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Many enveloped animal viruses, including emerging human pathogens Ebola, Nipah, andHendra viruses, produce a mixture of virus-particle sizes including very long, filamentous members 1-4 . However, the function of the filamentous particles is unknown. The main impediments to characterizing viral filaments are their phenotypic origin (a single infecting particle gives rise to a range of particle sizes) 5,6 , difficulty of purifying particles to homogeneity according to their size, and the apparent lack of filament advantage in vitro 7,8 . Influenza virus particles range in length by three orders of magnitude (~55 nm to ~30 µm). All influenza particles package at most a single genome, but the total number of the surfaceexposed viral glycoproteins, hemagglutinin (HA) and neuraminidase (NA), and the HA/NA ratio scale with particle length 6,9,10 . HA is the cell-entry protein of influenza, which mediates fusion between the viral and the endosomal membranes by the combined action of 3-5 active HA neighbors (fusion cluster) 11-13 . Here we identify influenza filaments as viral persisters increasing the probability of fusion-cluster formation and cell entry under HA-directed selective pressure. We fractionated viruses to enrich for spherical or filamentous particles and measured the single-particle kinetics of membrane fusion. As a surrogate for HAdirected selective pressure, we used a Fab fragment of a broadly neutralizing antibody that inactivates bound HA 14 . In its presence, filamentous particles fuse more rapidly and more efficiently than do spherical ones. We show that the infectious advantage of filaments derives from their enhanced fusion efficiency rather than from rate effects. Filaments also offer universal protection from extreme HA inactivation. Our results show how the virus can adapt to any condition limiting HA function, and suggest targeting viral filaments as a strategy to prolong vaccine effectiveness or to thwart viral pandemic adaptation.

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Hsp70-family chaperones bind short monomeric peptides with a weak characteristic affinity in the low micromolar range, but can also bind some aggregates, fibrils, and amyloids, with low nanomolar affinity. While this differential affinity enables Hsp70 to preferentially target potentially toxic aggregates, it is unknown how Hsp70s differentiate between monomeric and oligomeric states of a target protein. Here we examine the interaction of BiP (the Hsp70 paralog in the endoplasmic reticulum) with proIGF2, the pro-protein form of IGF2 that includes a long and mostly disordered E-peptide region that promotes proIGF2 oligomerization. We discover that electrostatic attraction enables the negatively charged BiP to bind positively charged E-peptide oligomers with low nanomolar affinity. We identify the specific BiP binding sites on proIGF2, and although some are positively charged, as monomers they bind BiP with characteristically low affinity in the micromolar range. We conclude that electrostatics enable BiP to preferentially recognize oligomeric states of proIGF2. Electrostatic targeting of Hsp70 to aggregates may be broadly applicable, as all the currently-documented cases in which Hsp70 binds aggregates with high-affinity involve clients that are expected to be positively charged.