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Soluble Toll-like receptor 2 is significantly elevated in HIV-1 infected breast milk and inhibits HIV-1 induced cellular activation, inflammation and infection

Henrick, Bethany M.; Yao, Xiao-Dan; Drannik, Anna G.; Abimiku, Alash’le; Rosenthal, Kenneth L.the INFANT Study Team

doi: 10.1097/QAD.0000000000000381
Basic Science

Objectives: 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.

Design: 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.

Conclusion: These results indicate novel mechanisms by which sTLR2 plays a critical role in inhibiting mother-to-child HIV transmission.

Supplemental Digital Content is available in the text

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.

Correspondence to Kenneth L. Rosenthal, Department of Pathology & Molecular Medicine, McMaster University, MDCL 4019, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada. Tel: +1 905 525 9140 x22375; fax: +1 905 522 6750; e-mail:

Received 24 January, 2014

Revised 11 June, 2014

Accepted 11 June, 2014

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