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Journal of Lipid Research, Vol. 43, 1670-1679, October 2002
Copyright © 2002 by Lipid Research, Inc.

A novel soluble analog of the HIV-1 fusion cofactor, globotriaosylceramide (Gb₃), eliminates the cholesterol requirement for high affinity gp120/Gb₃ interaction

Radhia Mahfoud^*, Murugesapillai Mylvaganam, Clifford A. Lingwood^, and Jacques Fantini^1,*

^* Institut Méditerranéen de Recherche en Nutrition, UMR-INRA 1111, Faculté des Sciences St-Jérôme, 13397 Marseille Cedex 20, France
Research Institute, Hospital for Sick Children, Toronto
Departments of Biochemistry and Laboratory Medicine & Pathobiology, University of Toronto, Canada

¹ To whom correspondence should be addressed. e-mail: jacques.fantini{at}univ.u-3mrs.fr

We have analyzed the interaction of adamantyl Gb₃ (adaGb₃), a semi-synthetic soluble analog of Gb₃, with HIV-1 surface envelope glycoprotein gp120. In this analog, which was orginally designed to inhibit verotoxin binding to its glycolipid receptor, Gb₃, the fatty acid chain is replaced with a rigid globular hydrocarbon frame (adamantane). Despite its solubility, adaGb₃ forms monolayers at an air-water interface. Compression isotherms of such monolayers demonstrated that the adamantane substitution resulted in a larger minimum molecular area and a more rigid, less compressible film than Gb₃. Insertion of gp120 into adaGb₃ monolayers was exponential whereas the gp120/Gb₃ interaction curve was sigmoidal with a lag phase of 40 min. Adding cholesterol into authentic Gb₃ monolayers abrogated the lag phase and increased the initial rate of interaction with gp120. This effect of cholesterol was not observed with phosphatidylcholine or sphingomyelin. In addition, verotoxin-bound adaGb₃ or Gb₃ plus cholesterol was recovered in fractions of comparable low density after ultracentrifugation through sucrose-density gradients in the presence of Triton X-100.

The unique biological and physico-chemical properties of adaGb₃ suggest that this analog may be a potent soluble mimic of Gb₃, providing a novel concept for developing GSL-derived viral fusion inhibitors.

Abbreviations: adaGb3, adamantyl Gb3; adaSGC, adamantyl-sulfatide; DPPC, dipalmitoyl-phosphatidylcholine; GSL, glycosphingolipid; PAPC, palmitoyl-arachidonoyl-phosphatidylcholine; SM, sphingomyelin

Supplementary key words lipid raft • microdomain • sphingolipid • infection • membrane

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