Research Highlights

Mucins: Breast milk sours HIV-1 transmission

MUC1 competes with HIV for DC-SIGN and blocks transmission to T cells

Dendritic cells can capture a variety of microorganisms using DC-SIGN, a surface glycan-binding protein. In most cases, DC-SIGN facilitates innate immune clearance of the offending pathogen. However, HIV-1 uses the lectin as a receptor to hijack dendritic cells for transmission to T cells. Although HIV-1 can be passed from mother to child through breast milk, exclusive breast-feeding in the first few months of life has been shown to protect against infection, possibly due to antiviral factors and natural antibodies against DC-SIGN present in human milk. In Molecular Immunology, Saeland et al. discover that MUC1, an epithelial mucin found in breast milk, specifically prevents HIV-1 transmission from dendritic cells to T cells by binding DC-SIGN.

The authors first noticed that purified breast milk fractions containing high molecular weight proteins blocked interactions between dendritic cells and gp120, the major HIV-1 surface glycoprotein. As mucins are rich in Lewis X structures, a known DC-SIGN epitope, Saeland et al. explored whether this high molecular weight component of breast milk could be responsible for inhibition of gp120 binding. They found that DC-SIGN strongly bound MUC1, and Lewis X in particular, and that this interaction could be inhibited by treatment with another DC-SIGN ligand or anti-DC-SIGN antibodies. Thus, the authors concluded that MUC1 interaction with DC-SIGN specifically impairs HIV-1 gp120 access to this lectin.

In order to determine if MUC1 interaction with DC-SIGN could prevent HIV-1 transmission, cells with and without DC-SIGN were pre-treated with milk fractions containing MUC1 and fractions lacking the mucin. When exposed to HIV-1 and co-incubated with CD4+ T cells, the cells expressing DC-SIGN were able to transmit the virus to T cells in the absence, but not the presence, of MUC1. The ability of MUC1 to block HIV-1 binding to DC-SIGN and prevent transmission was linked to the amount of Lewis X decorating the mucin. In a comparison of two human milk donors, MUC1 derived from the donor with a significantly higher Lewis X content bound DC-SIGN and inhibited HIV-1 transmission more efficiently than the donor with less MUC1-associated Lewis X.

MUC1 originates in the human milk fat globule membrane and is shed into milk, where it acts as a pathogen decoy receptor. Pathogens invading a newborn bind MUC1 from breast milk and are excreted before they are able to colonize. This study now reveals a second protective function of breast milk MUC1. Though genetic variation affecting the Lewis X content of MUC1 may modulate the level of protection, these results emphasize the importance of early breast-feeding for innate immune defense in newborns.

Author: Heather Buschman