Project Description
Public­ations

TP02: Virus-specific CD8+ T cell responses in hepatitis B virus/ hepatitis D virus co-infection: mechanisms of failure and strategies for restoration

Based on the identification of HDV-specific CD8+ T cell epitopes achieved during the first funding period, we will now study the mechanisms of HDV- as well as HBV-specific CD8+ T cell failure in persistent HBV/HDV co-infection. These analyses will include low input/single cell RNAseq, metabolic studies as well as high-dimensional cytometry analyses. In addition, strategies to restore T cell function will be tested, including checkpoint inhibition, addition of pro-inflammatory cytokines and TCR re-direction. Finally, we will take advantage of novel antiviral therapies for HBV/HDV co-infection and analyze the effect of antigen removal on virus-specific CD8+ T cells in HBV/HDV co-infection.
A. Karimzadeh H, Kiraithe MM, Oberhardt V, Salimi Alizei E, Bockmann J, Schulze Zur Wiesch J, Budeus B, Hoffmann D, Wedemeyer H, Cornberg M, Krawczyk A, Rashidi-Alavijeh J, Rodríguez-Frías F, Casil-las R, Buti M, Smedile A, Alavian SM, Heinold A, Emmerich F, Panning M, Gostick E, Price DA, Timm J, Hofmann M, Raziorrouh B, Thimme R, Protzer U, Roggendorf M, Neumann-Haefelin C. 2019. Muta-tions in hepatitis D virus allow it to escape detection by CD8+ T cells and evolve at the population lev-el. Gastroenterology. 156(6):1820-1833.
B. Schuch A, Salimi Alizei E, Heim K, Wieland D, Kiraithe MM, Kemming J, Llewellyn-Lacey S, Sogukpinar Ö, Ni Y, Urban S, Zimmermann P, Nassal M, Emmerich F, Price DA, Bengsch B, Luxenburger H, Neumann-Haefelin C, Hofmann M, Thimme R. 2019. Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. Gut. 68(5):905-915.
C. Schuch A, Zecher BF, Müller PA, Correia MP, Daul F, Rennert C, Tauber C, Schlitt K, Boettler T, Neumann-Haefelin C, Hengel H, Pircher H, Cerwenka A, Thimme R, Hofmann M. 2019. NK-cell re-sponses are biased towards CD16-mediated effector functions in chronic hepatitis B virus infection. J Hepatol. 70(3):351-360.
D. Jacobi FJ, Wild K, Smits M, Zoldan K, Csernalabics B, Flecken T, Lang J, Ehrenmann P, Emmerich F, Hofmann M, Thimme R, Neumann-Haefelin C, Boettler T. 2019. OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection. J Hepatol. 70(6):1103-1113.
E. Lang J, Neumann-Haefelin C, Thimme R. Immunological cure of HBV infection. 2019. Hepatol Int. 13(2):113-124.
F. Luxenburger H, Graß F, Baermann J, Boettler T, Marget M, Emmerich F, Panning M, Thimme R, Nitsch-ke K, Neumann-Haefelin C. 2018. Differential virus-specific CD8(+) T-cell epitope repertoire in hepatitis C virus genotype 1 versus 4. J Viral Hepat 25(7):779–790.
G. Grünvogel O, Colasanti O, Lee JY, Klöss V, Belouzard S, Reustle A, Esser-Nobis K, Hesebeck-Brinckmann J, Mutz P, Hoffmann K, Mehrabi A, Koschny R, Vondran FWR, Gotthardt D, Schnitzler P, Neumann-Haefelin C, Thimme R, Binder M, Bartenschlager R, Dubuisson J, Dalpke AH, Lohmann V. 2018. Secretion of hepatitis C virus replication intermediates reduces activation of toll like receptor 3 in hepatocytes. Gastroenterology. 154(8):2237-2251.
H. Karimzadeh H, Kiraithe MM, Kosinska AD, Glaser M, Fiedler M, Oberhardt V, Salimi Alizei E, Hofmann M, Mok JY, Nguyen M, van Esch WJE, Budeus B, Grabowski J, Homs M, Olivero A, Keyvani H, Ro-dríguez-Frías F, Tabernero D, Buti M, Heinold A, Alavian SM, Bauer T, Schulze Zur Wiesch J, Razior-rouh B, Hoffmann D, Smedile A, Rizzetto M, Wedemeyer H, Timm J, Antes I, Neumann-Haefelin C, Protzer U, Roggendorf M. 2018. Amino acid substitutions within HLA-B*27-restricted T cell epitopes prevent recognition by hepatitis delta virus-specific CD8+ T cells. J Virol. 92:e01891-17.
I. Neumann-Haefelin C, Thimme R. 2018. Entering the spotlight: hepatitis B surface antigen-specific B cells. J Clin Invest. 128(10):4257-4259.
J. Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C, Held W, Zehn D, Hofmann M, Thimme R. 2017. TCF1(+) hepatitis C virus-specific CD8(+) T cells are maintained after cessation of chronic antigen stimulation. Nat Commun 8:15050.