1. Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA
2. AIDS and Cancer Virus Program, Science Applications International Corporation–Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702, USA
3. Division of Biostatistics, School of Public Health, University of Minnesota, MMC 303, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA
4. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 2001 Sixth Street S.E., Minneapolis, Minnesota 55455, USA
5. Wisconsin National Primate Research Center, University of Wisconsin, 1220 Capitol Court, Madison, Wisconsin 53715, USA
6. Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, MMC 76, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA
7. Department of Computer Science and Engineering, Institute of Technology, University of Minnesota, 200 Union Street S.E., Minneapolis, Minnesota 55455, USA

Correspondence to: Ashley T. Haase¹ Correspondence and requests for materials should be addressed to A.T.H. (Email: haase001@umn.edu).

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 transmission^{2, 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 entry^{5, 6}. Here we show in this SIV–macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3 (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 compound⁷ with inhibitory activity against the production of MIP-3 and other proinflammatory cytokines⁸—can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it 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.

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