Poster Presentation 12th Australasian Virology Society Meeting 2024

Mechanism of viral neutralisation of herpes simplex virus glycoprotein by monoclonal antibody 2c (#208)

Naphak Modhiran 1 , Yu Shang Low 1 , Benjamin Liang 1 , Alberto Amarilla Ortiz 1 , Eduardo Albornoz Balmaceda 2 , Julio Aguado 3 , Stacey Cheung 1 , Christine Langer 4 , Jiadai Wu 5 , Tony Cunningham 6 , Andy Poumbourios 4 , Daniel Watterson 1
  1. The School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane St Lucia, QLD, Australia
  2. School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
  3. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia.
  4. Burnet Institute, Melbourne , Victoria, Australia
  5. School of Chemical and Biomolecular Engineering, the university of Sydney, Sydney, Australia
  6. Center for Virus Research, The Westmead Institute for Medical Research, New South Wales, Australia

Herpes simplex virus (HSV) is highly infectious and has widespread prevalence within the population. Herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2) are prototypical alphaherpesviruses that are characterized by their unique properties to infect trigeminal and dorsal root ganglionic neurons, respectively. Due to its ability to establish lifelong latency in hosts, and recur periodically, HSV can easily spread throughout the population, posing a worldwide health problem. These symptoms are especially severe in immunocompromised patients. Current treatment options for HSV infections include chemotherapeutics that target HSV thymidine kinase such as acyclovir (ACV). However, decades of use of these drugs have brought about viral resistance, with a high prevalance of ACV resistant HSV in immunocompromised patients. Infection of HSV requires the fusion of the viral envelope with the host lipid membrane by entry through extracellular virions or cell-cell spread. Notably, the glycoprotein B (gB) serves as the viral fusion protein, collaborating with gD and gH/gL heterodimer to mediate host-virus membrane fusion, making it a suitable target for vaccine and antiviral development. Currently, no approved vaccines and antibody therapies are available. However, there are various promising candidates in the pre-clinical and clinical phases of study. This includes murine-derived neutralizing monoclonal antibody targeting gB protein, known as mAb 2c, demonstrating protection of mice from lethal HSV-1 and HSV-2. However, the structural basis of how mAb 2c interacts with the gB protein remains elusive. Here, we determined the cryo-EM structure of gB in its postfusion form with bound mAb 2c at 3.1 Å resolution. We further demonstrated that mAb 2c also inhibits HSV-mediated IL-1β released from human-monocyte-derived microglia and neuronal cell death in brain organoids. Our work provided detailed epitope mapping of HSV gB and 2c, offering insights into the function of gB during HSV infection and contributing to herpesvirus vaccine and antiviral research.