Abstract
The majority of infants who breastfeed from their HIV-positive mothers remain uninfected despite constant and repeated exposure to virus over weeks to years. This phenomenon is not fully understood but has been closely linked to innate factors in breast milk (BM). Most recently we have focused on one such innate factor, soluble Toll-like receptor 2 (sTLR2) for its significant contribution as an inhibitor of inflammation triggered by bacterial and viral antigens. We hypothesized that sTLR2 in BM inhibits immune activation/inflammation and HIV-1 infection. sTLR2 protein profiles were analyzed in HIV-uninfected BM and showed dramatic variability in expression concentration and predominant sTLR2 forms between women. sTLR2 immunodepleted BM, versus mock-depleted BM, incubated with Pam3CSK4 lead to significant increases in IL-8 production in a TLR2-dependant fashion in U937, HEK293-TLR2, and Caco-2. Importantly, TLR2-specific polyclonal and monoclonal antibody addition to BM prior to cell-free R5 HIV-1 addition led to significantly (P<0.01, P<0.001, respectively) increased HIV-1 infection in TZM-bl reporter cells. To confirm these findings, sTLR2-depletion in BM led to significantly (P<0.001) increased HIV-1 infection in TZM-bl cells. Notably, immunodepletion does not allow for the complete removal of sTLR2 from BM, thus functional testing shown here may underestimate the total effect elicited by sTLR2 against HIV-1 and synthetic bacterial ligand. This study provides evidence for the first time that sTLR2 in BM may provide a dual protective role for infants breastfeeding from their HIV-infected mothers by; (1) immunomodulating pro-inflammatory responses to bacterial ligands, and (2) directly inhibiting cell-free HIV-1 infection. Thus, sTLR2 in BM may be critical to infant health and prove beneficial in decreasing vertical HIV-1 transmission to infants.
Highlights
Breast milk (BM) is unique in its ability to fulfill infant nutritional requirements and, arguably more importantly, protect the newborn from environmental and infectious agents during the early stages of life
We report on predominant forms of soluble Toll-like receptor 2 (sTLR2) in breast milk (BM) that vary between women and show that they have direct effects on inflammatory responses and HIV-1 infection
Results confirm previous findings that indicate sTLR2 is critical in suppressing inflammatory responses to bacterial pathogen associated molecular patterns (PAMPs) [22,23,25,26], and extend to show direct inhibition of cell-free R5 HIV-1 infection
Summary
Breast milk (BM) is unique in its ability to fulfill infant nutritional requirements and, arguably more importantly, protect the newborn from environmental and infectious agents during the early stages of life. A number of cohort studies have shown significantly reduced HIV-transmission rates when HIV-infected mothers exclusively breastfed (EBF) compared to mothers who mixed fed their infants [5,6,7,8]. This phenomena is not fully understood but may be linked to short-lived innate factors in BM that contribute to both reduced immune activation and inhibition of R5 HIV-1 [9,10], the predominant phenotype transmitted from mother-to-child [11,12,13,14]. Activation of the immune system, namely inflammation, is a strong prognostic marker of HIV infection [15], and has been associated with increased HIV acquisition risk caused by activation in the PLoS ONE | www.plosone.org sTLR2 in Milk Inhibits HIV Infection genital tract due to pre-existing sexually transmitted infections (STI) [16,17,18,19]
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