Qingsheng Li 1 , Jacob D. Estes 2 , Patrick M. Schlievert 1 , Lijie Duan 1 , Amanda J. Brosnahan 1 , Peter J. Southern 1 , Cavan S. Reilly 3 , Marnie L. Peterson 4 , Nancy Schultz-Darken 5 , Kevin G. Brunner 5 , Karla R. Nephew 5 , Stefan Pambuccian 6 , Jeffrey D. Lifson 2 , John V. Carlis 7 , Ashley T. Haase 1
4 March 2009
While there has been great progress in treating HIV-1 infection 1, 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– 4. Nonetheless, studies of vaginal transmission in the SIV-rhesus macaque model point to opportunities in the earliest stages of infection where 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-3α, 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, recruit CD4+T cells to fuel this obligate expansion. We then show that glycerol monolaurate, a widely used antimicrobial compound 7 with inhibitory activity against production of MIP-3α and other proinflammatory cytokines 8, can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This novel 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 development of effective interventions to block HIV-1 mucosal transmission.