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PNAS 103 (15): 5989-5994

Copyright © 2006 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / MICROBIOLOGY

Ligand-induced and nonfusogenic dissolution of a viral membrane

Mansun Law*,{dagger}, Gemma C. Carter*, Kim L. Roberts, Michael Hollinshead, and Geoffrey L. Smith{ddagger}

Department of Virology, Faculty of Medicine, Imperial College London, St. Mary’s Campus, Norfolk Place, London W2 1PG, United Kingdom

Communicated by Bernard Moss, National Institutes of Health, Bethesda, MD, February 7, 2006

Received for publication January 9, 2006.

Abstract: Hitherto, all enveloped viruses were thought to shed their lipid membrane during entry into cells by membrane fusion. The extracellular form of Vaccinia virus has two lipid envelopes surrounding the virus core, and consequently a single fusion event will not deliver a naked core into the cell. Here we report a previously underscribed mechanism in which the outer viral membrane is disrupted by a ligand-induced nonfusogenic reaction, followed by the fusion of the inner viral membrane with the plasma membrane and penetration of the virus core into the cytoplasm. The dissolution of the outer envelope depends on interactions with cellular polyanionic molecules and requires the virus glycoproteins A34 and B5. This discovery represents a remarkable example of how viruses manipulate biological membranes, solves the topological problem of how a double-enveloped virus enters cells, reveals a new effect of polyanions on viruses, and provides a therapeutic approach for treatment of poxvirus infections, such as smallpox.

Key Words: antiviral therapy • extracellular enveloped virus • membrane dissolution • Vaccinia virus • virus entry

Freely available online through the PNAS open access option.

*M.L. and G.C.C. contributed equally to this work.

{dagger}Present address: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.

Author contributions: M.L., G.C.C., K.L.R., M.H., and G.L.S. designed research; M.L., G.C.C., K.L.R., and M.H. performed research; M.L., G.C.C., K.L.R., M.H., and G.L.S. analyzed data; and M.L., G.C.C., and G.L.S. wrote the paper.

Conflict of interest statement: No conflicts declared.

{ddagger}To whom correspondence should be addressed. E-mail: glsmith{at}imperial.ac.uk

© 2006 by The National Academy of Sciences of the USA

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