Project TP 8

(C. Neumann-Haefelin)

Protective CD8+ T cell responses and role of viral escape in HBV infection

Virus-specific CD8+ T cells play a central role in HBV control. In chronic HBV infection, however, virus-specific CD8+ T cells have been shown to be functionally impaired. Despite these well accepted findings, central questions in HBV immunobiology have not been addressed. Specifically, CD8+ T cell epitopes that might be protective in outcome of HBV infection have not been defined and the role of viral escape in HBV persistence remains controversial. Indeed, only few HBV-specific CD8+ T cell epitopes, mostly restricted by HLA-A2, have been identified. Studies analyzing these HLA-A2 epitopes have suggested that viral escape does not play a major role in HBV-specific T cell failure. However, protective CD8+ T cell responses against human viruses such as HIV and HCV are typically restricted by HLA alleles other than A2 (e.g. B27, B57, A3) that exert the strongest selective pressure on the virus.

We have previously identified the first HLA-B27 restricted HBV-specific CD8+ T cell epitopes and obtained evidence for HLA-B27 driven viral escape. These results indicate that HLA-B27 may have a dominant and protective role in HBV infection and that viral escape is indeed a central mechanism of HBV-specific T cell failure, thus questioning the current concept in the field that viral escape does not play a major role in HBV infection.

To extend these preliminary findings and to confirm them on a broader scale, we aim to identify additional dominant HBV-specific CD8+ T cell epitopes restricted by likely protective HLA alleles such as HLA-B27, B57, and A3. These studies will be performed in a large cohort of patients with acute, resolved, or chronic HBV infection. The results will overcome the currently limited understanding of HBV immunopathogenesis that is restricted to the HLA-A2 background. By analyzing viral sequences corresponding to newly identified dominant CD8+ T cell epitopes, we will clarify the role of viral escape in persistent HBV infection. A full-genome HBV sequence analysis in a large patient cohort will allow the identification of HLA-associated sequence polymorphisms outside of identified epitopes. Since functional constraints, e.g. overlapping reading frames, are thought to strongly limit viral escape, we will analyze the impact of identified viral escape mutations (e.g. those identified for HLA-B27) on HBV replication in a cell culture model. Establishment of an HLA-B27 expressing cell culture system will allow the analysis of the effect of viral escape on HBV control by virus-specific CD8+ T cells. Finally, since viral escape has been described to have an important impact on CD8+ T cell phenotype and function in HIV and HBV infection, we will analyze the phenotype and function of HBV-specific CD8+ T cells targeting wild-type or mutated epitopes. In sum, our results will contribute to a better definition of protective HBV-specific CD8+ T cells, clarify the role of viral escape in HBV persistence, and may change currently accepted concepts of HBV immunobiology.
© Dep. of Infectious Diseases, Molecular Virology. University of Heidelberg
Activation of Type I and III Interferon Response by Mitochondrial and Peroxisomal MAVS and Inhibition by Hepatitis C Virus.Bender S, Reuter A, Eberle F, Einhorn E, Binder M, Bartenschlager R. PLoS Pathog. 2015 Nov 20;11(11):e1005264.

Virus-specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-helper Cells in Patients With Acute and Chronic HCV Infections. Raziorrouh B, Sacher K, Tawar RG, Emmerich F, Neumann-Haefelin C, Baumert TF, Thimme R, Boettler T. Gastroenterology. 2015 Nov 13. pii: S0016-5085(15)01622-4.

Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S. J Hepatol. 2015 Nov 11. pii: S0168-8278(15)00736-9. doi: 10.1016/j.jhep.2015.10.030. [Epub ahead of print]