Zehner, Matthias - B 11

Human Cytomegalovirus (HCMV) poses significant health risks for immune-compromised individuals and fetuses. Despite advances, it remains a leading infectious complication e.g., after transplantations, with associated morbidity and mortality. Harnessing antibodies presents a promising avenue against infectious diseases, yet understanding the role of humoral immunity in HCMV is strongly limited, including associated HCMV escape mechanisms. HCMV-RISE aims to dissect HCMV antibody escape dynamics by analyzing polyclonal IgGs and monoclonal antibodies (mAb) from HCMV patients. Native HCMV isolates from reactivation will be tested for their infectivity in presence of patient-de rived antibodies. Furthermore, the development of resistance under mAb pressure will be studied through long-term viral passaging and genomic analysis. Both genetic mutations and non-genetic escape mechanisms - such as in corporation of antibodies into virions, altered glycoprotein expression, and viral protease activity - will be systematically explored. Binding studies will help define how mutations impact antibody-virus interaction and viral tropism. To counteract escape, the project will evaluate synergistic antibody combinations, identify resistant epitopes, and assess cross-neutralization profiles. This work will provide mechanistic insights and translational strategies for improving HCMV-targeted therapies, with potential application to other viral infections. By bridging mechanistic understanding with therapeutic approaches, HCMV-RISE aims to close critical gaps in current antiviral strategies.

• Profile paired virus and IgG from defined patient cohorts to quantify autologous vs. heterologous neutralization and identify patterns of humoral control.
• Select and characterize HCMV escape phenotypes under defined monoclonal and polyclonal antibody pressure, using sequencing as a mechanistic readout to map resistance-associated viral changes.
• Integrate functional neutralization with multiplex antibody-binding and orthogonal assays to distinguish genetic vs. non-genetic mechanisms of antibody escape (including altered antigen accessibility, virion composition and Fc-dependent effects).
• Evaluate antibody combinations across strains and relevant cell types to increase potency and raise barriers to escape, as well as derive conserved targets and general resistance-aware principles for antibody-based interventions.

For more information, please visit the following page: Zehner Lab.

• Institute of Virology, Laboratory for Infection and Immune Biology, University Hospital Cologne
• Institute of Virology in Pediatrics; Weill Cornell Medical College (New York, US)
• Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne
• German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
• TTU Infections of the Immunocompromised Host, German Center for Infection Research (DZIF)