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Antimicrobial Agents and Chemotherapy, October 2006, p. 3367-3374, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00593-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Bile Salt-Stimulated Lipase from Human Milk Binds DC-SIGN and Inhibits Human Immunodeficiency Virus Type 1 Transfer to CD4⁺ T Cells

Marloes A. Naarding,¹ Annette M. Dirac,² Irene S. Ludwig,³ Dave Speijer,⁴ Susanne Lindquist,⁵ Eva-Lotta Vestman,⁵ Martijn J. Stax,¹ Teunis B. H. Geijtenbeek,³ Georgios Pollakis,^1, Olle Hernell,^5, and William A. Paxton^1*

Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands,¹ Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands,² Department of Molecular Cell Biology and Immunology, VU University Medical Centre, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands,³ Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands,⁴ Department of Clinical Sciences, Pediatrics, Umeå University, SE - 901 87 Umeå, Sweden⁵

Received 15 May 2006/ Returned for modification 14 July 2006/ Accepted 31 July 2006

A wide range of pathogens, including human immunodeficiency virus type 1 (HIV-1), hepatitis C virus, Ebola virus, cytomegalovirus, dengue virus, Mycobacterium, Leishmania, and Helicobacter pylori, can interact with dendritic cell (DC)-specific ICAM3-grabbing nonintegrin (DC-SIGN), expressed on DCs and a subset of B cells. More specifically, the interaction of the gp120 envelope protein of HIV-1 with DC-SIGN can facilitate the transfer of virus to CD4⁺ T lymphocytes in trans and enhance infection. We have previously demonstrated that a multimeric Le^X component in human milk binds to DC-SIGN, preventing HIV-1 from interacting with this receptor. Biochemical analysis reveals that the compound is heat resistant, trypsin sensitive, and larger than 100 kDa, indicating a specific glycoprotein as the inhibitory compound. By testing human milk from three different mothers, we found the levels of DC-SIGN binding and viral inhibition to vary between samples. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blotting, and matrix-assisted laser desorption ionization analysis, we identified bile salt-stimulated lipase (BSSL), a Lewis X (Le^X)-containing glycoprotein found in human milk, to be the major variant protein between the samples. BSSL isolated from human milk bound to DC-SIGN and inhibited the transfer of HIV-1 to CD4⁺ T lymphocytes. Two BSSL isoforms isolated from the same human milk sample showed differences in DC-SIGN binding, illustrating that alterations in the BSSL forms explain the differences observed. These results indicate that variations in BSSL lead to alterations in Le^X expression by the protein, which subsequently alters the DC-SIGN binding capacity and the inhibitory effect on HIV-1 transfer. Identifying the specific molecular interaction between the different forms may aid in the future design of antimicrobial agents.

Both of these authors contributed equally.

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