Knowledge of the molecular structure of trimeric surface glycoproteins and delineating the mechanisms of transmission are central to the design of effective immunogens and therapeutic agents to combat HIV/AIDS, influenza, Ebola and related enveloped viruses. Most of these enveloped viruses share similar mechanisms for viral entry, and as such, structural studies of these viruses may offer insight towards vaccine design for all three of these viruses. We have continued to make significant progress towards these goals over the last year. In our work on HIV, we continue to refine tomographic methods to determine the 3D structure of envelope glycoprotein spikes in situ on the virus surface at pregoressively higher resolutions. Our most exciting new results are from comparing the differences in structure between viral strains that utilize CXCR4 or CCR5 co-receptors, and are either primary or lab-adapted strains. These results are being prepared for publication. One of the important advances we made last year is progress towards broadly neutralizing antibodies against influenza. A substantial proportion of influenza-related childhood deaths are due to infection with influenza B viruses, which co-circulate in the human population as two antigenically distinct lineages defined by the immunodominant receptor binding protein, haemagglutinin. While broadly cross-reactive, protective monoclonal antibodies against the haemagglutinin of influenza B viruses have been described, none targeting the neuraminidase, the second most abundant viral glycoprotein, have been reported. In a paper published in Nature Microbiology, we analyzed a panel of five murine anti-neuraminidase monoclonal antibodies that demonstrate broad binding, neuraminidase inhibition, in vitro antibody-dependent cell-mediated cytotoxicity and in vivo protection against influenza B viruses belonging to both haemagglutinin lineages and spanning over 70 years of antigenic drift. Electron microscopic analysis of two neuraminidase-antibody complexes shows that the conserved neuraminidase epitopes are located on the head of the molecule and that they are distinct from the enzymatic active site. In the mouse model, one therapeutic dose of antibody 1F2 was more protective than the current standard of treatment, oseltamivir, given twice daily for six days. The Ebola virus is an emerging pathogen that has become a critical target for vaccine and therapeutic development. Ebola displays many copies of a single complex, the envelope glycoprotein, on the surface of mature virions. Our structural studies have involved using the Zmapp antibody cocktail, which is composed of the c2G4, c4G7 and c13C6 antibodies, bound to native, full-length Ebola envelope glycoprotein from the West African 2014 isolate embedded in filamentous viral-like particles. These studies have revealed that each of these antibodies binds to different regions of the Ebola glycoprotein spikes, and are providing new insights into mechanisms of viral entry and inform strategies for blocking this step.
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