Human milk oligosaccharides reduce HIV-1-gp120 binding to dendritic  cell-specific ICAM3-grabbing non-integrin (DC-SIGN).
Breast-feeding is the predominant postnatal transmission route for HIV-1 infection in children. However, a majority of breast-fed infants do not become HIV-infected despite continuous exposure to the virus through their mothers' milk over many months. What protects some breast-fed infants from HIV-1 infection? HIV-1 entry across the infant's mucosal barrier is partially mediated through binding of the HIV-1 surface glycoprotein gp120 to dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) on human dendritic cells. Lewis antigen glycans, present in human milk, bind to DC-SIGN and inhibit HIV-1 transfer to CD4 + T lymphocytes. Human milk contains a high amount of unbound, complex oligosaccharides (5-10 g/l) that carry one or more Lewis antigen glycans, and we hypothesized that they compete with gp120 for DC-SIGN binding. Here, we show in two independent assays that physiological concentrations of human milk oligosaccharides significantly reduce gp120 binding to DC-SIGN by more than 80%. These results may provide an additional explanation for the inhibitory effects of human milk on HIV-1 mother-to-child-transmission. Identifying the specific milk oligosaccharides that interact with DC-SIGN may guide the development of glycan-based drugs that prevent transmission of HIV-1 and other pathogens that use DC-SIGN as an entry point. However, blocking DC-SIGN may be a two-edged sword.
Hong
Patrick
P
Department of Microbiology, Immunology and Molecular Genetics, University of California-Los Angeles, 609 Charles E Young Drive, Los Angeles, CA 90095, USA.
Ninonuevo
Milady R
MR
Lee
Benhur
B
Lebrilla
Carlito
C
Bode
Lars
L
D001942:Breast Feeding; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control; D037181:Lectins, C-Type / Q000378:metabolism*; D007983:Lewis Blood Group Antigens; D008895:Milk, Human / Q000737:chemistry / Q000276:immunology*; D009844:Oligosaccharides / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism*; D053585:Virus Attachment / Q000187:drug effects; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D007983:Lewis Blood Group Antigens; D009844:Oligosaccharides; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin