Arrested infektion: sonderings steg i viralt inträde med artificiella membran
Tidsperiod: 2018-01-01 till 2021-12-31
Projektledare: Peter Kasson
Medarbetare: Steven Boxer, Mark Yeager
Budget: 2 856 000 SEK
Enveloped viruses such as influenza, HIV, and Zika enter cells via a process of membrane fusion between the viral envelope and a cellular membrane, mediated by viral fusion proteins. The non-protein components necessary for fusion are an attractive, if difficult, target for antiviral drug development because they cannot mutate as readily as the viral proteins and are indeed host-derived rather than virus-encoded. However, probing the detailed mechanism of viral fusion to target these components has been challenging because fusion protein conformational rearrangements to activate fusion are rate-limiting under normal circumstances, and the membrane interactions we wish to understand and disrupt occur relatively quickly. We will dissect these hidden steps and identify factors for future inhibition using a combination of single-virus fluorescence microscopy, high-resolution cryo-EM, and molecular dynamics simulation. To access intermediates that are normally short-lived, we will use membrane-coated nanoparticles that can bind virus in a manner similar to cell membranes but should not permit fusion. We primarily study influenza virus but will also perform experiments on flaviviruses, since both are highly dependent on lipid factors but have different requirements for cell entry. Success in this project will yield a better mechanistic understanding of enveloped viral entry mechanisms and a set of new host-lipid targets that could be manipulated by future antiviral therapies.