1. Glycerol monolaurate prevents mucosal SIV transmission.
- Author
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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, and Haase AT
- Subjects
- Acute Disease, Animals, Body Fluids metabolism, Body Fluids virology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, Cell Cycle Proteins metabolism, Cervix Uteri drug effects, Cervix Uteri immunology, Cervix Uteri virology, Chemokine CCL20 immunology, Chemokine CCL20 metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Female, GPI-Linked Proteins, Gene Expression Profiling, HIV-1 physiology, Interleukin-8 metabolism, Membrane Proteins metabolism, Mucous Membrane immunology, RNA, Viral blood, Receptors, CCR5 immunology, Receptors, CCR5 metabolism, Simian Acquired Immunodeficiency Syndrome genetics, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus drug effects, Simian Immunodeficiency Virus genetics, Simian Immunodeficiency Virus growth & development, Simian Immunodeficiency Virus physiology, Time Factors, Vagina drug effects, Vagina virology, Laurates pharmacology, Macaca mulatta virology, Monoglycerides pharmacology, Mucous Membrane drug effects, Mucous Membrane virology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Acquired Immunodeficiency Syndrome transmission
- Abstract
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 we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3alpha (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 compound with inhibitory activity against the production of MIP-3alpha 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.
- Published
- 2009
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