title: Soluble toll-like receptor 2 is significantly elevated in HIV-1 infected breast milk and inhibits HIV-1 induced cellular activation, inflammation and infection.
abstract: OBJECTIVE
  We previously demonstrated that immunodepletion of soluble Toll-like receptor 2 (sTLR2) from human breast milk significantly increased HIV infection in vitro. The aims of this study were to characterize sTLR2 levels in breast milk from HIV-infected and uninfected women, and identify a mechanism by which sTLR2 inhibits HIV-induced cellular activation and infection.
  
  
  METHODS
  Blinded studies of breast milk from HIV-infected and uninfected Nigerian and Canadian women were evaluated for levels of sTLR2, proinflammatory cytokines and viral antigenemia. In-vitro experiments were conducted using cell lines to assess sTLR2 function in innate responses and effect on HIV infection.
  
  
  RESULTS
  Breast milk from HIV-infected women showed significantly higher levels of sTLR2 than uninfected breast milk. Further, sTLR2 levels correlated with HIV-1 p24 and interleukin (IL)-15, thus suggesting a local innate compensatory response in the HIV-infected breast. Given the significantly higher levels of sTLR2 in breast milk from HIV-infected women, we next demonstrated that mammary epithelial cells and macrophages, which are prevalent in milk, produced significantly increased levels of sTLR2 following exposure to HIV-1 proteins p17, p24 and gp41 or the TLR2 ligand, Pam3CSK4. Our results also demonstrated that sTLR2 physically interacts with p17, p24 and gp41 and inhibits HIV-induced nuclear factor kappa-light-chain-enhancer of activated B cells activation, and inflammation. Importantly, binding of sTLR2 to HIV-1 proteins inhibited a TLR2-dependent increase in chemokine receptor 5 expression, thus resulting in significantly reduced HIV-1 infection.
  
  
  CONCLUSIONS
  These results indicate novel mechanisms by which sTLR2 plays a critical role in inhibiting mother-to-child HIV transmission.
authors.affiliation: aMcMaster Immunology Research Centre, Michael G. DeGroote Institute for Infectious Disease Research, Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada bInstitute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA. *The INFANT Study Team: Innate Factors Associated with Nursing Transmission.
authors.forename: Bethany M
authors.initials: BM
authors.lastname: Henrick
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Yao
authors.forename: Anna G
authors.initials: AG
authors.lastname: Drannik
authors.forename: Alash'le
authors.initials: A
authors.lastname: Abimiku
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rosenthal
mesh_terms: D000328:Adult; D015153:Blotting, Western; D001942:Breast Feeding; D002170:Canada; D002460:Cell Line; D024161:Collagen Type XI / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D007249:Inflammation / Q000276:immunology; D008895:Milk, Human / Q000737:chemistry / Q000276:immunology*; D009549:Nigeria; D011247:Pregnancy; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
chemical_list: C574182:COL11A1 protein, human; D024161:Collagen Type XI; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7