Cure of chronic hepatitis C – long-term effects on HCV-specific and heterologous immune responses
Functionally exhausted HCV-specific CD18+ T cells are not universally restored by blockade of distinct co-regulatory molecules
(Owusu Sekyere et al., J Hepatol. 2015)
The central aim of the project of the groups of Markus Cornberg and Heiner Wedemeyer is to understand the effects of co-regulatory molecules on antigen-specific T cell properties during chronic hepatitis C virus infection and how these properties change when the virus is cleared by direct acting antiviral agents (DAA). This model is a unique opportunity to investigate the effect of the pathogen and its clearance on the immune system.
Viral persistence is associated with T cell exhaustion. The failure to control virus infections can be explained in part by up-regulation of co-regulatory “check-point” receptors on virus-specific T cells. We and others showed that antiviral effector functions of hepatitis virus-specific T cells can be increased by blocking T cell co-regulatory pathways such as PD-1, 2B4 or CTLA-4. However, there is large inter-individual variability in responsiveness to this check-point inhibition and optimal combinations need to be defined. In some cases, combination of check-point inhibitors had even negative effects on T cell functionality. In addition it is largely unknown in humans if elimination of a pathogen can restore T cell exhaustion and how this also affects unrelated immune responses.
This project of Heiner Wedemeyer and Markus Cornberg investigates the effects of blocking several co-regulatory pathways in chronic HCV infections on the virus-specific T cell repertoire and functionality. In addition, we aim to understand in more detail how a persistent viral infection affects co-regulatory molecules and T cell properties (cognate and unrelated) and importantly how this changes when the infection is cleared by DAA.
We will take advantage of the approval of novel DAA against HCV, which will enable a cure of HCV infection in more than 95% of cases and thus allow us to prospectively study the evolution of virus-specific T cell responses and repertoires during and after HCV Elimination.
This project can potentially give new insights into basic principles how persistent virus infections influence T cell responses in humans and might have clinical implications to personalize therapeutic applications of antibodies blocking T cell co-inhibition which are already in clinical use.
Heiner Wedemeyer and Markus Cornberg are talking about their research at CRC 900
Heiner Wedemeyer and Markus Cornberg have been part of the CRC since its founding in 2010 and in project A5 focus on research into chronic hepatitis C infections and their effects on the immune system.
Publications of the project A5
Direct-Acting Antiviral–Induced Hepatitis C Virus Clearance Does Not Completely Restore the Altered Cytokine and Chemokine Milieu in Patients With Chronic Hepatitis C. Hengst J, Falk CS, Schlaphoff V, Deterding K, Manns MP, Cornberg M, Wedemeyer H. J Infect Dis. 2016 Dec 15;214(12)
The third signal cytokine IL-12 rather than immune checkpoint inhibitors contribute to the functional restoration of hepatitis D virus-specific T-cells. Schirdewahn T, Grabowski J, Sekyere SO, Bremer B, Wranke A, Lunemann S, Schlaphoff V, Kirschner J, Hardtke S, Manns MP, Cornberg M, Wedemeyer H, Suneetha PV. J Infect Dis. 2016 Oct 31. pii: jiw514.
Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy. Hengst J, Strunz B, Deterding K, Ljunggren HG, Leeansyah E, Manns MP, Cornberg M, Sandberg JK, Wedemeyer H, Björkström NK. Eur J Immunol. 2016 Sep;46(9):2204-10.
Hepatitis C virus infection from the perspective of heterologous immunity. Cornberg M, Wedemeyer H. Curr Opin Virol. 2016 Jan 27;16:41-48.
Frequency, Private Specificity, and Cross-Reactivity of Preexisting Hepatitis C Virus (HCV)-Specific CD8+ T Cells in HCV-Seronegative Individuals: Implications for Vaccine Responses. Zhang S, Bakshi RK, Suneetha PV, Fytili P, Antunes DA, Vieira GF, Jacobs R, Klade CS, Manns MP, Kraft AR, Wedemeyer H, Schlaphoff V, Cornberg M. J Virol. 2015 Aug;89(16):8304-17.
Type I Interferon Elevates Co-Regulatory Receptor Expression on CMV- and EBV-Specific CD8 T Cells in Chronic Hepatitis C. Owusu Sekyere S, Suneetha PV, Hardtke S, Falk CS, Hengst J, Manns MP, Cornberg M, Wedemeyer H, Schlaphoff V. Front Immunol. 2015 Jun 10;6:270.
A heterogeneous hierarchy of co-regulatory receptors regulates exhaustion of HCV-specific CD8 T cells in patients with chronic hepatitis C. Owusu Sekyere S, Suneetha PV, Kraft AR, Zhang S, Dietz J, Sarrazin C, Manns MP, Schlaphoff V, Cornberg M, Wedemeyer H. J Hepatol. 2015 Jan;62(1):31-40.
Hepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection. Suneetha PV, Pischke S, Schlaphoff V, Grabowski J, Fytili P, Gronert A, Bremer B, Markova A, Jaroszewicz J, Bara C, Manns MP, Cornberg M, Wedemeyer H. Hepatology. 2012 Mar;55(3):695-708.
Dual function of the NK cell receptor 2B4 (CD244) in the regulation of HCV-specific CD8+ T cells. Schlaphoff V, Lunemann S, Suneetha PV, Jaroszewicz J, Grabowski J, Dietz J, Helfritz F, Bektas H, Sarrazin C, Manns MP, Cornberg M, Wedemeyer H. PLoS Pathog. 2011 May;7(5):e1002045.