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DC-specific ICAM3-grabbing non-integrin (DC-SIGN), which is expressed on DCs, can interact with a variety of pathogens such as HIV-1, hepatitis C, Ebola, cytomegalovirus, Dengue virus, Mycobacterium, Leishmania, and Candida albicans. We demonstrate that human milk can inhibit the DC-SIGN-mediated transfer of HIV-1 to CD4^sup +^ T lymphocytes as well as viral transfer by both immature and mature DCs. The inhibitory factor directly interacted with DC-SIGN and prevented the HIV-1 gp120 envelope protein from binding to the receptor. The human milk proteins lactoferrin, α-lactalbumin, lysozyme, β-casein, and secretory leukocyte protease inhibitor did not bind DC-SIGN or demonstrate inhibition of viral transfer. The inhibitory effect could be fully alleviated with an Ab recognizing the Lewis X (Le^sup X^) sugar epitope, commonly found in human milk. Le^sup X^ in polymeric form or conjugated to protein could mimic the inhibitory activity, whereas free Le^sup X^ sugar epitopes could not. We reveal that a Le^sup X^ motif present in human milk can bind to DC-SIGN and thereby prevent the capture and subsequent transfer of HIV-1 to CD4^sup +^ T lymphocytes. The presence of such a DC-SIGN-binding molecule in human milk may both influence antigenic presentation and interfere with pathogen transfer in breastfed infants.
Nonstandard abbreviations used: DC-SIGN, DC-specific ICAM3-grabbing non-integrin; iDC, immature DC; Le^sup X^, Lewis X; mDC, mature DC; L-SIGN, liver and lymph node-specific ICAM3-grabbing non-integrin; MTCT, mother-to-child transmission; PAA, polyacrylamide; R5, CCR5 coreceptor using HiV-1 isolate; SLPI, secretory leukocyte protease inhibitor; TCID, tissue culture infectious dose; X4, CXCR4 coreceptor using HIV-1 isolate.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J Clin. Invest. 115:3256-3264 (2005). doi:10.1172/JCI2510S.
Introduction
DCs can capture an array of infectious agents and present their antigens to T lymphocytes. DCs express, among other receptors, the DC-specific ICAM3-grabbing non-integrin (DC-SIGN) receptor, a C-type lectin, which contains an external calcium-dependent mannose-binding lectin domain (1, 2). DC-SIGN interacts with the envelope glycoprotein gp!20 of HIV-I, HIV-2, and SIV (3-8), as well as other pathogens such as hepatitis C (9, 10), Ebola (11), cytomegalovirus (12), Dengue virus (13), Mycobacterium (14-16), Leishmania (17, 18), Candida albicans (19), and Heltcobacterpylori (20, 21). DC-SIGN has been implicated as playing an important role in HIV-I transmission and the establishment of infection (4,...