The two coordinated program areas (PB) Molecular Mechanisms of Viral Pathogenesis (PB1) and Innovative Antiviral Therapies (PB2) represent the LIV’s research principles and shape its research profile. The program areas highlight the applied aspect of the institute’s basic research in virology in which fundamental mechanisms of viral pathogenesis are to be identified across all virus species. Using the latest technologies and (small animal) infection models, multidisciplinary discoveries are to be converted into therapeutic approaches and tested in preclinical trials.
Overarching Focus Topics
Another building block in the research profile of the LIV are the internal key topics ‘Determinants of the host spectrum’, ‘Immune control of viruses’, ‘Viral latency’ and ‘Structure and dynamics of viral morphogenesis’.
The concept of the overarching topics is to bundle the broad virological expertise of the LIV research teams into common questions and to investigate basic, universally valid mechanisms of virus multiplication, pathogenesis and cellular virus defense across laboratories and virus species.
The overarching topics make targeted use of the broad spectrum of virus systems investigated at the LIV, network the LIV program areas and thus sustainably strengthen the research profile of the LIV. In the medium to long term, the concept is intended to promote both the joint acquisition of third-party funds and the transfer of research results into therapeutic approaches and preclinical studies.
Host Range Determinants
The first overarching topic Host Range Determinants focuses on the joint identification and characterization of determinants of the host spectrum of various human pathogenic viruses (influenza viruses, SARS and MERS coronaviruses, arboviruses, Zika, hepatitis C viruses (HCV) and cytomegaloviruses (CMV)). The aim is to generate a better understanding of cellular restriction mechanisms and viral antagonists during acute and chronic infections in permissive and non-permissive host cells. The different stages of the infection cycle from receptor recognition to virus release as well as the triggered immune response will be investigated. The use of different viruses allows identifying common and differential mechanisms that define the viral host spectrum. Furthermore, we investigate which countermeasures viruses of different species have developed during evolution to break through intracellular host barriers and thus adapt to new hosts. Using the expertise and infrastructure available at LIV, the basic mechanisms and factors with respect to their influence on the pathogenesis in infection models are investigated in detail in the technology platform Small Animal Models.
Immune Control of Viruses
The aim of the second overarching topic, Immune Control of Viruses, is the development of immunotherapeutic approaches that enhance or newly induce antiviral immune responses. The joint research activities in the overarching topic focus on investigations of cellular factors of intrinsic, innate and adaptive immunity, using various in vitro model systems, including newly established organoid systems, as well as the humanized mouse models developed at the LIV.
In addition, samples from patient cohorts are used to study virus-specific and vaccine-induced immune responses. Translational studies investigate various acute and persistent viral infections (human adenovirus (HAdV), CMV, human immunodeficiency virus-1 (HIV-1), BKV (BKV), influenza virus, HBV and SARS-CoV-2), with the aim of validating the relevance of the findings from in vitro and animal experiments in clinical studies and, in the long term, creating the conditions for testing antiviral therapy concepts in pre-clinical and clinical studies at the site.
Viral Latency & Persistence
The third overarching topic, Viral Latency and Persistence, is devoted to research on latent or chronically persistent viruses (e.g. HIV-1, Herpes Simplex Viruses (HSV), Kaposi's Sarcoma Associated Herpes Virus (KSHV), Epstein-Barr Virus (EBV), CMV, Merkel Cell Polyoma Virus (MCPyV), BKV, or HAdV). The formation of viral persistence or latency reservoirs represents a particular challenge in the fight against these infections. The aim is to identify the molecular factors and mechanisms that are responsible for the establishment and control of latent or chronic infections with the help of suitable model systems, to investigate pathogenicity mechanisms of such infections and to develop new methods for eradicating viral reservoirs. In addition to virus-specific factors, the focus of this research area is on mechanisms of viral latency and persistence, e.g. with regard to the epigenetic regulation of viral and cellular chromatin. With these topics, the focus ties in with the research program of the overarching topic Immune Control of Viruses, both with respect to mechanisms of immune evasion during long-term persistence and with respect to virally induced pathogenesis in the immunodeficient host.
Structure and Dynamics of viral Morphogenesis
The fourth overarching topic Structure and Dynamics of viral Morphogenesis deals with the structural changes in the assembly and disassembly of viral particles over time (morphogenesis). The focus is on quantitative approaches and the integration of data over a wide range of spatial and temporal resolution. Using different virus models (e.g. HAdV, HCV, as well as various corona, herpes, noro- and retroviruses), specifics of host interaction will be characterized and cross-species principles derived. Furthermore, the expertise and infrastructure available at the LIV in the field of a broad spectrum of microscopic and mass spectrometric methods will be used and further developed, for example in the field of correlative imaging or the use of novel radiation sources (European XFEL). Dynamic membrane modulations, specific lipid environments of membrane proteins or the influence of glycosylation patterns are further development areas of this overarching topic. A particular strength lies in the combination and integration of complementary data from different techniques, such as electron microscopy and mass spectrometry or molecular modeling, which allow a deeper understanding of the interrelationships.