Cooperative mechanisms of innate and adaptive immune responses targeting hepatitis C virus infection
Final Report Abstract
An effective hepatitis C virus (HCV) vaccine is urgently needed for global eradication of HCV infection and liver disease. While the role of neutralizing adaptive immune responses for HCV infection has been studied in great detail, the role of innate immune mechanisms for viral escape and protection against HCV infection is only partially understood. Interferon-induced transmembrane proteins (IFITMs) are innate effector proteins restricting host cell entry of enveloped viruses, including HCV. However, their clinical impact on acute or chronic HCV infection has not yet been determined. Within the project, we were able to show that IFITMs mediate viral escape in clinical cohorts of HCV infected patients. We show that HCV variants isolated before seroconversion are more sensitive to the antiviral activity of IFITMs than variants from patients isolated from chronic infection post-seroconversion. Furthermore, HCV variants from patients escaping viral neutralizing responses during liver transplantation exhibited a significantly higher resistance to IFITMs than variants that are eliminated post transplantation. Gain-of-function studies and mechanistic studies revealed that IFITMs markedly enhance the antiviral activity of neutralizing antibodies, suggesting a cooperative effect of human monoclonal antibodies and IFITMs for antibody-mediated neutralization, driving the selection pressure in viral evasion. Perturbation studies with the IFITM-antagonist amphotericin B revealed that modulated membrane-properties could be responsible for the IFITM-mediated enhancement of neutralization. In conclusion, our results identify a previously unknown function of IFITMs for viral escape and antibody-mediated HCV neutralization in acute and chronic HCV infection. Understanding of viral immune evasion from B cell responses, an important concern during chronic HCV infection, will contribute to the development of a protective HCV vaccine. In parallel, we aimed to identify determinants of an effective neutralizing response against HCV by defining the specificity of the B cell response by characterizing structural and functional properties of anti-HCV envelope antibodies. The role of neutralizing antibodies targeting the E2 protein have been well studied, however the role of antibodies targeting E1 and the E1E2 interface is much less well understood. Additionally, the interaction of neutralizing and non-neutralizing antibodies as well as the role of extraneutralizing properties is largely unknown. We identified neutralizing antibodies targeting the E1/E2 interface and found that binding of these antibodies altered the ability of the virus to interact with virusreceptors CD81 and SR-BI. Further investigations of the role of these antibodies could enable the identification of highly conserved synergistic neutralization-determining epitopes. Additionally, we have taken the necessary steps to establish the techniques to generate a high-resolution map of the neutralizing and extra-neutralizing antibody response during HCV infection, that allows for the identification of determinants for viral clearance and could prove highly useful to inform vaccine design.
Publications
- In vivo combination of human anti-envelope glycoprotein E2 and -Claudin-1 monoclonal antibodies for prevention of hepatitis C virus infection. Antiviral Res. 2019 Feb;162:136-141
Mailly L, Wrensch F, Heydmann L, Fauvelle C, Brignon N, Zeisel MB, Pessaux P, Keck ZY, Schuster C, Fuerst TR, Foung SKH, Baumert TF
(See online at https://doi.org/10.1016/j.antiviral.2018.12.018) - Interferon-Induced Transmembrane Proteins Mediate Viral Evasion in Acute and Chronic Hepatitis C Virus Infection. Hepatology. 2019 Nov;70(5):1506-1520
Wrensch F, Ligat G, Heydmann L, Schuster C, Zeisel MB, Pessaux P, Habersetzer F, King BJ, Tarr AW, Ball JK, Winkler M, Pöhlmann S, Keck ZY, Foung SKH, Baumert TF
(See online at https://doi.org/10.1002/hep.30699) - The Innate Antiviral Response in Animals: An Evolutionary Perspective from Flagellates to Humans. Viruses. 2019 Aug 16;11(8):758
Majzoub K, Wrensch F, Baumert TF
(See online at https://doi.org/10.3390/v11080758) - Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip. J. Int J Mol Sci. 2020 Apr 26;21(9):3057
Goto K, Roca Suarez AA, Wrensch F, Baumert TF, Lupberger J
(See online at https://doi.org/10.3390/ijms21093057)
