Future possible extensions of this work include relaxing the assumption that all cities were equally susceptible at the start of the autumn wave of the pandemic. The variation in the onset of infection in cities may, in part, be due to the differing susceptibility of each city owing to differing attack rates experienced in the spring -summer wave, or population-level immunity from the 1890 pandemic or seasonal strains. However, the low case fatality of the first wave and age-specificity of infection between waves need to be understood before spatial heterogeneity in susceptibility can be discerned. There are varying reports on the magnitude and mechanism of the effect of infection during the first wave on attack rates in subsequent waves [24] [25] [26] [45] [46] [47] . Further analysis of the datasets considered here may provide an opportunity to disentangle these effects.  Charge-Surrounded Pockets and Electrostatic Interactions with Small Ions Modulate the Activity of Retroviral Fusion Proteins Refolding of viral class-1 membrane fusion proteins from a native state to a trimer-of-hairpins structure promotes entry of viruses into cells. Here we present the structure of the bovine leukaemia virus transmembrane glycoprotein (TM) and identify a group of asparagine residues at the membrane-distal end of the trimer-of-hairpins that is strikingly conserved among divergent viruses. These asparagines are not essential for surface display of pre-fusogenic envelope. Instead, substitution of these residues dramatically disrupts membrane fusion. Our data indicate that, through electrostatic interactions with a chloride ion, the asparagine residues promote assembly and profoundly stabilize the fusion-active structures that are required for viral envelope-mediated membrane fusion. Moreover, the BLV TM structure also reveals a charge-surrounded hydrophobic pocket on the central coiled coil and interactions with basic residues that cluster around this pocket are critical to membrane fusion and form a target for peptide inhibitors of envelope function. Charge-surrounded pockets and electrostatic interactions with small ions are common among class-1 fusion proteins, suggesting that small molecules that specifically target such motifs should prevent assembly of the trimer-of-hairpins and be of value as therapeutic inhibitors of viral entry. Bovine Leukemia Virus (BLV) and Human T-Cell Leukemia Virus Type-1 (HTLV-1) are related deltaretroviruses that cause aggressive lymphoproliferative disorders in a small percentage of infected hosts [1, 2, 3, 4, 5, 6] . Like other enveloped viruses, retroviruses must catalyse fusion of the viral and target cell membranes to promote entry of the viral capsid into the target cell. The retroviral class I fusion protein consists of the transmembrane glycoprotein (TM) component of the envelope glycoprotein complex [7] . Envelope is displayed on the surface of the virus or infected cell as a trimer, with three surface glycoprotein (SU) subunits linked by disulphide bonds to a spike of three TM subunits [8] . Experimentally validated models suggest that SU-mediated receptor engagement induces isomerisation of the inter-subunit disulphide bonds and initiates a cascade of conformational changes that activate the fusogenic properties of TM [9, 10] . Membrane fusion is achieved by re-folding of the TM from a native non-fusogenic structure through a rod-like pre-hairpin intermediate, in which the C-and N-terminal segments are embedded in the viral and target cell membranes respectively [7, 8] . The pre-hairpin intermediate then resolves to a trimer-of-hairpins structure, which pulls the membranes together and facilitates lipid mixing and membrane fusion [7, 8, 11, 12] . For several viruses membrane fusion is sensitive to inhibition by peptides that mimic a C-terminal region of the trimer-of-hairpins [13, 14, 15, 16, 17, 18, 19] . The C-terminal fragment of the HTLV-1 trimer-of-hairpins exhibits a short a-helical motif embedded in an extended non-helical peptide structure referred to as the leash and a-helical region (LHR) [20, 21] . The LHR-based mimetics are structurally distinct from the prototypic extensively a-helical peptide inhibitors of human immunodeficiency virus but are reminiscent of the leash regions observed in influenza haemagglutinin [20, 21, 22, 23] .