Glycerol Monolaurate Prevents Mucosal SIV Transmission

Nature. 2009 Apr 23;458(7241):1034-8. doi: 10.1038/nature07831. Epub 2009 Mar 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • Laurates / pharmacology*
  • Macaca mulatta / virology*
  • Membrane Proteins / metabolism
  • Monoglycerides / pharmacology*
  • Mucous Membrane / drug effects*
  • Mucous Membrane / immunology
  • Mucous Membrane / virology*
  • RNA, Viral / blood
  • Receptors, CCR5 / immunology
  • Receptors, CCR5 / metabolism
  • Simian Acquired Immunodeficiency Syndrome / genetics
  • Simian Acquired Immunodeficiency Syndrome / prevention & control*
  • Simian Acquired Immunodeficiency Syndrome / transmission*
  • 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

Substances

  • CCL20 protein, human
  • Cell Cycle Proteins
  • Chemokine CCL20
  • GML protein, human
  • GPI-Linked Proteins
  • Interleukin-8
  • Laurates
  • Membrane Proteins
  • Monoglycerides
  • RNA, Viral
  • Receptors, CCR5
  • monolaurin