Antibody-mediated targeting of HCMV infection

• Applicant: Dr. Matthias Zehner
• Subject Area: Virology ; Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 541796042

The human cytomegalovirus (HCMV) poses a significant public health issue, causing severe diseases in immunocompromised individuals and congenital infections, often leading to perma-nent disabilities. Despite its vast implications, our therapeutic arsenal is limited, often associated with profound side effects, rendering them unsuitable for high-risk groups, such as pregnant women. Additionally, no approved vaccine is currently available. Monoclonal antibodies (mAbs) emerge as a promising avenue for the treatment and prevention of infectious diseases. However, HCMV boasts an intricately complex surface, comprising diverse protein complexes. Each potentially holds a distinct role in the infection. Deepening our understanding of HCMV infection and the associated antibody response is paramount to har-ness the therapeutic potential of mAbs against HCMV. This endeavor is still nascent, highlighting the pressing scientific and medical need to decipher the HCMV infection biology and uncover novel countermeasures. The HCMV-ABTARGETING proposal's primary aim is to systematically decipher the HCMV infection biology. I have recently demonstrated that refined B cell analysis protocols can offer a detailed look into the antibody response against HCMV, unveiling sensitive antibody-target sites. Building on this, HC ii.) MV-ABTARGETING will spotlight two surface components: i.) the pre-fusion state of gB, a central component of HCMV infection, and gH/UL116, an HCMV surface complex with an undefined role. High-throughput single cell isolation techniques, as well as enhancing B cell analysis methods and fine-tuning mAb production protocols will enable me to gain extensive insights into the related mAb response. Leveraging this newfound knowledge, I will closely examine the HCMV cell-to-cell transmission, a key infection mechanism in vivo. By creating small mAb constructs targeting gB and gH, we aim to augment their penetration into the intercellular space, the site of cell-to-cell spread and block this pathway of HCMV. Concurrently, employing the new identified antibodies, the presumed yet obscure gH-gB interaction essential for membrane fusion will be analyzed. Finally, I will use the newly identified mAbs to dissect the surface complex gH/UL116, exploring its therapeutic potential. Cutting-edge techniques will be applied such as generating HCMV strains that specifically hinder gH/UL116 surface expression without impacting other HCMV facets. In addition, I will deploy intracellular UL116-specific mAbs to disrupt the HCMV assembly mechanism. Moreover, multiple antibody effector functions beside neutralization and their role in the defense against HCMV will be addressed. With this comprehensive approach, the HCMV-ABTARGETING proposal will substantially enhance our understanding of HCMV infection biology, laying the groundwork for novel substantial prevention and therapeutic approaches.

• DFG Programme: Research Grants