M, Cornberg M, Protzer U, Manns MP, Fleig WE, Dollinger MM, Zeuzem S. Prophylaxis, diagnosis and therapy of hepatitis C virus (HCV) infection: the German guidelines on the management of HCV infection. Z Gastroenterol. 2010 Feb;48(2):289-351.

Hoffmann D, Wolfarth B, Hörterer HG, Halle M, Reichhuber C, Nadas K, Tora C, Erfle V, Protzer U and Schätzl HM. Elevated Epstein–Barr Virus Loads and Lower Antibody Titers in Competitive Athletes. J Med Virology 2010, 82:446–451.

Bailly-Maitre B, Belgardt BF, Jordan SD, Coornaert B, John von Freyend M, Kleinridders A, Mauer J, Cuddy M, Kress CL, Willmes D, Essig M, Hampel B, Protzer U, Reed JC, Bruning JC. Hepatic Bax-inhibitor (BI)-1 inhibits IRE1a and protects from obesity-associated insulin resistance and glucose intolerance. J Biol Chem. 2010, 285(9):6198-207.

Hösel M, Quasdorff M, Webb D, Zedler  U, Esser K, Arzberger S, Wiegmann K, Kirschning CJ, Langenkamp A, Rose-John S and Protzer UNot interferon, but IL-6 controls early gene expression in Hepatitis B virus (HBV) infection. Hepatology 2009, 50:1773-1782.

Stahl S, Sacher T, Bechtold A, Protzer U, Ganss R, Hämmerling GJ, Arnold B, Garbi N. Tumor agonist peptides break tolerance and elicit effective CTL responses in an inducible mouse model of hepatocellular carcinoma Immunol Letters 2009,123(1):31-7

Op den Brouw ML, Binda RS, van Roosmalen MH, Protzer U, Janssen HL, van der Molen RG, Woltman AM. Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus. Immunology. 2009 Feb;126(2):280-9.

Cornberg M, Protzer U, Dollinger MM, Petersen J, Wedemeyer H, Berg T, Jilg W, Erhardt A, Wirth S, Schirmacher P, Fleig WE, Manns MP The German guideline for the management of hepatitis B virus infection: short version. J Viral Hepatitis 2008 Aug;15 Suppl 1:1-21.

Jenke AC, Wilhelm AD, Orth V, Lipps HJ, Protzer U, Wirth S. Long term suppression of HBV replication by shRNA expression using the S/MAR based replicating vector system pEPI-1. Antimicrob Agents Chemotherapy 2008, 52(7):2355-9.

Bohne F, Chmielewski M, Ebert G, Wiegmann K, Kürschner T, Schulze A, Urban S, Krönke M, Abken H, Protzer U. T cells Redirected Against Hepatitis B Virus Surface Proteins Eliminate Infected Hepatocytes. Gastroenterology 2008, 134: 239-47.   

Quasdorff M, Hösel M, Odenthal M, Zedler U, Bohne F, Gripon P, Dienes HP, Stippel D, Goeser T, Protzer U. A concerted action of HNF1 α and HNF4α links hepatitis B virus replication to hepatocyte differentiation. Cellular Micobiology 2008, 10:1478-1490.

Cornberg M, Protzer U, Dollinger M, Petersen J, Wedemeyer H, Berg T, Jilg W, Erhardt A, Wirth S, Schirmacher P, Fleig WE, Manns M. Prophylaxis, diagnosis and therapy of hepatitis B virus (HBV) infection: the german guidelines for the management of HBV infection. Z Gastroenterol. 2007, 45:1281-328

Protzer U, Seyfried S, Quasdorff M, Sass G, Svorcova M, Webb D, Bohne F, Hösel M, Schirmacher P, Tiegs G. Antiviral activity and hepatoprotection by heme oxygenase-1 in hepatitis B virus infection. Gastroenterology 2007, 133: 1156-65.  
Bohne F, Protzer U. Adoptive T-cell therapy as a therapeutic option in chronic viral hepatitis. J. Viral Hepatitis 2007, 14, Suppl 1: 45-50.

Wedemeyer H, Cornberg M, Protzer U, Berg T, Dollinger MM. German guidelines on diagnosis and therapy of hepatitis B. Dtsch Med Wochenschr. 2007 Aug;132(34-35):1775-82.

Cornberg M, Protzer U, Dollinger M, Petersen J, Wedemeyer H, Berg T, Jilg W, Erhardt A, Wirth S, Schirmacher P, Fleig WE, MannsM. Prophylaxis, Diagnosis and Therapy of Hepatitis-B-Virus-(HBV-)Infection: Upgrade of the German Guideline. Z. Gastroenterologie 2007, 45:525-574.

Jost S, Turelli P, Mangeat B, Protzer U, Trono D. Induction of antiviral cytidine deaminases does not explain the inhibition of hepatitis B virus replication by interferons. J Virology 2007, 81: 10588-10596.

Untergasser A, Zedler U, Langenkamp A, Hösel M, Quasdorff M, Esser K, Tapperzhofen B, Kolanus W and Protzer U. Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection. Hepatology 2006, 43: 539-547.

Siebler J, Protzer U, Wirtz S, Schuchmann M, Hohler T, Galle PR, Neurath MF. Overexpression of STAT-1 by adenoviral gene transfer does not inhibit hepatitis B virus replication. Eur J Gastroenterol Hepatol. 2006 ,18:167-74.

Shin E-C, Protzer U, Untergasser A, Feinstone SM, Rice CM, Hasselschwert D, Rehermann B. Liver-Directed Interferon-g Gene Delivery in Chronic Hepatitis C. Journal of Virology 2005, 79:13412-13420.
I

sogawa M, Kakimi K, Kamamoto H, Moriyasu F, Protzer U and Chisari FV. Differential Dynamics of the Peripheral and Intrahepatic Cytotoxic T Lymphocyte Response to a Secreted Viral Antigen Produced in the Liver. Virology 2005, 333: 293-300.

Dumortier J, Schönig K, Giese T, Bujard H, Protzer U. The Tet-system allows tight control and liver-specific gene expression in vivo following adenoviral gene transfer into mice. Gene Therapy 2005, 12:668-677.

Zhang Z, Protzer U, Hu Z, Jacob J, Liang TJ. Inhibition of cellular proteasome activities enhances hepadnaviral replication in a HBx dependent manner. Journal of Virology 2004, 78: 4566-4572.

Untergasser A & Protzer U. Hepatitis B virus vectors allow elimination of viral gene expression and insertion of foreign promoters. Human Gene Therapy 2004, 15: 203-210.

Sprinzl M, Dumortier J, Protzer U. Construction of recombinant adenoviruses that produce infectious hepattis B virus. Methods in Molecular Medicine 2004, 96:203-218.

Schulze-Bergkamen H, Untergasser A, Dax A, Vogel H, Büchler P, Klar E, Lehnert T, Friess H, Büchler M, Kirschfink M, Stremmel W, Krammer P, Müller M, Protzer U. Primary human hepatocytes - a valuable tool for investigation of apoptosis and hepatitis B virus infection Journal of Hepatology 2003, 38: 736-744.

Klöcker U, Kürschner T, Oberwinkler H, Protzer U. Presence of replicating virus in recombinant hepadnavirus stocks results from homologous recombination and can be eliminated be the use of a packaging cell line. Journal of Virology 2003, 77 (5): 2873-2881.

Li Y, Hacker HJ, Protzer U, Kopp-Schneider A, Bannasch P. Woodchuck Hepatitis B Virus Replication and Antigen Expression Gradually Decreases in Preneoplastic Hepatocellular Lineages Journal of Hepatology 2002, 37 (4): 478.

Sprinzl M, Oberwinkler H, Schaller H, Protzer U. Hepatitis B virus genome transfer with adenoviral vectors into cultured cells and mice: crossing the species barrier Journal of Virology 2001, 75: 5108-5118.

Radecke K, Protzer U, Trippler M, Gerken G. Variation of the Hepatitis B Virus Core Gene during High-dose Interferon Alpha Therapy. Journal of Medical Virology 2000, 62: 479-486.

Klöcker U, Schultz U, Schaller H, Protzer U. Liver macrophages release mediators after endotoxin stimulation that inhibit an early step in hepadnavirus replication.  Journal of Virology 2000, 74 (12): 5525-5533.

Hegenbarth S, Gerolami R, Protzer U, Tran PL, Brechot C, Gerken G, Knolle PA. Liver sinusoidal endothelial cells are not permissive for adenovirus type 5  Human Gene Therapy 2000, 11 (3): 481-486.

Protzer U, Nassal M, Chiang PW, Kirschfink M, Schaller H. Interferon gene transfer by a novel hepatitis B virus vector efficiently suppresses wildtype-virus infection. PNAS 1999, 96: 10818-10823.

Herr W,  Protzer U, Lohse A, Meyer zum Büschenfelde KH, Wölfel T. Characterization of cytotoxic T-cell response in HIV infected patients and seronegative high-risk contact persons. Journal of Infectious Diseases 1998,178: 260-165.

Protzer U, Naumann U, Bartenschlager R, Berg T, Hopf U, Meyer zum Büschenfelde KH, Neuhaus P, Gerken G. Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation. Hepatology 1998, 27(1): 254-263.

Naumann U, Protzer U, Berg T, Leder K, Lobeck H, Fukumoto T, Bechstein WO, Gerken G, Hopf U, Neuhaus P. A pretransplant infection with precore mutants of Hepatitis B Virus does not influence the outcome of orthotopic liver transplantation in patients on high-dose anti-HBs immuno-prophylaxis. Hepatology 1997, 26 (2): 478-484.

Protzer U, Ochsendorf FR, Leopolder-Ochsendorf A, Holtermüller KH. Exacerbation of Lichen Planus during Interferon-Alpha-2a Therapy of Chronic Active Hepatitis C. Gastroenterology 1993; 104 (3): 903-905.

Reviews / Buchbeiträge

 

Protzer U, Maini M, Knolle P.
Living in the Liver.
Nature Reviews in Immunology 2012, 12: 201-213

Lucifora J & Protzer U.
Hepatitis B Virus X Protein: A Key Regulator of the Virus Life Cycle.
In: "The Viral Genome", Viral Genomes - Molecular Structure, Diversity, Gene Expression Mechanisms and Host-Virus Interactions. Maria Laura Garcia and Victor Romanowski (Ed.).
InTech 2012, ISBN: 978-953-51-0098-0

Kutscher S, Bauer T, Dembrek C, Sprinzl M, Protzer U.
Design of Therapeutic Vaccines: Hepatitis B as an Example.

Microbial Biotechnology 2012, Mar;5(2):270-82.

Bauer T, Sprinzl M, Protzer U.
Immune control of Hepatitis B Virus.
Digestive Diseases 2011: 29: 423-433.

Protzer U & Abken H.
Can engineered "designer" T cells out-smart chronic hepatitis B?
Hepatitis Research and Treatment, 2010, Article ID 901216

Ridell S & Protzer U.
Carving the CAR
(News & Views comment).
Gene Therapy 2010, 17(10):1191-2. 

Quasdorff M & Protzer U.
Control of Hepatitis B virus at the level of transcription.
J Viral Hepatitis, 2010, 2010 Aug;17(8):527-36. 

Hoffmann D, Nadas K, Protzer U.
Hepatitis Viruses.
In: Kessler HH (ed.):  „Molecular Diagnostics of Infectious Diseases”.
De Gruyter, Berlin / New York, 2009.

Laer D, Baum C, Protzer U.
Antiviral gene therapy.
Handb Exp Pharmacol. 2009;(189):265-97

Protzer U & Urban S.
Hepatitis B Virus: Targeting the The Viral Life Cycle.
In: Protzer U, Weber O (eds). Comparative Hepatitis. Birkenhäuser 2008.

Cornberg M, Manns M, Protzer U.
Infektionserkrankungender Leber. Virushepatitis.
In: Mertes, Marre. Klinische Infektiologie. Urban & Schwarzenegger 2007.

Oberwinkler H, Sprinzl M, Untergasser A, Protzer U.
Transfer of HBV genomes into mice.
In: Roggendorf M, v. Weizsäcker F (eds) „Current Models of Viral Hepatitis“. In: Doerr DW (ser. ed) Monographs in Virology. Karger AG, Basel, Switzerland, 2005.

Sprinzl M, Dumortier J, Protzer U
Construction of recombinant adenoviruses that produce infectious HBV.
In: R. Hamatke, J. Lau (eds.). „Hepatitis B and D Protocols“, 96 (Vol. II), Chapter 18, pg 209-218. J.M. Walker (ser. ed.) Methods in Molecular Medicine. The Humana Press Inc., Totowa NJ, 2004.

Protzer U, Schaller H.
Immune Escape of Hepatitis B Viruses.
Virus Genes 2000, 21: 27-37.

G. Gerken, U. Protzer, B. Goergen, K.-H. Meyer zum Büschenfelde.
Clinical Significance of the Polymerase Chain Reaction Assay in Chronic Hepatitis B Virus Carriers.

In: PCR: Protocols for Diagnosis of Human and Animal Diseases.
Y. Becker, G. Darai (Editors).
Springer Verlag, Heidelberg, Berlin, 1995

Third party funding

  • DFG SFB 576 / 760, DFG SFB_TR36
  • Helmholtz Alliance “Immunotherapy of Cancer”, Focus Hepatocellular Carcionoma
  • Helmholtz Initiative "Synthetic Biology"
  • BMBF Consortium HOPE („Hepatitis B Therapy Optimized by Phenotypic Evaluation“): Coordinator and Principal Investigator

Research collaborations:

  • Janssen Pharmaceuticals, Beerse, Belgium
  • Siemens Molecular Diagnostics, Berkley, USA 
  • Micromet Inc., Munich, Germany
  • Rheinbiotech – Dynavax Europe, Düsseldorf, Germany