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.

免疫逃逸驱动HIV-1重组进化的分子机制研究

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.