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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,{ddagger} Olle Hernell,5,{ddagger} and William A. Paxton1*

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 LeX 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 (LeX)-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 LeX 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.

* Corresponding author. Mailing address: Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Phone: 31-30-5664739. Fax: 31-20-6916531. E-mail: w.a.paxton{at}amc.uva.nl.

{ddagger} Both of these authors contributed equally.

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.



This article has been cited by other articles:

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