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Journal of Virology, September 2008, p. 9191-9205, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00424-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Induction of the G{alpha}q Signaling Cascade by the Human Immunodeficiency Virus Envelope Is Required for Virus Entry{triangledown}

Brooke Harmon and Lee Ratner*

Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri

Received 26 February 2008/ Accepted 8 July 2008

Binding of human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) with the primary receptor CD4 and one of two coreceptors, CXCR4 or CCR5, activates a signaling cascade resulting in Rac-1 GTPase activation and stimulation of actin cytoskeletal reorganizations critical for HIV-1-mediated membrane fusion. The mechanism by which HIV-1 Env induces Rac-1 activation and subsequent actin cytoskeleton rearrangement is unknown. In this study, we show that Env-mediated Rac-1 activation is dependent on the activation of G{alpha}q and its downstream targets. Fusion and Rac-1 activation are mediated by G{alpha}q and phospholipase C (PLC), as shown by attenuation of fusion and Rac-1 activation in cells either expressing small interfering RNA (siRNA) targeting G{alpha}q or treated with the PLC inhibitor U73122. Rac-1 activation and fusion were also blocked by multiple protein kinase C inhibitors, by inhibitors of intracellular Ca2+ release, by Pyk2-targeted siRNA, and by the Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS). Fusion was blocked without altering cell viability or cell surface localization of CD4 and CCR5. Similar results were obtained when cell fusion was induced by Env expressed on viral and cellular membranes and when cell lines or primary cells were the target. Treatment with inhibitors and siRNA specific for G{alpha}i or G{alpha}s signaling mediators had no effect on Env-mediated Rac-1 activation or cell fusion, indicating that the G{alpha}q pathway alone is responsible. These results could provide a new focus for therapeutic intervention with drugs targeting host signaling mediators rather than viral molecules, a strategy which is less likely to result in resistance.

* Corresponding author. Mailing address: Box 8069, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-8836. Fax: (314) 747-2120. E-mail: lratner{at}im.wustl.edu

{triangledown} Published ahead of print on 16 July 2008.

Journal of Virology, September 2008, p. 9191-9205, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00424-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dai, J., Agosto, L. M., Baytop, C., Yu, J. J., Pace, M. J., Liszewski, M. K., O'Doherty, U. (2009). Human Immunodeficiency Virus Integrates Directly into Naive Resting CD4+ T Cells but Enters Naive Cells Less Efficiently than Memory Cells. J. Virol. 83: 4528-4537 [Abstract] [Full Text]  


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