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Ken Rosenthal McMaster University AFRI-CAN 2013 Entebbe, Uganda

Ken Rosenthal McMaster University AFRI-CAN 2013 Entebbe, Uganda. SOLUBLE TOLL-LIKE RECEPTOR 2 (sTLR2) IS SIGNIFICANTLY ELEVATED IN HIV-1-INFECTED BREAST MILK AND INHIBITS HIV-1 INFECTION AND INFLAMMATION. Breastfeeding and HIV.

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Ken Rosenthal McMaster University AFRI-CAN 2013 Entebbe, Uganda

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  1. Ken Rosenthal McMaster University AFRI-CAN 2013 Entebbe, Uganda SOLUBLE TOLL-LIKE RECEPTOR 2 (sTLR2) IS SIGNIFICANTLY ELEVATED IN HIV-1-INFECTED BREAST MILK AND INHIBITS HIV-1 INFECTION AND INFLAMMATION

  2. Breastfeeding and HIV Exclusively breast feed (EBF) infants are 2 to 10-fold less likely to be infected compared to infants who are non-EBF.

  3. Hypothesis Short-lived innate factors present in breast milk inhibit vertical transmission of HIV-1 from mother-to-child.

  4. Cellular Localization of Toll-Like Receptors (TLRs)

  5. Soluble TLR2: Breast Milk • Recognizes a wide-range of ‘danger-associated’ molecules • Decoy receptor that limits signaling through membrane-bound TLR2 • High concentration in breast milk • The biological significance of sTLR2 and HIV remains unknown

  6. Schematic of sTLR2 cleavage and antibody binding

  7. Increased sTLR2 in Milk of HIV-Infected Women Correlates with p24 Levels

  8. Significantly Increased TLR Expression in Breast Milk Cells from HIV-Infected Nigerian Women

  9. Significantly Elevated IL-15 & RANTES in Breast Milk from Uninfected Compared to HIV-infected Nigerian Women

  10. Significant Decrease of Inflammatory Mediator IL-8 by sTLR2 A B

  11. Inhibition of HIV-1 Infection by sTLR2 produced in vitro A B

  12. Specific Binding of sTLR2 in Human Milk to HIV Proteins

  13. CONCLUSIONS • Depletion of sTLR2 in human milk resulted in significantly increased IL-8 production in U937 monocytes, HEK-293-TLR2 EC’s and human intestinal EC’s. • sTLR2-depletion of milk led to significantly (P<0.001) increased HIV infection in vitro. • sTLR2 produced in vitro from a TLR2-tranformed cell line significantly reduced cell-free R5 HIV infection and was reversed after neutralization by anti-TLR2 Abs. • sTLR2 significantly reduced proinflammatory cytokine production in HIV-exposed cells. • sTLR2 was significantly increased in milk of HIV-infected Nigerian women and correlated with p24 levels.

  14. CONCLUSIONS • Breast milk cells from HIV-infected Nigerian women have significantly increased expression of numerous Toll-Like Receptors (TLRs) compared to uninfected Nigerian women. • Breast milk from uninfected Nigerian & Canadian women contains significantly increased levels of IL-15 and RANTES compared to HIV-infected breast milk. • sTLR2 directly binds to specific HIV structural proteins. • Overall, our data suggest that sTLR2 in human milk may be critical to infant health and prove beneficial in prevention of mother-to-child HIV transmission (PMTCT).

  15. Acknowledgements Rosenthal Laboratory: Bethany Henrick Xiao-Dan Yao Kakon Nag Anna Drannik Sumiti Jain Jen Newton Amy Patrick Collaborators: Dr. Alash’le Abimiku Institute of Human Virology Cohort Participants in Hamilton & Nigeria Hamilton Midwives & Lactation Consultants Supported by:

  16. Questions?

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