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Journal of Virology, September 2008, p. 8316-8329, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00665-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CD81 Is a Central Regulator of Cellular Events Required for Hepatitis C Virus Infection of Human Hepatocytes{triangledown} ,{dagger}

Michela Brazzoli,1 Alessia Bianchi,2 Sara Filippini,2 Amy Weiner,3 Qing Zhu,3 Mariagrazia Pizza,1 and Stefania Crotta1*

Department of Molecular Immunology, Novartis Vaccines and Diagnostics, via Fiorentina 1, 53100 Siena, Italy,1 Department of Experimental Biomedical Sciences, University of Padua, via G. Colombo 3, 35121 Padua, Italy,2 Novartis Vaccines and Diagnostics, 4560 Horton St. M/S 4.3, Emeryville, California 946083

Received 26 March 2008/ Accepted 13 June 2008

Infection with hepatitis C virus (HCV) is still a major public health problem, and the events leading to hepatocyte infection are not yet fully understood. Combining confocal microscopy with biochemical analysis and studies of infection requirements using pharmacological inhibitors and small interfering RNAs, we show here that engagement of CD81 activates the Rho GTPase family members Rac, Rho, and Cdc42 and that the block of these signaling pathways drastically reduces HCV infectivity. Activation of Rho GTPases mediates actin-dependent relocalization of the HCV E2/CD81 complex to cell-cell contact areas where CD81 comes into contact with the tight-junction proteins occludin, ZO-1, and claudin-1, which was recently described as an HCV coreceptor. Finally, we show that CD81 engagement activates the Raf/MEK/ERK signaling cascade and that this pathway affects postentry events of the virus life cycle. In conclusion, we describe a range of cellular events that are manipulated by HCV to coordinate interactions with its multiple coreceptors and to establish productive infections and find that CD81 is a central regulator of these events.

* Corresponding author. Mailing address: Department of Molecular Immunology, Novartis Vaccines and Diagnostics, via Fiorentina 1, 53100 Siena, Italy. Phone: 39 0577 243436. Fax: 39 0577 3564. E-mail: stefania.crotta{at}novartis.com

{triangledown} Published ahead of print on 25 June 2008.

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

Journal of Virology, September 2008, p. 8316-8329, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00665-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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