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Klinik für Innere Medizin IIGastroenterologie, Hepatologie, Endokrinologie und Infektiologie

Group of Christoph Neumann-Haefelin

Research interest

Hepatitis C virus (HCV) has infected 170 million people worldwide. Only a minority of patients (~30%) can clear the virus spontaneously, while the majority develops chronic infection. Virus-specific CD8+ T cells are the primary effector cells against HCV, but it is still not well understood why they fail to eliminate the virus in most patients. Interestingly, patients which are positive for the HLA allele B27 have a much better chance to eliminate HCV. We identified the first HLA-B27 restricted HCV-specific CD8+ T cell epitope and demonstrated the mechanisms of protection by this immunodominant epitope. In our current studies we search for further immunodominant (and possibly protective) CD8+ T cell epitopes. In addition, we analyse the general mechanisms of immunodominance (e.g., why are some epitopes targeted in most patients, while other epitopes are targeted only in few patients). Finally, we determine the mechanisms that contribute to CD8+ T cell success or failure in the context of different immunodominant HCV epitopes.

Hepatitis B virus (HBV) has infected 350 million people worldwide. Most adults clear the virus spontaneously in the acute phase of infection. For those patients who develop chronic HBV infection, however, no definitive antiviral therapy leading to viral clearance is availbale to date. In contrast to HCV infection, only little effort has been made in the identification of HBV-specific CD8+ T cell epitopes, thus limiting our understanding of factors that contribute to CD8+ T cell failure in patients developping chronic HBV infection. We specifically aim to identify HLA-B restricted, possibly protective HBV-specific CD8+ T cell responses and to clarify a possible role of viral escape mutations in HBV-specific CD8+ T cell failure.

Members

PD Dr. Christoph Neumann-Haefelin ( Group leader) 0761/270-32800
Philipp Ehrenmann (MD student)0761/270-35110
Janine Kemming (PhD student) 0761/270-35110
Hendrik Luxenburger (MD student)0761/270-35110
Valerie Oberhardt (PhD student)0761/270-35110
Elahe Salimi (PhD student)0761/270-35110
Elisa Wüstrich (BTA)0761/270-35090
In addition, we work in close cooperation with the group of Robert Thimme.

Funding

Our studies are supported by:

Selected publications

  1. Nitschke K, Barriga A, Schmidt J, Timm J, Viazov S, Kuntzen T, Kim AY, Lauer GM, Allen TM, Gaudieri S, Rauch A, Lange CM, Sarrazin C, Eiermann T, Sidney J, Sette A, Thimme R, López D, Neumann-Haefelin C (2013). HLA-B∗27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T-cell epitope. J Hepatol., in press

  2. Ashraf S, Nitschke K, Warshow UM, Brooks CR, Kim AY, Lauer GM, Hydes TJ, Cramp ME, Alexander G, Little AM, Thimme R, Neumann-Haefelin C, Khakoo SI (2013). Synergism of tapasin and HLA in resolving HCV infection. Hepatology, in press.

  3. Schmidt J, Iversen AK, Tenzer S, Gostick E, Price DA, Lohmann V, Distler U, Bowness P, Schild H, Blum HE, Klenerman P, Neumann-Haefelin C, Thimme R (2012). Rapid antigen processing and presentation of a protective and immunodominant HLA-B*27-restricted hepatitis C virus-specific CD8+ T-cell epitope. PLoS Pathog. 8:e1003042.

  4. Ziegler S, Ruhl M, Tenckhoff H, Wiese M, Heinemann FM, Horn PA, Spengler U, Neumann-Haefelin C, Nattermann J, Timm J; East-German HCV Study Group (2013). Susceptibility to chronic hepatitis C virus infection is influenced by sequence differences in immunodominant CD8+ T cell epitopes. J Hepatol. 58:24-30.

  5. Grafmueller S, Billerbeck E, Blum HE, Neumann-Haefelin C, Thimme R (2012). Differential antigen specificity of hepatitis C virus-specific interleukin 17- and interferon γ-producing CD8(+) T cells during chronic infection. J Infect Dis. 205:1142-1146.

  6. Neumann-Haefelin C, Oniangue-Ndza C, Kuntzen T, Schmidt J, Nitschke K, Sidney J, Caillet-Saguy C, Binder M, Kersting N, Kemper MW, Power KA, Ingber S, Reyor LL, Hills-Evans K, Kim AY, Lauer GM, Lohmann V, Sette A, Henn MR, Bressanelli S, Thimme R, Allen TM (2011). HLA-B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations. Hepatology 54:1157-1166.

  7. Schmidt J, Neumann-Haefelin C, Altay T, Gostick E, Price DA, Lohmann V, Blum HE, Thimme R (2011). Immunodominance of HLA-A2 restricted hepatitis C virus-specific CD8+ T cell responses is linked to naive precursor frequency. J Virol 85: 5232-5236.

  8. Witkowski M, Spangenberg HC, Neumann-Haefelin C, Büttner N, Breous E, Kersting N, Drognitz O, Hopt UT, Blum HE, Semmo N, Thimme R (2011). Lack of ex vivo peripheral and intrahepatic α-fetoprotein-specific CD4+ responses in hepatocellular carcinoma. Int J Cancer 129: 2171-2182.

  9. Oniangue-Ndza C, Kuntzen T, Kemper M, Berical A, Wang YE, Neumann-Haefelin C, Foote PK, Hills-Evans K, Reyor LL, Kane K, Gladden AD, Bloom AK, Power KA, Thimme R, Lauer GM, Henn MR, Kim AY, Allen TM (2011). Compensatory mutations restore the replication defects caused by cytotoxic T lymphocyte escape mutations in hepatitis C virus polymerase. J Virol. 85:11883-11890.

  10. Raziorrouh B, Ulsenheimer A, Schraut W, Heeg M, Kurktschiev P, Zachoval R, Jung MC, Thimme R, Neumann-Haefelin C, Horster S, Wächtler M, Spannagl M, Haas J, Diepolder HM, Grüner NH (2011). Inhibitory molecules that regulate expansion and restoration of HCV-specific CD4+ T cells in patients with chronic infection. Gastroenterology 141:1422-1431.

  11. Ruhl M, Knuschke T, Schewior K, Glavinic L, Neumann-Haefelin C, Chang DI, Klein M, Heinemann FM, Tenckhoff H, Wiese M, Horn PA, Viazov S, Spengler U, Roggendorf M, Scherbaum N, Nattermann J, Hoffmann D, Timm J; East German HCV Study Group (2011). CD8+ T-cell response promotes evolution of hepatitis C virus nonstructural proteins. Gastroenterology 140:2064-2073.

  12. Neumann-Haefelin C, Timm J, Schmidt J, Kersting N, Fitzmaurice K, Oniangue-Ndza C, Kemper M, Humphreys I, McKiernan S, Kelleher D, Lohmann V, Bowness P, Huzly D, Rosen HR, Kim AY, Lauer GM, Allen TM, Barnes E, Roggendorf M, Blum HE, Thimme R (2010). The protective effect of HLA-B27 in hepatitis C virus infection requires presence of a genotype-specific immunodominant CD8+ T cell epitope. Hepatology 51: 54-62.

  13. Dazert E, Neumann-Haefelin C (equal contribution), Bressanelli S, Fitzmaurice K, Kort J, Timm J, McKiernan S, Kelleher D, Gruener N, Tavis JE, Rosen, HR, Shaw J, Bowness P, Blum HE, Klenerman P, , Bartenschlager R, Thimme R (2009). Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response. J Clin Invest 119: 376-386.

  14. Neumann-Haefelin C, Timm J, Spangenberg HC, Wischniowski N, Nazarova N, Kersting N, Roggendorf M, Allen TM, Blum HE, Thimme R (2008). Virological and Immunological Determinants of Intrahepatic Virus-Specific CD8+ T-Cell Failure in Chronic Hepatitis C Virus Infection. Hepatology 47: 1824-1836.

  15. Neumann-Haefelin C, Frick DN, Wang JJ, Pybus OG, Salloum S, Narula GS, Eckart A, Biezynski A, Eiermann T, Klenerman P, Viazov S, Roggendorf M, Thimme R, Reiser M, Timm J (2008). Analysis of the evolutionary forces in an immunodominant CD8 epitope in the hepatitis C virus at a population level. J Virol. 82: 3438-3451.

  16. Salloum S, Oniangue-Ndza C, Neumann-Haefelin C, Hudson L, Giugliano S, aus dem Siepen M, Nattermann J, Spengler U, Lauer G, Wiese M, Klenerman P, Bright H, Scherbaum N, Thimme R, Roggendorf M, Viazov S, Timm J (2008). Escape from HLA-B*08 restricted CD8 T cells by hepatitis C virus is associated with fitness costs. J Virol 82:11803-11812.

  17. Neumann-Haefelin C, Killinger T, Timm J, Southwood S, McKinney D, Blum HE, Thimme R (2007). Absence of viral escape within a frequently recognized HLA-A26 restricted CD8+ T cell epitope targeting the functionally constrained hepatitis C virus NS5A/5B cleavage site. J Gen Virol. 88: 1986-1991.

  18. Neumann-Haefelin C, McKiernan S, Ward S, Viazov S, Spangenberg HC, Killinger T, Baumert TF, Nazarova N, Sheridan I, Pybus O, von Weizsacker F, Roggendorf M, Kelleher D, Klenerman P, Blum HE, Thimme R (2006). Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution. Hepatology 43: 563-572

  19. Spangenberg HC, Viazov S, Kersting N, Neumann-Haefelin C, McKinney D, Roggendorf M, von Weizsacker F, Blum HE, Thimme R (2005). Intrahepatic CD8+ T-cell failure during chronic hepatitis C virus infection. Hepatology 42: 828-837.

  20. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, Blum HE, von Weizsacker F, Thimme R (2005). T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol 79: 7860-7867.


Selected review articles

  1. Neumann-Haefelin C (2013). HLA-B27-mediated protection in HIV and hepatitis C virus infection and pathogenesis in spondyloarthritis: two sides of the same coin? Curr Opin Rheumatol. 25: 426-433.

  2. Neumann-Haefelin C, Thimme R (2013). Adaptive immune responses in hepatitis C virus infection. Curr Top Microbiol Immunol. 369: 243-462.
  3. Schmidt N, Neumann-Haefelin C, Thimme R (2012). Cellular immune responses to hepatocellular carcinoma: lessons for immunotherapy. Dig Dis. 30:483-491.

  4. Neumann-Haefelin C, Thimme R (2011). Success and failure of virus-specific T cell responses in hepatitis C virus infection. Dig Dis. 29:416-422.

  5. Schmidt J, Thimme R, Neumann-Haefelin C (2011). Host genetics in immune-mediated hepatitis C virus clearance. Biomark Med. 5:155-169.

  6. Neumann-Haefelin C (2011). Protektiver Effekt von HLA-B27 auf den Verlauf der HIV- und Hepatitis-C-Virus-Infektion. Dtsch Med Wochenschr. 136: 320-324.

  7. Thimme R, Neumann-Haefelin C, Boettler T, Blum HE (2008). Adaptive immune responses to hepatitis C virus: from viral immunobiology to a vaccine. Biol Chem. 389: 457-467.

  8. Neumann-Haefelin C, Spangenberg HC, Blum HE, Thimme R (2007). Host and viral factors contributing to CD8+ T cell failure in hepatitis C virus infection. World J Gastroenterol. 13: 4839-4847.

  9. Neumann-Haefelin C, Thimme R (2007). Impact of the genetic restriction of virus-specific T cell responses in hepatitis C virus infection. Genes Immun. 8: 181-92.

  10. Neumann-Haefelin C, Blum HE, Chisari FV, Thimme R (2005). T cell response in hepatitis C virus infection. J Clin Virol 32: 75-85.