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Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection1, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission2 3 4. Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)-rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry5 6. Here we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3α (also known as CCL20), plasmacytoid dendritic cells and CCR5+ cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruits CD4+ T cells to fuel this obligate expansion. We then show that glycerol monolaurate—a widely used antimicrobial compound7with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines8—can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIVin vitro, andin vivoit can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission.