Elucidating the molecular determinants of Henipavirus envelope-antibody and envelope-receptor interactions on viral entry

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PROJECT SUMMARY: The identification of new Henipaviruses (HNVs) in Africa, China and Australia lend way to concerns about the risk of possible spillover events. Yet, there are no FDA approved therapeutics and the role of receptor usage on pathogenicity is still undetermined. Within this proposal, we aim to leverage our extensive preliminary results to further our understanding of the molecular determinants of envelope-antibody and envelope-receptor interactions on viral neutralization and viral pathogenicity. In recent work, we have identified an immune- accessible region on the NiV and HeV fusion glycoprotein that is targeted by several antibodies. Experiments proposed in Aim 1 will elucidate a mechanism for how these antibodies neutralize HNVs and will characterize novel antibodies against the divergent GhV fusion glycoprotein by utilizing a rapid, directed-evolution platform to identify escape mutants. Additionally, we have performed structure-guided mutagenesis to better understand HNV receptor binding protein and receptor interactions. The experiments directly proposed in Aim 2 will further characterize these mutants and assess the ability to confer use of this receptor to other HNVs using viruses. The work proposed here will ultimately support the development of HNV therapeutics and the understanding of the contributions of receptor usage on HNV pathogenicity.