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Project A1

Impact of Hepatitis C Virus Core and NS5A on Induction of Pro-carcinogenic Alterations and HCC Development

Principal Investigators: Dr. Volker Lohmann, Prof. Dr. Ralf Bartenschlager

 

 

Short Summary

Chronic hepatitis C virus (HCV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), but the underlying mechanisms are poorly understood. This project aims to clarify the mechanisms by which HCV in particular the two viral proteins core and non-structural protein 5A, contribute to tumor formation. We will use authentic cell culture systems and the mosaic mouse model to study a) the role of core-associated steatosis and interference with the tumor suppressor DDX3 and b) the mechanisms underlying NS5A-mediated induction of b-catenin signaling.

 

List of relevant publications

  1. Appel N, Zayas M, Miller S, Krijnse-Locker J, Schaller T, Friebe P, Kallis S, Engel U, Bartenschlager R (2008) Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. PLoS Pathog 4:e1000035.
  2. Scholtes C, Diaz O, Icard V, Kaul A, Bartenschlager R, Lotteau V, Andre P (2008) Enhancement of genotype 1 hepatitis C virus replication by bile acids through FXR. J Hepatol 48:192-99
  3. Schaller T, Appel N, Koutsoudakis G, Kallis S, Lohmann V, Pietschmann T, Bartenschlager R (2007) Analysis of hepatitis C virus superinfection exclusion by using novel fluorochrome gene-tagged viral genomes. J Virol 81:4591-603.
  4. Binder M, Kochs G, Bartenschlager R, Lohmann V (2007) Hepatitis C virus escape from the interferon regulatory factor 3 pathway by a passive and active evasion strategy. Hepatology 46:1365-74.
  5. Kaul A, Woerz I, Meuleman P, Leroux-Roels G, Bartenschlager R (2007) Cell culture adaptation of hepatitis C virus and in vivo viability of an adapted variant. J Virol 81:13168-79
  6. Miyanari Y, Atsuzawa K, Usuda N, Watashi K, Hishiki T, Zayas M, Bartenschlager R, Wakita T, Hijikata M, Shimotohno K (2007) The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 9:1089-97.
  7. Shavinskaya A, Boulant S, Penin F, McLauchlan J, Bartenschlager R (2007) The lipid droplet binding domain of hepatitis C virus core protein is a major determinant for efficient virus assembly. J Biol Chem 282:37158-69.
  8. Binder M, Quinkert D, Bochkarova O, Klein R, Kezmic N, Bartenschlager R, Lohmann V (2007) Identification of determinants involved in initiation of hepatitis C virus RNA synthesis by using intergenotypic replicase chimeras. J Virol 81:5270-83.
  9. Pietschmann T, Kaul A, Koutsoudakis G, Shavinskaya A, Kallis S, Steinmann E, Abid K, Negro F, Dreux M, Cosset FL, Bartenschlager R (2006) Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras. Proc Natl Acad Sci U S A 103:7408-13.
  10. Ghaziani T, Shan Y, Lambrecht RW, Donohue SE, Pietschmann T, Bartenschlager R, Bonkovsky HL (2006) HCV proteins increase expression of heme oxygenase-1 (HO-1) and decrease expression of Bach1 in human hepatoma cells. J Hepatol 45:5-12.
  11. Windisch MP, Frese M, Kaul A, Trippler M, Lohmann V, Bartenschlager R (2005) Dissecting the interferon-induced inhibition of hepatitis C virus replication by using a novel host cell line. J Virol 79:13778-93.
  12. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Krausslich HG, Mizokami M, Bartenschlager R, Liang TJ (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791-96.
  13. Schulze-Krebs A, Preimel D, Popov Y, Bartenschlager R, Lohmann V, Pinzani M, Schuppan D (2005) Hepatitis C virus-replicating hepatocytes induce fibrogenic activation of hepatic stellate cells. Gastroenterology 129:246-58.
  14. Lee SH, Kim YK, Kim CS, Seol SK, Kim J, Cho S, Song YL, Bartenschlager R, Jang SK (2005) E2 of hepatitis C virus inhibits apoptosis. J Immunol 175:8226-35.
  15. Benali-Furet NL, Chami M, Houel L, De Giorgi F, Vernejoul F, Lagorce D, Buscail L, Bartenschlager R, Ichas F, Rizzuto R, Paterlini-Brechot P (2005) Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. Oncogene 24:4921-33.
  16. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167-72.
  17. Appel N, Pietschmann T, Bartenschlager R (2005) Mutational analysis of hepatitis C virus nonstructural protein 5A: potential role of differential phosphorylation in RNA replication and identification of a genetically flexible domain. J Virol 79:3187-94.
  18. Appel N, Herian U, Bartenschlager R (2005) Efficient rescue of hepatitis C virus RNA replication by trans-complementation with nonstructural protein 5A. J Virol 79:896-909.
  19. Quinkert D, Bartenschlager R, Lohmann V (2005) Quantitative analysis of the hepatitis C virus replication complex. J Virol 79:13594-605.
  20. Schwer B, Ren S, Pietschmann T, Kartenbeck J, Kaehlcke K, Bartenschlager R, Yen TS, Ott M (2004) Targeting of hepatitis C virus core protein to mitochondria through a novel C-terminal localization motif. J Virol 78:7958-68.
  21. Penin F, Brass V, Appel N, Ramboarina S, Montserret R, Ficheux D, Blum HE, Bartenschlager R, Moradpour D (2004) Structure and function of the membrane anchor domain of hepatitis C virus nonstructural protein 5A. J Biol Chem 279:40835-43.
  22. Lohmann V, Hoffmann S, Herian U, Penin F, Bartenschlager R (2003) Viral and cellular determinants of hepatitis C virus RNA replication in cell culture. J Virol 77:3007-19.
  23. Zech B, Kurtenbach A, Krieger N, Strand D, Blencke S, Morbitzer M, Salassidis K, Cotten M, Wissing J, Obert S, Bartenschlager R, Herget T, Daub H (2003) Identification and characterization of amphiphysin II as a novel cellular interaction partner of the hepatitis C virus NS5A protein. J Gen Virol 84:555-60.
  24. Bukh J, Pietschmann T, Lohmann V, Krieger N, Faulk K, Engle RE, Govindarajan S, Shapiro M, St Claire M, Bartenschlager R (2002) Mutations that permit efficient replication of hepatitis C virus RNA in Huh-7 cells prevent productive replication in chimpanzees. Proc Natl Acad Sci U S A 99:14416-21.
  25. Lohmann V, Körner F, Dobierzewska A, Bartenschlager R (2001) Mutations in hepatitis C virus RNAs conferring cell culture adaptation. J Virol 75:1437-49.
  26. Krieger N, Lohmann V, Bartenschlager R (2001) Enhancement of Hepatitis C Virus RNA Replication by Cell Culture- Adaptive Mutations. J Virol 75:4614-24.
  27. Pietschmann T, Lohmann V, Rutter G, Kurpanek K, Bartenschlager R (2001) Characterization of cell lines carrying self-replicating hepatitis C virus RNAs. J Virol 75:1252-64.
  28. Lohmann V, Körner F, Koch JO, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110-13.
  29. Koch JO, Bartenschlager R (1999) Modulation of hepatitis C virus NS5A hyperphosphorylation by nonstructural proteins NS3, NS4A, and NS4B. J Virol 73:7138-46.
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