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Journal of Virology, August 2003, p. 8237-8248, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8237-8248.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cholesterol Depletion of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus with ß-Cyclodextrin Inactivates and Permeabilizes the Virions: Evidence for Virion-Associated Lipid Rafts

David R. M. Graham,1 Elena Chertova,2 Joanne M. Hilburn,2 Larry O. Arthur,2 and James E. K. Hildreth1*

The Leukocyte Immunochemistry Laboratory, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,1 AIDS Vaccine Program, SAIC Frederick, NCI-Frederick, Frederick, Maryland 217022

Received 2 October 2002/ Accepted 7 May 2003

Recent evidence suggests that human immunodeficiency virus type 1 (HIV-1) particles assemble and bud selectively through areas in the plasma membrane of cells that are highly enriched with glycosylphosphatidylinositol-anchored proteins and cholesterol, called lipid rafts. Since cholesterol is required to maintain lipid raft structure and function, we proposed that virion-associated cholesterol removal with the compound 2-hydroxy-propyl-ß-cyclodextrin (ß-CD) might be disruptive to HIV-1 and simian immunodeficiency virus (SIV). We examined the effect of ß-CD on the structure and infectivity of cell-free virions. We found that ß-CD inactivated HIV-1 and SIV in a dose-dependent manner and permeabilized the viral membranes, resulting in the loss of mature Gag proteins (capsid, matrix, nucleocapsid, p1, and p6) without loss of the envelope glycoproteins. SIV also lost reverse transcriptase (RT), integrase (IN), and viral RNA. IN appeared to be only slightly diminished in HIV-1, and viral RNA, RT, matrix, and nucleocapsid proteins were retained in HIV-1 but to a much lesser degree. Host proteins located internally in the virus (actin, moesin, and ezrin) and membrane-associated host proteins (major histocompatibility complex classes I and II) remained associated with the treated virions. Electron microscopy revealed that under conditions that permeabilized the viruses, holes were present in the viral membranes and the viral core structure was perturbed. These data provide evidence that an intact viral membrane is required to maintain mature virion core integrity. Since the viruses were not fixed before ß-CD treatment and intact virion particles were recovered, the data suggest that virions may possess a protein scaffold that can maintain overall structure despite disruptions in membrane integrity.

* Corresponding author. Mailing address: Johns Hopkins School of Medicine, Department of Pharmacology and Molecular Sciences, 725 N. Wolfe St., 320A Physiology Bldg., Baltimore, MD 21205. Phone: (410) 955-3017. Fax: (410) 955-1894. E-mail: jhildret{at}jhmi.edu.

Journal of Virology, August 2003, p. 8237-8248, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8237-8248.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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