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Journal of Virology, October 2002, p. 10128-10137, Vol. 76, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.20.10128-10137.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Adaptation of Alphaviruses to Heparan Sulfate: Interaction of Sindbis and Semliki Forest Viruses with Liposomes Containing Lipid-Conjugated Heparin

Jolanda M. Smit,¹ Barry-Lee Waarts,¹ Koji Kimata,² William B. Klimstra,^3, Robert Bittman,⁴ and Jan Wilschut^1*

Molecular Virology Section, Department of Medical Microbiology, University of Groningen, 9713 AV Groningen, The Netherlands,¹ Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-11, Japan,² Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7290,³ Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 11367⁴

Received 21 February 2002/ Accepted 8 July 2002

Passage of Sindbis virus (SIN) in BHK-21 cells has been shown to select for virus mutants with high affinity for the glycosaminoglycan heparan sulfate (HS). Three loci in the viral spike protein E2 (E2:1, E2:70, and E2:114) have been identified that mutate during adaptation and independently confer on the virus the ability to bind to cell surface HS (W. B. Klimstra, K. D. Ryman, and R. E. Johnston, J. Virol. 72:7357-7366, 1998). In this study, we used HS-adapted SIN mutants to evaluate a new model system involving target liposomes containing lipid-conjugated heparin (HepPE) as an HS receptor analog for the virus. HS-adapted SIN, but not nonadapted wild-type SIN TR339, interacted efficiently with HepPE-containing liposomes at neutral pH. Binding was competitively inhibited by soluble heparin. Despite the efficient binding of HS-adapted SIN to HepPE-containing liposomes at neutral pH, there was no fusion under these conditions. Fusion did occur, however, at low pH, consistent with cellular entry of the virus via acidic endosomes. At low pH, wild-type or HS-adapted SIN underwent fusion with liposomes with or without HepPE with similar kinetics, suggesting that interaction with the HS receptor analog at neutral pH has little influence on subsequent fusion of SIN at low pH. Finally, Semliki Forest virus (SFV), passaged frequently on BHK-21 cells, also interacted efficiently with HepPE-containing liposomes, indicating that SFV, like other alphaviruses, readily adapts to cell surface HS. In conclusion, the liposomal model system presented in this paper may serve as a novel tool for the study of receptor interactions and membrane fusion properties of HS-interacting enveloped viruses.

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* Corresponding author. Mailing address: Department of Medical Microbiology, Molecular Virology Section, University of Groningen, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands. Phone: 31 50 3632733. Fax: 31 50 3638171. E-mail: J.C.Wilschut{at}med.rug.nl.

Present address: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130.

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Journal of Virology, October 2002, p. 10128-10137, Vol. 76, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.20.10128-10137.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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