Project Description

TP02: Viral escape from dominant virus-specific CD8+ T cell responses and restoration strategies in HBV mono- and HBV/HDV co-infection

The HBV-specific CD8+ T cell epitope repertoire is poorly defined, and only two HDV-specific CD8+ T cell epitopes have been described. In addition, the role of viral escape in CD8+ T cell failure in HBV mono- and HBV/HDV co-infection remains elusive. We will therefore define the repertoire of HBV- and HDV-specific CD8+ T cell epitopes and characterize the role as well as determinants and limitations of viral escape in CD8+ T cell failure. In addition, we will determine the relative role of HBV- and HDV-specific CD8+ T cells in co-infection and aim to restore antiviral efficacy in the co-infection setting.
Luxenburger H, Graß F, Baermann J, Boettler T, Marget M, Emmerich F, Panning M, Thimme R, Nitschke K, Neumann-Haefelin C. Differential virus-specific CD8(+) T-cell epitope repertoire in hepatitis C virus genotype 1 versus 4. J Viral Hepat. 2018 Feb 3. doi: 10.1111/jvh.12874. (Epub ahead of print) PubMed PMID: 29397015.
Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C, Held W, Zehn D, Hofmann M, Thimme R. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation. 2017. Nat Commun. 8:15050. doi: 10.1038/ncomms15050.
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. 2014. HLA-B*27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T-cell epitope. J Hepatol 60: 22-29.
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 (equal contribution). 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.
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. Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require com- pensatory mutations. Hepatology 54: 1157-1166.
Neumann-Haefelin C, Timm J, Schmidt J, Kersting N, Fitzmaurice K, Oniangue-Ndza C, Kemper MN, 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.
Dazert E/ Neumann-Haefelin C (equal contribution), Bressanelli S, Fitzmaurice K, Kort J, Timm J, McKi- ernan S, Kelleher D, Gruener N, Tavis JE, Rosen HR, Shaw J, Bowness P, Blum HE, Klenerman P, Bar- tenschlager R, Thimme R. 2009. Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV es- cape from a protective HLA-B27-restricted human immune response. J Clin Invest 119: 376-386.
Neumann-Haefelin C, Timm J, Spangenberg HC, Wischniowski N, Nazarova N, Kersting N, Roggendorf M, Allen TM, Blum H, 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.