The cryoEM structure of a simian immunodeficiency virus protein bound to primate proteins shows how a mutation in early humans allowed our ancestors to escape infection while monkeys and apes did not. SIV’s Nef protein forms a solid link between two primate proteins, tetherin and AP-2, forcing the destruction of tetherin, which normally prevents new SIV virions from budding off. A mutation in human tetherin disrupted binding, thwarting SIV budding — until HIV evolved a work-around.