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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: rosenthl@mcmaster.ca

Received 24 January, 2014

Revised 11 June, 2014

Accepted 11 June, 2014

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

Copyright © 2014 Wolters Kluwer Health, Inc.