HIV-1 gp120 induces TLR2- and TLR4-mediated innate immune activation in human female genital epithelium

J Immunol. 2013 Oct 15;191(8):4246-58. doi: 10.4049/jimmunol.1301482. Epub 2013 Sep 16.


Although women constitute half of all HIV-1-infected people worldwide (UNAIDS World AIDS Day Report, 2011), the earliest events in the female reproductive tract (FRT) during heterosexual HIV-1 transmission are poorly understood. Recently, we demonstrated that HIV-1 could directly impair the mucosal epithelial barrier in the FRT. This suggested that the HIV-1 envelope glycoprotein gp120 was being recognized by a membrane receptor on genital epithelial cells, leading to innate immune activation. In this study, we report that pattern-recognition receptors TLR2 and -4 bind to HIV-1 gp120 and trigger proinflammatory cytokine production via activation of NF-κB. The gp120-TLR interaction also required the presence of heparan sulfate (HS). Bead-binding assays showed that gp120 can bind to HS, TLR2, and TLR4, and studies in transfected HEK293 cells demonstrated that HS and TLR2 and -4 were necessary to mediate downstream signaling. Exposure to seminal plasma from HIV-1-infected and uninfected men with gp120 added to it induced a significant proinflammatory cytokine response from genital epithelial cells and disruption of tight junctions, indicating a role for gp120 in mucosal barrier disruption during HIV-1 heterosexual transmission. These studies provide, for the first time to our knowledge, a possible mechanism by which HIV-1 gp120 could directly initiate innate immune activation in the FRT during heterosexual transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Line
  • Cytokines / biosynthesis
  • Enzyme Activation
  • Epithelium / immunology
  • Epithelium / virology
  • Female
  • Genitalia, Female / immunology*
  • Genitalia, Female / virology
  • HEK293 Cells
  • HIV Envelope Protein gp120 / immunology*
  • HIV Envelope Protein gp120 / metabolism*
  • HIV Infections / immunology*
  • HIV Infections / transmission
  • HIV-1* / immunology
  • HIV-1* / metabolism
  • Heparitin Sulfate
  • Humans
  • Immunity, Innate
  • Male
  • Middle Aged
  • Mucous Membrane / immunology
  • Mucous Membrane / virology
  • NF-kappa B / metabolism
  • Protein Binding
  • Semen / metabolism
  • Semen / virology
  • Signal Transduction / immunology
  • Tight Junctions / metabolism
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism*


  • Cytokines
  • HIV Envelope Protein gp120
  • NF-kappa B
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • gp120 protein, Human immunodeficiency virus 1
  • Heparitin Sulfate