A cocktail of two broadly-neutralizing HIV-1 antibodies (bNAbs) protected primates against infection with a mixed population of HIV viruses - conditions that mimic real-world transmission - researchers report. The findings suggest that combination therapies might be essential to prevent HIV in people. People become exposed to a so-called "swarm" of variable viruses during real-world transmission events, because HIV has a high mutation rate, but most laboratory studies demonstrating protection by bNAbs only used isolated strains of the pathogen. Here, Boris Julg and colleagues administered two different bNAbs to rhesus macaques before infecting them with a mixture of two strains of simian-human immunodeficiency virus (SHIV). Animals receiving either of the two bNAbs individually all became infected, yet passively immunizing the primates with both antibodies together conferred 100% protection. The bNAbs each recognized different regions on the HIV outer envelope protein, and the scientists observed pronounced variability in the targets for both antibodies in the viruses that evolved resistance in the primates, as well as from sequences of viruses that had been isolated from human patients. The authors say their study highlights that viral diversity can compromise protection by bNAbs, emphasizing a need for regimens that protect against several targets. A related paper in Science by Xu et al. describes the construction of single antibodies that recognize multiple regions on the HIV outer envelope protein, engaging three targets simultaneously as a potential strategy to overcome innate HIV diversity.