Judith Margarete Gottwein

Short presentation

The research of my group is focusing on Hepatitis C Virus (HCV), which poses a severe public health burden. HCV is estimated to cause chronic hepatitis in at least 70.000 million individuals worldwide, leading to liver cirrhosis and liver cancer. Every year, HCV causes approximately 450.000 deaths, making it one of the biggest killers in infectious diseases. We are driven by the idea that our research on antivirals and vaccines will help combat this deadly infection. In addition, HCV has become a model RNA virus used to elucidate important principles in virology and immunology. We hope to use our findings for HCV to further the understanding and the control of other important human viral infections.

Key achievements

We have developed infectious cell culture systems for the major HCV genotypes, facilitating the study of HCV in vitro and providing a base for a cell culture based whole HCV particle vaccine. We have used these systems for studies of the effect of various antivirals, their mechanism of action and associated resistance.

We have revealed that different HCV variants showed differential sensitivity to neutralizing antibodies, indicating existence of various HCV serotypes, but also that vaccination with HCV envelope proteins was able to induce antibodies neutralizing different genotypes. We have developed serum-free genotype 1-6 viral particles with unique characteristics, an important first step towards development of a whole HCV particle vaccine.

Current and future research

We are interested in finding out how HCV can escape from antivirals, rendering them inefficient. We are elucidating genetic correlates and mechanisms underlying HCV resistance to antivirals and we aim at development of diagnostic assays to identify resistance in HCV infected patients. Even though recently efficient antivirals have been developed, resistance to these compounds is emerging with the risk of spread in human populations.

There is no vaccine against HCV. However, such a vaccine is urgently needed to control this virus on a global level. We would like to make a difference by development of a prophylactic HCV vaccine. We are focussing on optimization of a bioprocess for the development of a whole virus inactivated HCV vaccine. Efficient production of HCV particles in large scale mammalian cell culture and efficient purification of HCV from cell culture is of key importance. An alternative vaccine strategy is focussing on the use of virus like particles as vaccine antigen. We are interested in using the established technologies for the development of vaccines for other human viruses, for which vaccines are needed.

Access my OrcID profile at: https://orcid.org/0000-0003-2805-0256

Access my Google scholar profile: https://scholar.google.com/citations?user=PkkiYwUAAAAJ&hl=de

CV

Personal Data

Born: February 24, 1975; married, two children
Citizenship: German
Country of Residence: Denmark
E-mail: [email protected]

Current positions
2005-present, Senior Researcher, Copenhagen Hepatitis C Program (CO-HEP), Dept. of Infectious Diseases, Copenhagen University Hospital, Hvidovre
2014-present, Associate Professor, Dept. of International Health, Immunology, and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen

Education
1994-2001 Studies of Medicine, Heidelberg University (final exam 15. Nov 2001)
1997-1998 Researcher, Dept. of Pathology, Case Western Reserve University
6. Dec 2001 Doctoral Degree (Dr. med.), Heidelberg University
2002-2003 Researcher, Dept. of Neuropathology, University Hospital Zürich
2003-2004 Clinician, Dept. of Internal Medicine, Spital Limmattal Zürich
4. Nov 2003 License to Practice as a Doctor
2004-2005 Clinician and Researcher, Dept. of Internal Medicine, University Hospital Bonn

Scientific focus areas
HCV vaccine development
Antiviral resistance
HCV cell culture systems

Publication statistics (also see list of publications)
Total number of publications in peer reviewed journals: 46
H-index: 24 Google Scholar (May 2018)
Total number of citations: 2521 Google Scholar (May 2018)

Patents (also see list of publications)
My activities have resulted in 16 patent applications filed 2007-2017 (Region H/KU licensed HCV culture systems to Apath, USA). 12 of these patents have been issued in the US 2013-2015.

Scientific recognitions
German national fellowship award: 1994-2001
EASL Awards: 2007, 2009
International Symposium on HCV and Related Viruses Awards: 2007, 2008, 2010
Various Presentations at Conferences including invited speeches (EASL, International Symposium on HCV and Related Viruses, ESACT, Nordic HIV and Hepatitis): 2007-17
Member of EASL and ASM
Associate Professor " Experimental Control of Hepatitis C Virus” (2014)

Current collaborators
K. Bossart, Integrated Research Associates, USA; J. Pravsgaard Christensen and A. Randrup Thomsen, UCPH, Denmark; J.-S. Diallo, Ottawa Hospital Research Institute, Canada; Y. Genzel and U. Reichel, Max Planck Institute Magdeburg, Germany; H. Krarup, Aalborg University, Denmark; Law, The Scripps Research Institute, USA; Lehmann, Case Western Reserve University, USA; Meuleman, Ghent University; Rice, The Rockefeller University; Walker, The Ohio State University; Wolff, Technische Hochschule Mittelhessen

Supervision of scientists
-Former PhD students (year of thesis): Tanja B. Jensen (2014), Christian K. Mathiesen (2014), Stéphanie Serre (2014), Sanne B. Jensen (2017)
-Current PhD students: Rodrigo Vélazquez-Moctezuma, Long V. Pham, Anne F. Pihl, Garazi P. Alzua, Anna F. Offersgaard
-Former Master students (year of thesis): Tanja B. Jensen (2007), Sanne B. Jensen (2011), Anne F. Pihl (2015), Garazi P. Alzua (2017), Anna F. Offersgaard (2017)
-Current Master students: Karen A. Gammeltoft
-Former Postdoctoral fellows: Tanja B. Jensen (2014), Christian K. Mathiesen (2014/15), Stéphanie Serre (2014/15)
-Former Research Assistants: Maria Knudsen, Jacob Lademann, Tanja B. Jensen, Nanna Hansen, Stéphanie Serre, Christian K. Mathiesen, Sanne B. Jensen, Qi Tang, Anne F. Pihl

Management experience
Since 2005: establishment of laboratory facilities at Hvidovre Hospital/CO-HEP
Since 2009: main responsibilities for project management

Teaching activity
Supervision of PhD-, Masters- and Bachelor-students (see above); Lectures for Medicine - 3rd year students at Copenhagen University; Virology Laboratory Course, Medicine - 3rd year students at Copenhagen University; Clinical Rotation, Human Biology

Languages
German: Native
Fluent: English, Danish
Basic: Spanish

Publications in Peer Reviewed Journals

1. Gottwein JM, Blanchard TG, Targoni OS, Eisenberg JC, Zagorski BM, Redline RW, Nedrud JG, Tary-Lehmann M, Lehmann PV, Czinn SJ. Protective anti-Helicobacter immunity is induced with aluminum hydroxide or complete Freund's adjuvant by systemic immunization. J Infect Dis. 2001; 184, 308-314.

2. Rogivue C, Gottwein J, Aguzzi A, Glatzel M. Transmissible spongiform encephalopathies in humans. Schweizer Archiv Für Tierheilkunde 2002; 144, 685-690.

3. Glatzel M, Gottwein J, Aguzzi A. The role of prions in transmissible spongiform encephalopathies. Schweizer Archiv Für Tierheilkunde 2002; 144, 633-638.

4. Eisenberg JC, Czinn SJ, Garhart CA, Redline RW, Bartholomae WC, Gottwein JM, Nedrud JG, Emancipator SE, Boehm BB, Lehmann, PV, Blanchard TG. Protective efficacy of anti-Helicobacter pylori immunity following systemic immunization of neonatal mice. Infection and Immunity 2003; 71, 1820-1827.

5. Gottwein J, Wiesli P, Achermann E. Thyroid storm as first manifestation of hyperthyroidism. Swiss Medical Weekly 2005, 37, 933-935.

6. Gottwein J, Zbinden R, Maibach RC, Herren T. Etiologic diagnosis of Capnocytophaga canimorsus meningitis by broad-range PCR. European Journal of Clinical Microbiology & Infectious Diseases 2006; 25, 132-134.

7. Gottwein JM, Bukh J. Hepatitis C virus host cell interactions uncovered. Proc Natl Acad Sci USA 2007;104:13215-13216.

8. Gottwein JM, Scheel TKH, Hoegh AM, Lademann JB, Eugen-Olsen J, Lisby G, Bukh J. Robust Hepatitis C Genotype 3a Cell Culture Releasing Adapted Intergenotypic 3a/2a (S52/JFH1) Viruses. Gastroenterology 2007;133:1614-1626.

9. Scheel TK, Gottwein JM, Jensen TB, Prentoe JC, Hoegh AM, Alter HJ, Eugen-Olsen J, Bukh J. Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralization. Proc Natl Acad Sci U S A 2008;105:997-1002.

10. Gottwein JM, Bukh J. Cutting the gordian knot-development and biological relevance of hepatitis C virus cell culture systems. Adv Virus Res. 2008;71:51-133.

11. Jensen TB, Gottwein JM, Scheel TKH, Hoegh AM, Eugen-Olsen J, Bukh J. Highly efficient JFH1-based cell culture system of hepatitis C virus genotype 5a: failure to control infection with homologous neutralizing antibody treatment. J Infect Dis. 2008;198:1756 –1765.

12. Gottwein JM, Scheel TKH, Jensen TB, Lademann JB, Prentoe JC, Knudsen ML, Hoegh AM, Bukh J. Development and Characterization of Hepatitis C Virus Genotype 1-7 Cell Culture Systems: Role of CD81 and SR-BI and Effect of Antiviral Drugs. Hepatology 2009;49:364-377.

13. Terjung B, Soehne J, Lechtenberg B, Gottwein J, Muennich M, Herzog V, Maehler M, Sauerbruch T, Spengler U. p-ANCA in Autoimmune Liver Disorders Recognize Human Beta-Tubulin Isotype 5 and Cross-react with Microbial Protein FtsZ. Gut 2010;59(6):712-3.

14. Gottwein JM, Scheel TK, Callendret B, Li YP, Eccleston HB, Engle RE, Govindarajan S, Satterfield W, Purcell RH, Walker CM, Bukh J. Novel infectious cDNA clones of hepatitis C virus genotype 3a (strain S52) and 4a (strain ED43): genetic analyses and in vivo pathogenesis studies. J Virol. 2010; 84(10):5277-93.

15. Scheel TKH, Gottwein JM, Mikkelsen M, Jensen TB, Bukh J. Recombinant HCV variants with NS5A from genotypes 1-7 have different sensitivities to an NS5A inhibitor but not interferon-α. Gastroenterology 2011; 140(3):1032-42.

16. Prentoe JC, Jensen TB, Meuleman P, Serre S, Scheel TKH, Leroux-Roels G, Gottwein JM, Bukh J. Hypervariable region 1 differentially impacts viability of hepatitis C virus strains of genotypes 1 to 6 and impairs virus neutralization. J Virol. 2011; 85(5):2224-34.

17. Scheel TK, Gottwein JM, Carlsen TH, Li YP, Jensen TB, Spengler U, Weis N, Bukh J. Efficient culture adaptation of hepatitis C virus recombinants with genotype-specific core-NS2 by using previously identified mutations. J Virol. 2011; 85(6):2891-906.

18. Li YP, Gottwein JM, Scheel TK, Jensen TB, Bukh J. MicroRNA-122 antagonism against hepatitis C virus genotypes 1-6 and reduced efficacy by host RNA insertion or mutations in the HCV 5' UTR. Proc Natl Acad Sci U S A 2011; 108(12):4991-6.

19. Gottwein JM, Jensen TB, Mathiesen CK, Meuleman P, Serre SB, Lademann JB, Ghanem L, Scheel TK, Leroux-Roels G, Bukh J. Development and Application of Hepatitis C Reporter Viruses with Genotype 1-7 Core-NS2 Expressing Fluorescent Proteins or Luciferase in modified JFH1 NS5A. J Virol. 2011; 85(17):8913-28.

20. Gottwein JM, Scheel TK, Jensen TB, Ghanem L, Bukh J. Differential Efficacy of Protease Inhibitors against HCV Genotype 2a, 3a, 5a, and 6a NS3/4A Protease Recombinant Viruses. Gastroenterology 2011; 141(3):1067-79.

21. Meunier JC, Gottwein JM, Houghton M, Russell R, Houghton M, Emerson SU, Houghton M, Bukh J, Purcell RH. Vaccine-induced cross-genotype reactive neutralizing antibodies against hepatitis C virus. J Infect Dis. 2011; 204(8):1186-90.

22. Li YP, Ramirez S, Gottwein JM, Bukh J. Non-genotype-specific role of the hepatitis C virus 5' untranslated region in virus production and in inhibition by interferon. Virology 2011; 421(2):222-34.

23. Li YP, Ramirez S, Gottwein JM, Scheel TK, Mikkelsen L, Purcell RH, Bukh J. Robust full-length hepatitis C virus genotype 2a and 2b infectious cultures using mutations identified by a systematic approach applicable to patient strains. Proc Natl Acad Sci U S A 2012; 109(18):E1101-10.

24. Scheel TK, Prentoe J, Carlsen TH, Mikkelsen LS, Gottwein JM, Bukh J. Analysis of functional differences between hepatitis C virus NS5A of genotypes 1-7 in infectious cell culture systems.
PLoS Pathog. 2012; 8(5):e1002696.

25. Saeed M, Scheel TK, Gottwein JM, Marukian S, Dustin LB, Bukh J, Rice CM. Efficient replication of genotype 3a and 4a HCV replicons in human hepatoma cells. Antimicrob Agents Chemother. 2012; 56(10): 5365-73.

26. Li YP, Ramirez S, Jensen SB, Purcell RH, Gottwein JM, Bukh J. Highly efficient full-length hepatitis C virus genotype 1 (strain TN) infectious culture system. Proc Natl Acad Sci U S A 2012;109(48):19757-62.

27. Gottwein JM, Jensen SB, Li YP, Ghanem L, Scheel TK, Serre SB, Mikkelsen L, Bukh J. Combination treatment with HCV protease and NS5A inhibitors is effective against recombinant genotype 1a, 2a and 3a virus. Antimicrob Agents Chemother. 2013; 57(3): 1291-303.

28. Scheel TK, Galli A, Li YP, Mikkelsen LS, Gottwein JM, Bukh J. Productive Homologous and Non-homologous Recombination of Hepatitis C Virus in Cell Culture. PLoS Pathog. 2013: 9(3):e1003228.

29. Pedersen J, Carlsen TH, Prentoe J, Ramirez S, Jensen TB, Forns X, Alter H, Foung SK, Law M, Gottwein J, Weis N, Bukh J. Neutralization resistance of hepatitis C virus can be overcome by recombinant human monoclonal antibodies. Hepatology 2013; 58(5):1587-97.

30. Gottwein JM, Bukh J. Viral hepatitis: Cell-culture-derived HCV-a promising vaccine antigen.
Nat Rev Gastroenterol Hepatol. 2013; 10(9):508-9.

31. Galli A, Scheel TK, Prentoe JC, Mikkelsen LS, Gottwein JM, Bukh J. Analysis of hepatitis C virus Core/NS5A co-localization using novel cell culture systems expressing Core-NS2 and NS5A of genotype 1-7. J Gen Virol. 2013; 94(Pt 10):2221-35.

32. Gottwein JM, Jensen SB, Serre SBN, Ghanem L, Scheel TKH, Jensen TB, Krarup H, Uzcategui N, Mikkelsen LS, Bukh J. Adapted J6/JFH1-based hepatitis C virus recombinants with genotype-specific NS4A show similar efficacy to lead protease inhibitors, interferon-alpha and a putative NS4A inhibitor. Antimicrob Agents Chemother. 2013; 57(12):6034-49.

33. Serre SBN, Krarup H, Bukh J, Gottwein JM. Identification of IFN-alpha Induced Envelope Mutations of Hepatitis C Virus In Vitro Associated with Increased Viral Fitness and Interferon Resistance. J Virol. 2013; 87(23):12776-93.

34. Prentoe J, Serre SB, Ramirez S, Nicosia A, Gottwein JM, Bukh J. Hypervariable Region 1 Deletion and Required Adaptive Envelope Mutations Confer Decreased Dependency on Scavenger Receptor Class B Type I and Low Density Lipoprotein Receptor for Hepatitis C Virus. J Virol. 2013; 88(3):1725-39.

35. Ramirez S, Li YP, Jensen SB, Pedersen J, Gottwein JM, Bukh J. Highly efficient infectious cell culture of three HCV genotype 2b strains and sensitivity to lead protease, NS5A, and polymerase inhibitors. Hepatology 2014; 59(2):395-407.

36. Li YP, Ramirez S, Humes D, Jensen SB, Gottwein JM, Bukh J. Differential Sensitivity of 5'UTR-NS5A Recombinants of Hepatitis C Virus Genotypes 1-6 to Protease and NS5A Inhibitors. Gastroenterology 2014; 146(3):812-821.

37. Mathiesen CK, Jensen TB, Prentoe J, Nicosia A, Law M, Bukh J, Gottwein JM. Production and Characterization of High-Titer Serum-Free Cell Culture Grown Hepatitis C Virus Particles of Genotype 1-6. Virology 2014; 458-459:190-208

38. Sundararaman S, Karulin AY, Ansari T, BenHamouda N, Gottwein J, Laxmanan S, Levine SM, Loffredo JT, McArdle S, Neudoerfl C, Roen D, Silina K, Welch M, Lehmann PV. High Reproducibility of ELISPOT Counts from Nine Different Laboratories. Cells 2015; 4(1):21-39.

39. Mathiesen CK, Prentoe J, Meredith LW, Jensen TB, Krarup H, McKeating JA, Gottwein JM, Bukh J. Adaptive Mutations Enhance Assembly and Cell-to-Cell Transmission of a High-Titer Hepatitis C Virus Genotype 5a Core-NS2 JFH1-Based Recombinant. J Virol. 2015;89(15):7758-75.

40. Jensen SB, Serre SB, Humes DG, Ramirez S, Li YP, Bukh J, Gottwein JM. Substitutions at NS3 Residue 155, 156, or 168 of Hepatitis C Virus Genotypes 2 to 6 Induce Complex Patterns of Protease Inhibitor Resistance. Antimicrob Agents Chemother. 2015;59(12):7426-36.

41. Serre SB, Jensen SB, Ghanem L, Humes DG, Ramirez S, Li YP, Krarup H, Bukh J, Gottwein JM. Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle. Antimicrob Agents Chemother. 2016;60(6):3563-78.

42. Ramirez S, Mikkelsen LS, Gottwein JM, Bukh J. Robust HCV Genotype 3a Infectious Cell Culture System Permits Identification of Escape Variants With Resistance to Sofosbuvir. Gastroenterology. 2016;151: 973-985.

43. Pham LV, Ramirez S, Carlsen THR, Li YP, Gottwein JM, Bukh J. Efficient Hepatitis C Virus Genotype 1b Core-NS5A Recombinants Permit Efficacy Testing of Protease and NS5A Inhibitors.
Antimicrob Agents Chemother. 2017;61(6).

44. Gottwein JM, Pham LV, Mikkelsen LS, Ghanem L, Ramirez S, Scheel TKH, Carlsen THR, Bukh J. Efficacy of NS5A Inhibitors Against Hepatitis C Virus Genotypes 1-7 and Escape Variants. Gastroenterology. 2018;154:1435-1448.

45. Pham LV, Ramirez S, Gottwein JM, Fahnøe U, Li YP, Pedersen J, Bukh J. HCV Genotype 6a Escape from and Resistance to Velpatasvir, Pibrentasvir, and Sofosbuvir in Robust Infectious Cell Culture Models. Gastroenterology. 2018 (Epub ahead of print)

46. Galli A, Mens H, Gottwein JM, Gerstoft J, Bukh J. Antiviral Effect of Ribavirin against HCV Associated with Increased Frequency of G-to-A and C-to-U Transitions in Infectious Cell Culture Model. Sci Rep. 2018; 8(1):4619.

List of Patents and Patent Applications

Issued US Patents

1. Efficient cell culture system for hepatitis C virus genotype 2b.
Patent #: 8,663,653 (March 04, 2014)
Inventors: Gottwein JM, Knudsen ML, Scheel TKH, and Bukh J

2. Efficient cell culture system for hepatitis C virus genotype 5a.
Patent #: 8,618,275 B2 (December 31, 2013)
Jensen TB, Gottwein JM, Scheel TKH, Eugen-Olsen J, and Bukh J

3. Efficient cell culture system for hepatitis C virus genotype 6a.
Patent #: 8,569,472 B2 (October 29, 2013)
Inventors: Gottwein JM, Scheel TKH, Jensen TB, and Bukh J

4. Efficient cell culture system for hepatitis C virus genotype 1a and 1b.
Patent #: 8,563,706 B2 (October 22, 2013)
Inventors: Scheel TKH, Prentø J, Gottwein JM, Jensen TB, and Bukh J

5. Efficient cell culture system for hepatitis C virus genotype 7a.
Patent #: 8,506,969 B2 (August 13, 2013)
Inventors: Gottwein JM, Scheel TKH, Jensen TB, and Bukh J

6. Adaptive mutations allow establishment of JFH1-based cell culture systems for hepatitis C virus genotype 4a.
Patent #: 8,454,974 B2 (June 4, 2013)
Inventors: Scheel TKH, Gottwein JM, Eugen-Olsen J, and Bukh J

7. Infectious genotype 1a, 2a, 3a, 5a and 6a hepatitis C virus lacking the hypervariable region 1 (HVR1).
Patent #: 8,846,891 (September 30, 2014)
Inventors: Prentø JC, Gottwein JM, Scheel TKH, Jensen TB, and Bukh J

8. Hepatitis C reporter virus recombinant expressing reporter tagged NS5A protein.
Patent #: 8,772,022 (July 8, 2014)
Inventors: Gottwein JM, Lademann JB, Scheel TKH, Jensen TB, Li Y, Prentoe JC, and Bukh J

9. Cell culture system of hepatitis C genotype 3a releasing intergenotypic recombinant JFH1 virus with Core through NS2 of strain S52.
Patent #: 8,945,584 (February 3, 2015)
Inventors: Gottwein JM, Scheel TKH, Eugen-Olsen J, and Bukh J

10. Infectious Hepatitis C Viruses of Genotype 3a and 4a and Uses thereof.
Inventors: Gottwein JM, Scheel TKH, Purcell R, and Bukh J
Patent #: 8,946,398 (February 3, 2015)

11. JFH-1 based HCV Cell Culture Systems for NS5A of genotype 1-7.
Inventors: Scheel TKH, Gottwein JM, Jensen TB, and Bukh J
Patent #: 9,388,389 (July 12, 2016)

12. HCV full-length infectious cell culture systems and applications thereof.
Inventors: Li YP, Ramirez S, Gottwein JM, Scheel TKH, and Bukh J
Patent #: 9,382,517 (July 5, 2016)

Filed Patents - not yet issued

1. High-titer HCV full-length genotype 2b infectious cell culture systems and applications thereof.
Inventors: Ramirez S, Li YP, Gottwein JM, Bukh J

2. Novel HCV culture systems and direct-acting antiviral sensitivity.
Inventors: Li Y, Ramirez S, Humes D, Gottwein J, Bukh J

3. Development of methods for production of a whole virus vaccine candidate stock and novel adaptive mutations in hepatitis C virus.
Inventors: Mathiesen CK, Jensen TB, Bukh J, Gottwein JM

4. Efficient cell culture system for hepatitis C virus genotype 6a
Inventors: Pham LV, Ramirez S, Gottwein J, Li YP, Pedersen J, Bukh J

Region H/Copenhagen University have licensed the JFH1-based HCV culture systems to Apath, USA (2010 and 2013)