Membrane perturbation and fusion pore formation in influenza hemagglutinin-mediated membrane fusion - A new model for fusion

Low pH-induced fusion mediated by the hemagglutinin (HA) of influenza virus involves conformational changes in the protein that lead to the insertion of a "fusion peptide" domain of this protein into the target membrane and i s thought to perturb the membrane, triggering fusion, By using whole virus, purified HA, or HA ectodomains, we found that shortly after insertion, por es of less than 26 Angstrom in diameter were formed in liposomal membranes. As measured by a novel assay, these pores stay open, or continue to close and open, for minutes to hours and persist after pH neutralization. With vi rus and purified HA, larger pores, allowing the leakage of dextrans, were s een at times web after insertion. For virus, dextran leakage was simultaneo us with lipid mixing and the formation of "fusion pores," allowing the tran sfer of dextrans from the liposomal to the viral interior or vice versa, Po res did not form in the viral membrane in the absence of a target membrane. Based on these data, we propose a new model for fusion, in which HA initia lly forms a proteinaceous pore in the target, but not in the viral membrane , before a lipidic hemifusion intermediate is formed.