MUC1 in human milk blocks transmission of human immunodeficiency virus from dendritic cells to T cells

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Molecular Immunology (Impact Factor: 2.97). 05/2009; 46(11-12):2309-16. DOI: 10.1016/j.molimm.2009.03.025
Source: PubMed


Mother-to-child transmission of human immunodeficiency virus-1 (HIV-1) occurs frequently via breast-feeding. HIV-1 targets DC-SIGN+ dendritic cells (DCs) in mucosal areas that allow efficient transmission of the virus to T cells. Here, we demonstrate that the epithelial mucin MUC1, abundant in milk, efficiently bound to DC-SIGN on DC. The O-linked glycans within the mucin domain contained Lewis X structures, that were specifically recognized by the receptor. Interestingly, MUC1 prevented DC-SIGN-mediated transmission of HIV-1 from DCs to CD4+ T cells. We hypothesize that repetitive units of Lewis X, within the mucin domain, play an important role in inhibiting transmission of HIV-1 from mother to child.

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    • "In support of this view, Lewis X epitopes on MUC1 from human milk blocked the interaction of fluorescent beads coated with HIV-gp120-Fc with dendritic cells. Furthermore, MUC1 blocked DC-SIGN-mediated transmission of HIV from dendritic cells to CD4+ T cells (Saeland et al. 2009). "
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    ABSTRACT: Breastfeeding is known to have many health benefits for a newborn. Not only does human milk provide an excellent source of nutrition, it also contains components that protect against infection from a wide range of pathogens. Some of the protective properties of human milk can be attributed to the immunoglobulins. Yet there is another level of defence provided by the "sweet" protective agents that human milk contains, including free oligosaccharides, glycoproteins and glycolipids. Sugar epitopes in human milk are similar to the glycan receptors that serve as pathogen adhesion sites in the human gastrointestinal tract and other epithelial cell surfaces; hence the milk glycans can competitively bind to and remove the disease-causing microorganisms before they cause infection. The protective value of free oligosaccharides in human milk (HMOs) has been well researched and documented. Human milk glycoconjugates have received less attention but appear to play an equally important role. Here we bring together the breadth of research that has focused on the protective mechanisms of human milk glycoconjugates, with a particular focus on the glycan moieties that may play a role in disease prevention. In addition, human milk glycoconjugates are compared to bovine milk glycoconjugates in terms of their health benefits for the human infant.
    Glycobiology 09/2013; 23(12):1425-1438. DOI:10.1093/glycob/cwt072 · 3.15 Impact Factor
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    • "restricted, up to 15–20 % of children born to infected mothers have been reported as becoming infected by this route (Lehman & Farquhar, 2007). Studies have, however, shown that several components of breast milk may inhibit DC-SIGN-mediated virus transmission (Groot et al., 2005; Hong et al., 2009; Naarding et al., 2005, 2006; Requena et al., 2008; Saeland et al., 2009; Yagi et al., 2010). "
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    ABSTRACT: Binding of HIV to C-type lectin receptors may either result in enhanced trans-infection of T cells or virus degradation. We have investigated the efficacy of HIV-1 utilization of Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), a C-type lectin receptor, in the setting of intrauterine or intrapartum mother-to-child transmission. Viruses isolated from HIV-1 infected mothers, at delivery, and from their vertically infected children, early after birth and later in disease, were analysed for use of DC-SIGN, binding and ability to mediate trans-infection. DC-SIGN-use of the child's early virus tended to be reduced as compared with the corresponding maternal isolate. Furthermore, the children's late isolate displayed enhanced DC-SIGN utilization compared with the corresponding early virus. These results were also supported in head-to-head competition assays and suggest that HIV-1 variants displaying efficient DC-SIGN-use are not selected for during intrauterine or intrapartum mother-to-child transmission. However, viruses with increased DC-SIGN-use may evolve later in paediatric HIV-1 infections.
    Journal of General Virology 12/2012; 94(Pt_4). DOI:10.1099/vir.0.043620-0 · 3.18 Impact Factor
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    • "In clinical studies, components in breast milk, including IL-15 [4], long-chain fatty acids [5] and erythropoietin [6] have been linked to lower rates of post-natal HIV-1 transmission. In vitro, breast milk mucin (MUC1) effectively blocks binding and transfer of virus from dendritic cells (DC) to CD4+ T cells [7], [8] and inhibits HIV-1 infection [9], [10]. The inhibitory effects of MUC1 are attributed to a rich array of repeating LewisX motifs, consistent with a direct role for LewisX in preventing binding of HIV-1 to DC-SIGN [7], [8]. "
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    ABSTRACT: Transmission of HIV-1 during breastfeeding is a significant source of new pediatric infections in sub-Saharan Africa. Breast milk from HIV-positive mothers contains both cell-free and cell-associated virus; however, the impact of breast milk on HIV-1 infectivity remains poorly understood. In the present study, breast milk was collected from HIV-positive and HIV-negative Tanzanian women attending antenatal clinics in Dar es Salaam. Milk was analyzed for activity in vitro against both cell-free and cell-associated HIV-1. Potent inhibition of cell-free R5 and X4 HIV-1 occurred in the presence of milk from all donors regardless of HIV-1 serostatus. Inhibition of cell-free HIV-1 infection positively correlated with milk levels of sialyl-Lewis(X) from HIV-positive donors. In contrast, milk from 8 of 16 subjects enhanced infection with cell-associated HIV-1 regardless of donor serostatus. Milk from two of these subjects contained high levels of multiple pro-inflammatory cytokines including TNFα, IL-1β, IL-6, IL-8, MIP-1α, MIP-1β, MCP-1 and IP-10, and enhanced cell-associated HIV-1 infection at dilutions as high as 1∶500. These findings indicate that breast milk contains innate factors with divergent activity against cell-free and cell-associated HIV-1 in vitro. Enhancement of cell-associated HIV-1 infection by breast milk may be associated with inflammatory conditions in the mother and may contribute to infant infection during breastfeeding.
    PLoS ONE 08/2012; 7(8):e43815. DOI:10.1371/journal.pone.0043815 · 3.23 Impact Factor
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