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Journal of Virology, December 2003, p. 12865-12874, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12865-12874.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Binding of Human Immunodeficiency Virus Type 1 to Immature Dendritic Cells Can Occur Independently of DC-SIGN and Mannose Binding C-Type Lectin Receptors via a Cholesterol-Dependent Pathway

Suryaram Gummuluru,1,2* Mark Rogel,1 Leonidas Stamatatos,3 and Michael Emerman1*

Division of Human Biology, Fred Hutchinson Cancer Research Center,1 Seattle Biomedical Research Institute, Seattle, Washington 98109,2 Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 021183

Received 28 March 2003/ Accepted 2 September 2003

Interactions of human immunodeficiency virus type 1 (HIV-1) with immature dendritic cells (DC) are believed to be multifactorial and involve binding to the CD4 antigen, DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), mannose binding C-type lectin receptors (MCLR), and heparan sulfate proteoglycans (HSPG). In this study we assessed the relative contributions of these previously defined virus attachment factors to HIV binding and accumulation in DC and the subsequent transfer of the bound virus particle to CD4+ T cells. Using competitive inhibitors of HIV-1 attachment to DC, we have identified the existence of DC-SIGN-, MCLR-, and HSPG-independent mechanism(s) of HIV attachment and internalization. Furthermore, virus particles bound by DC independently of CD4, DC-SIGN, MCLR, and HSPG are efficiently transmitted to T cells. Treatment of virus particles with the protease subtilisin or treatment of immature DC with trypsin significantly reduced virus binding, thus demonstrating the role of HIV envelope glycoprotein interactions with unidentified DC-surface factor(s). Finally, this DC-mediated virus binding and internalization are dependent on lipid rafts. We propose that pathways to HIV-1 attachment and uptake in DC exhibit functional redundancy; that is, they are made up of multiple independent activities that can, at least in part, compensate for one another.

* Corresponding author. Mailing address for Suryaram Gummuluru: Boston University School of Medicine, Department of Microbiology, Room R-518, 715 Albany St., Boston, MA 02118. Phone: (617) 414-8075. Fax: (617) 638-4286. E-mail: rgummulu{at}bu.edu. Mailing address for Michael Emerman: Fred Hutchinson Cancer Research Center, Division of Human Biology, Mail Stop C2-023, P.O. Box 19024, 1100 Fairview Ave. N., Seattle, WA 98109-1104. Phone: (206) 667-5058. Fax: (206) 667-6523. E-mail: memerman{at}fhcrc.org.

Journal of Virology, December 2003, p. 12865-12874, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12865-12874.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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