The broad species tropisms and the ability to cause fatal disease in both animals and humans have distinguished the Henipaviruses', Hendra virus (HeV) and Nipah virus (NiV) from all other known paramyxoviruses. These viruses can be amplified and cause disease in animals and be transmitted to humans where infection is manifested as a severe respiratory illness and/or febrile encephalitis. They are now classified as biological safety level-4 (BSL-4) agents, and they possess several characteristics which make them highly adaptable for their use as bioterror agents as well. HeV appeared first in eastern Australia in 1994 and was transmitted to humans from infected horses; NiV first appeared in 1998-99 in peninsular Malaysia and was predominantly passed from infected pigs to humans, but several other animal species also became infected. Recently, both NiV and HeV continue to make their presence known, and in early 2004 two NiV outbreaks in Bangladesh have occurred totaling some 53 human cases of infection and another outbreak in 2005 in the same area claimed 12 more lives. HeV has reappeared in Australia in late 2004, with two cases of fatal infection in horses and one non-fatal human case. Significant observations in the recent NiV outbreaks have been made, including a higher incidence of acute respiratory distress syndrome, person-to-person transmission, higher case fatality rates (~70%), and no direct link to infected animals. Understanding their cell biology, how they mediate host cell infection and cross species transmission is now important and will aid our understanding of their pathogenic mechanisms and in the development of therapeutics, intervention, and vaccine strategies. Over the past five years my laboratory has studied the biochemical and functional properties of the viral glycoproteins and their fusogenic cellular tropisms, the budding of virus-like-particles, and most recently identified a receptor employed by both HeV and NiV (ephrin-B2). We have also produced candidate subunit vaccines as well as fusion inhibitors and human monoclonal antibody therapeutics. Using the data and systems we have developed, our objectives in the present proposal are to dissect apart certain details of the viral-mediated membrane fusion process and the assembly and budding steps of virus particles. Specifically, we will: i) Characterize virus particle assembly and identify the Henipavirus late domain element(s) in matrix, ii) Identify and define the domains involved in the interaction between the viral F and G glycoproteins; and iii) Characterize and define the interaction between ephrin-B2 and G; mapping their binding sites and exploring the consequences of receptor binding on the F and G interaction. ? ? ? ?
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