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Journal of Virology, July 2004, p. 7138-7147, Vol. 78, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.13.7138-7147.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Actin Cytoskeletal Reorganizations and Coreceptor-Mediated Activation of Rac during Human Immunodeficiency Virus-Induced Cell Fusion{dagger}

S. E. Pontow,1 N. Vander Heyden,1 S. Wei,2 and L. Ratner1*

Department of Internal Medicine, Molecular Oncology Division, Washington University School of Medicine, St. Louis, Missouri 63110,1 Immunology Program, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, Florida 336122

Received 6 November 2003/ Accepted 19 February 2004

The membrane fusion events which initiate human immunodeficiency virus type 1 (HIV-1) infection and promote cytopathic syncytium formation in infected cells commence with the binding of the HIV envelope glycoprotein (Env) to CD4 and an appropriate coreceptor. Here, we show that HIV Env-coreceptor interactions activate Rac-1 GTPase and stimulate the actin filament network reorganizations that are requisite components of the cell fusion process. Disrupting actin filament dynamics with jasplakinolide or latrunculin A arrested fusion at a late step in the formation of Env-CD4-coreceptor complexes. Time-lapse confocal microscopy of living cells revealed vigorous activity of actin-based, target cell membrane extensions at the target cell-Env-expressing cell interface. The expression of dominant-negative forms of actin-regulating Rho-family GTPases established that HIV Env-mediated syncytium formation relies on Rac-1 but not on Cdc42 or Rho activation in target cells. Similar dependencies were found when cell fusion was induced by Env expressed on viral or cellular membranes. Additionally, Rac activity was specifically upregulated in a coreceptor-dependent manner in fusion reaction cell lysates. These results define a role for HIV Env-coreceptor interactions in activating the cellular factors essential for virus-cell and cell-cell fusion and provide evidence for the participation of pertussis toxin-insensitive signaling pathways in HIV-induced membrane fusion.

* Corresponding author. Mailing address: Department of Internal Medicine, Molecular Oncology Division, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8069, St. Louis, MO 63110. Phone: (314) 362-8836. Fax: (314) 747-2120. E-mail: lratner{at}im.wustl.edu.

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

Journal of Virology, July 2004, p. 7138-7147, Vol. 78, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.13.7138-7147.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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