Since January 2020 COVID-19 research at the Wuhan-Essen Joint Laboratory, HUST, Wuhan
Several SGVIVI members are active in the joint research on SARS-CoV-2 and COVID-19 at the Wuhan-Essen Joint Laboratory of Infection and Immunity. For more info please go to www.uni-due.de/china/cooperation
During the time of travel restrictions due to the Corona crisis we continuously hold video conferences and jointly discuss the project progress. In addition to other funding sources these projects are generously supported by Stiftung Universitätsmedizin.
Coordinators: PD Dr. Kathrin Sutter, Dr. Jia LIU Targeting the host immune response to control chronic viral infections
Network funding within the frame of the DFG-NSFC "Mobility Programme" for 2020-2022, granted in November 2019
In the last 10 years the members of this collaborative network studied the interaction of the immune system with several different viruses that establish chronic infections in their hosts. These studies provided new concepts of immune regulation and dysregulation in chronic virus infections that can now be utilized for therapeutic approaches and vaccine development. We exclusively focus on HIV and HBV because therapeutic cure is very rarely achieved for these two chronic infections. The special feature of HBV and retroviruses that makes it so difficult to achieve cure is the reservoir of the virus. Both viruses have persistent forms of their genome, which serve as template for virus production and cannot be targeted by current direct-acting antiviral drugs. Thus, a successful therapy must also address the question of how to tackle the viral reservoir. Now is the time to test novel immunotherapy options, especially combination therapies, in preclinical models of infectious diseases. The overall aim of this collaborative network of Chinese and German researchers is to develop novel immunotherapies or combination therapies to achieve complete or functional cure of chronic HIV and HBV infections.
In the last decade a successful collaborative network between German and Chinese virologists, mainly senior PIs of the former TRR60 (www.uni-due.de/trr60) was established. With this Mobility Programme the next generation of junior PIs from Germany and China aim to set up a new collaborative international network. The funding will help to reinforce scientific collaborations between China and Germany by joint annual workshops as well as student exchanges and group leader visits. The project is coordinated by PD Dr. Kathrin Sutter and Dr. Jia LIU. The members on the German side are: Mirko Trilling, Wibke Bayer, Ruth Bröring, Torben Knuschke, Viktoriya Sokolova (all from Essen), Marek Widera (Frankfurt) and Vladimir Temchura (Erlangen). The members on the Chinese side are: Baoju WANG, Jun WU, Ejuan ZHANG, Shi LIU, Chunchen WU (all Wuhan) and Jieliang CHEN (Shanghai).
Dr. Kathrin Sutter and Dr. Jia LiuIFNα subtype-specific susceptibility of HBV in the course of infection
乙型肝炎病毒感染过程中干拢素 α 亚型特异敏感性研究
Joint funding granted by German Research Foundation (DFG) and National Natural Science Foundation of China (NSFC) in December 2018
Chronic hepatitis B virus (HBV) infection continues to be a major health problem worldwide, and remains hard to be cured. Immunotherapy with Interferon α (IFNα) is an important method for the clinical treatment of chronic hepatitis B. IFNα exhibits direct antiviral effect as well as immunomodulatory activities, which can induce sustained antiviral responses in part of the treated chronic hepatitis B patients. However, our previous studies have demonstrated that the clinically used subtype (IFNα2) is not the most effective subtype for the anti-HBV treatment among all IFNα subtypes. So far very little is known about the IFNα subtype-specific susceptibility during the course of HBV infection and its related cellular and molecular mechanism. In the current project, by employing human clinical samples, in vitro cellular models as well as in vivo animal models, we want to firstly study the induction of IFNA subtypes in different tissues from HBV-infected patients and we will correlate this with ISG expression pattern in different patient cohorts. We also aim to investigate the antiviral effects of specific human IFNα subtypes on HBV cccDNA, which is a major hurdle in eradicating HBV. Further analysis of the immune response against HBV in the context of IFN-mediated immunotherapies and the role of individual cell subsets will be investigated. The results of the study will provide theoretical and experimental evidences for designing new targeted immunotherapeutic strategies for chronic hepatitis B infection.
Prof. Dr. Daniel Hoffmann and Prof. Dr. Rongge YangImmune escape driven evolution of HIV-1 probed by circulating recombinant forms
Joint funding granted by German Research Foundation (DFG) and National Natural Science Foundation of China (NSFC) in December 2017
One of the most important defense mechanisms against the Human Immunodeficiency Virus 1 (HIV-1) is recognition of viral fragments by the Human Leucocyte Antigen (HLA) and cytotoxic T lymphocytes (CTLs), leading to the elimination of infected cells. Unfortunately, this mechanism selects mutants of HIV-1 that can evade CTL response. One known way to generate such mutants is by viral recombination. In some cases these recombinant forms can spread in the host population and become so-called circulating recombinant forms (CRFs). Remarkably, most of the HIV-1 infections in China today are caused by CRFs, which motivates our first hypothesis: The high prevalence of specific CRFs in China can be explained by their ability to efficiently evade CTL response in a host population with a specific background of HLA alleles.
Our second, related hypothesis (“non-locality” hypothesis) is that HIV-1 in general cannot evade CTL response by local changes of viral genes, despite the recognition of viral fragments by CTL/HLA being local. If the non-locality hypothesis is valid, we have to expect a fundamental impact of viral recombination on the ability of HIV-1 immune escape, which again we will test with CRFs. To test these two hypotheses we will first collect pairs of HLA alleles and HIV-1 genome sequences from publicly available sources and from additional HLA/HIV-1 analyses in China and Germany. Based on these data we will devise a quantitative computational model that allows for the prediction of the effects of specific mutations in CRFs on viral replication and CTL response. These predictions will then be tested experimentally by cellular assays. The project links molecular causes of viral immune escape to the prevalence of viral strains in host populations with specific genomic backgrounds.
This knowledge is also relevant for vaccination strategies involving T cell immunity.
Dr. Kathrin Sutter, Prof. Dr. Zhenghong Yuan, Prof. Dr. Ulf Dittmer, Dr. Jieliang ChenAntiviral activity of different IFNα subtypes during HBV infection in vitro
(more details will follow here)
PD Dr. Ruth Bröring and Dr. Jia LiuFunction and Mechanism Analysis of Liver Sinusoidal Endothelial Cells Regulating CD8+ T Cell Immunity during HBV Infection
(further cooperating SGVIVI members: Dongliang Yang and Mengji Lu)
Liver sinusoidal endothelial cells (LSEC) play a crucial role in maintaining the homeostasis of the hepatic microenvironment through induction of Ag-specific T cell tolerance. It has been shown that virus infection or TLR stimulation can induce the maturation of LSEC, which revert their suppressive properties to induce T cell immunity. However, little is known about whether and how the LSEC regulate T cell immunity during HBV infection. In this project the collaborators investigate the function and mechanism of LSEC regulating CD8+ T cell immunity in HBV infection models.
Prof. Dr. Ulf Dittmer and Prof. Dr. Rongge YangEvaluation of neutralizing susceptibility of HIV-1 CRF01_AE variants by a panel of broadly neutralizing antibodies
Broadly neutralizing antibodies (bnAb) are very potent agents that block primary HIV infection or control HIV replication in infected patients. Several clinical trials are currently under way to test the efficacy of bnAb in HIV therapy. While it has been established that such bnAb neutralize a many HIV isolates from different clades, not much is known about their potential against interlude variants of HIV. HIV-1 CRF01_AE is the most frequent HIV recombinant in China, but ist neutralization susceptibility against bnAb has not been investigated so far. We use HIV-1 CRF01_AE env-pseudovirus based neutralization assays to test bnAb that target the CD4 binding site, the V1V2 loop, the V3 glycan, or the membrane-proximal external region of HIV-1. The results will be very important to design antibody-based therapies against HIV recombinants in China.