Glycerol monolaurate prevents mucosal SIV transmission

Abstract

Clinical trials of microbicides as a means of preventing the transmission of HIV-1 to women have proved disappointing. Now a study in the simian immunodeficiency virus (SIV)–rhesus macaque vaginal transmission model for HIV infection suggests that a prophylactic approach might yet be worth pursuing. The commonly used antimicrobial compound glycerol monolaurate (GML) was found to suppress SIV infection even after repeated virus exposure. But its mechanism of action was surprising. The host's inflammatory response to the virus, rather than helping, was shown to fuel the infection by recruiting the very CD4+ T cells that the virus targets. GML's prophylactic action appeared to result from its ability to block this host response, rather than from a direct effect on the virus. This points to cell signalling and innate host responses in the mucosal cells as potential targets for drugs and vaccines aimed at preventing infection by HIV — and by other pathogens too if they use similar infection strategies. Glycerol monolaurate in a microbicide is shown to protect monkeys from infection after intra-vaginal exposure to high doses of SIV. The suppressive activity may be due to the inhibition of target cell recruitment due to glycerol-monolaurate-mediated inhibition of epithelial cell signalling and inflammatory cytokine expression. 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 compound7 with 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 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.