HIV This Week

Li Q, Estes JD, Schlievert PM, Duan L, Brosnahan AJ, Southern PJ, Reilly CS, Peterson ML, Schultz-Darken N, Brunner KG, Nephew KR, Pambuccian S, Lifson JD, Carlis JV & Haase AT. Glycerol monolaurate prevents mucosal SIV transmission. Nature 2009 [Epub ahead of print] doi:10.1038/nature07831

Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection, 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. 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. Here Li and colleagues 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 1 T cells to fuel this obligate expansion . They then show that glycerol monolaurate—a widely used antimicrobial compound with inhibitory activity against the production of MIP-3a and other proinflammatory cytokines— 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.

Editors’ note: This study reveals that the endocervix, the inner surface of the cervix linking the vagina with the uterus or womb, is the predominant site for initial infected cell clusters. There are not enough target cells there for SIV infection to take hold but the inflammatory response of the innate mucosal immune system calls more target cells to this site, expanding the infected founder cell population which then allows establishment of self-propagating infection in lymph tissues. In this encouraging report, inexpensive and safe glycerol monolaurate brakes this vicious cycle of signalling and inflammatory response to prevent acute SIV infection in several repeatedly exposed animals. Longer-term and well-powered studies with larger numbers of animals are clearly warranted.