Mechanisms of viral fusion The flu is an infectious disease caused by influenza viruses (IVs). Viral particles fusion with the host cell membrane is a critical step for entry and infection. Health © Sebastian Kaulitzki, Thinkstock Glycoprotein haemagglutinin (HA) on the membrane (envelope) of the virus binds sugars on the surfaces of epithelial cells in the nose, throat, lungs and intestines of mammals and birds. HA regulates fusion by interacting with membrane lipids, but the nature of this interaction is not well understood. Developing a drug that inhibits viral entry is an important goal. The EU-funded INFLUENZA FUSION (Understanding the effects of influenza hemagglutinin mutations on viral membrane fusion) was a three-year proposal that aimed to identify targets by developing mechanistic models of how the IV enters the cell. The first project goal was the development of a structural model to represent the role of influenza HA in viral fusion. The researchers tested hypothesis implicating lipid tail protrusion in the cell membrane as a very important feature of the fusion event. Lipid tail protrusion is a rare event when the tails of the lipid molecules point out away from the interior of the lipid bilayer. Comparison of the wild type and mutant influenza showed correlation in the ability of the viruses to cause membrane fusion in vivo and induce lipid tail protrusion. The work was expanded to include studies of the fusion mechanisms of dengue virus and tick-borne encephalitis enveloped viruses similar to influenza. These viruses have very distinct requirements on membrane lipid composition for achieving fusion. This study included simulation of the insertion of fusion peptides into the lipid bilayer and subsequent membrane association. As hypothesised, dengue fusion peptides showed increased insertions into bilayers consisting of a specific mixture of lipids. INFLUENZA FUSION has the potential to aid in prediction of fusion protein structures and dynamics. Using this combined approach, researchers hope to shed light on IVs fusion mechanisms and elucidate future antiviral drug targets. Keywords Viral fusion, influenza virus, haemagglutinin, INFLUENZA FUSION, dengue virus
