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Glycerol monolaurate prevents mucosal SIV transmission

Abstract

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.

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Figure 1: Mapping early expansion of infection in endocervix.
Figure 2: Influx and infection of CD4 + T cells in cervix in early infection.
Figure 3: pDCs, cytokines and chemokines associated with endocervical epithelium after exposure to SIV.
Figure 4: GML inhibits HIV-1 induced expression of MIP-3α and IL-8 in HVECs and in cervical and vaginal fluids.
Figure 5: GML prevents mucosal transmission and acute infection.

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Acknowledgements

We thank C. Miller and D. Lu at the California National Primate Research Center, for helpful discussion and virus stocks, J. Kemnitz at the Wisconsin National Primate Research Center, for discussion and administrative support, and C. O’Neill and T. Leonard for help with the manuscript and figures. This work was supported in part by National Institute of Health (NIH) grants R21 AI071976 and P01 AI066314 (A.T.H.), funds from the National Cancer Institute, NIH, under contracts N01-CO-12400 and HHSN266200400088C (J.D.L.), and grant number P51 RR000167 from the National Center for Research Resources, a component of the NIH, to the Wisconsin National Primate Research Center. This research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grant numbers RR15459-01 and RR020141-01. This publication’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or NIH.

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Correspondence to Ashley T. Haase.

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Li, Q., Estes, J., Schlievert, P. et al. Glycerol monolaurate prevents mucosal SIV transmission. Nature 458, 1034–1038 (2009). https://doi.org/10.1038/nature07831

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