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Refining the Mechanisms of Heniparvirus-Mediated Membrane Fusion Through Mutagenesis of Hendra virus Envelope Glycoproteins

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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Hendra virus HeV and Nipah virus NiV are two newly emergent zoonoses within the family Paramyxoviridae that are currently classified as Biological Safety Level 4 BSL-4 agents because of their lethality and the lack of approved therapeutics or vaccines. Paramyxoviruses are enveloped viruses and their entry into cells is via Class I fusion. Although inferences can be made based on what is known about fusion and entry by other prototypical Class I fusion viruses, there remain steps in the process of fusion and entry by paramyxoviruses which are not well understood. For instance, although it is know that the fusion glycoprotein F and the attachment glycoprotein G interact to promote fusion, it is not known how, when, or through what domains they interact. In addition, although the henipavirus cellular receptors have recently been discovered to be ephrinB2 and ephrinB3, it is not known which residues of G bind the receptors or how exactly receptor binding by G triggers F-mediated fusion. Using site-directed mutagenesis of HeV G, we have identified residues in the putative beta-sheets 1 and 4 of the globular head of G that are critical for binding both receptors. In addition, we have investigated the contribution of a series of stalk region isoleucines to the proteins various functional characteristics, and found that mutation of these residues causes G to assume a post-receptor binding conformation in the absence of receptor a subtle conformational alteration which blocks fusion. In addition, through characterization of these mutants, we have been able to draw certain conclusions regarding the mechanism of fusion and entry by henipaviruses. Specifically, our data support a model whereby F and G are preassociated prior to receptor binding, and receptor-induced conformational changes in G serve to trigger F-mediated fusion.

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