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Journal of Virology, June 2008, p. 5212-5219, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00008-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

West Nile Virus Entry Requires Cholesterol-Rich Membrane Microdomains and Is Independent of {alpha}vβ3 Integrin{triangledown} ,{dagger}

Guruprasad R. Medigeshi,* Alec J. Hirsch, Daniel N. Streblow, Janko Nikolich-Zugich, and Jay A. Nelson

Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 N.W. 185th Avenue, Beaverton, Oregon 97006

Received 2 January 2008/ Accepted 18 March 2008

West Nile virus (WNV) has been the leading cause of viral encephalitis in the United States since 1999. The endocytic processes involved in the internalization of infectious WNV by various cell types are not well characterized, and the involvement of cholesterol-rich membrane microdomains, or lipid rafts, in the life cycle of WNV has not been investigated previously. In this study, we found that the depletion of cellular cholesterol levels by brief treatment with methyl-β-cyclodextrin resulted in a 100-fold reduction of the titers of infectious WNV released into the culture supernatant, as well as a reduction in the number of WNV genome copies in the cholesterol-depleted cells. The addition of exogenous cholesterol to cholesterol-depleted cells reversed this effect. Cholesterol depletion postinfection did not affect WNV growth, suggesting that the effect occurs at the level of WNV entry. We also showed that while WNV entry did not require {alpha}vβ3 integrin and focal adhesion kinase, WNV particles failed to be internalized by cholesterol-depleted cells. Finally, we showed the colocalization of the WNV envelope protein and cholera toxin B, which is internalized in a lipid raft-dependent pathway, in microdomain clusters at the plasma membrane. These data suggest that WNV utilizes lipid rafts during initial stages of internalization and that the lipid rafts may contain a factor(s) that may enhance WNV endocytosis.

* Corresponding author. Mailing address: Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 N.W. 185th Ave., Beaverton, OR 97006. Phone: (503) 494-2434. Fax: (503) 494-6862. E-mail: medigesh{at}ohsu.edu

{triangledown} Published ahead of print on 2 April 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, June 2008, p. 5212-5219, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.00008-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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