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he only confirmed mechanism for protein-mediated membrane fusion involves the formation of helix bundles, in which helices attached to two membranes pack against one another to draw together the membranes. In the final fused state, six-helix bundles are formed by HIV Env and paramyxovirus F proteins, members of the class I group of viral fusion proteins. Although the class I founding member, influenza HA, also forms a six-helix bundle, Heather Park, Jennifer Gruenke, and Judith White (University of Virginia, Charlottesville, VA) now show that this bundle is not sufficient for fusion. For HA, interactions between a nonhelical region and a trimer of helices cause fusion. Using mutational analyses, the group shows that fusion requires contacts between a long chain, which they call the leash, near the viral membrane with the helices near the target membrane (usually a host endosome as the virus escapes into the cytoplasm). They suggest that packing T