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Journal of Virology, January 2003, p. 1524-1539, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1524-1539.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Induces the Phosphatidylinositol 3-Kinase-PKC-{zeta}-MEK-ERK Signaling Pathway in Target Cells Early during Infection: Implications for Infectivity

Pramod P. Naranatt,1 Shaw M. Akula,1 Christopher A. Zien,2 Harinivas H. Krishnan,1 and Bala Chandran1*

Department of Microbiology, Molecular Genetics and Immunology,1 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 661602

Received 2 July 2002/ Accepted 11 October 2002

Human herpesvirus 8 (HHV-8) is implicated in the pathogenesis of Kaposi's sarcoma. HHV-8 envelope glycoprotein B (gB) possesses the RGD motif known to interact with integrin molecules, and HHV-8 infectivity was inhibited by RGD peptides, by antibodies against {alpha}3 and ß1 integrins, and by soluble {alpha}3ß1 integrin (S. M. Akula, N. P. Pramod, F.-Z. Wang, and B. Chandran, Cell 108:407-419, 2002). Anti-gB antibodies immunoprecipitated the virus {alpha}3 and ß1 complexes, and virus-binding studies suggest a role for {alpha}3ß1 in HHV-8 entry. HHV-8 infection induced the integrin-mediated activation of focal adhesion kinase (FAK), implicating a role for integrin and the associated signaling pathways in HHV-8 entry into the target cells. Immediately after infection, target cells exhibited morphological changes and cytoskeletal rearrangements, suggesting the induction of signal pathways. As early as 5 min postinfection, HHV-8 activated the MEK-ERK1/2 pathway. The focal adhesion components phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase C-{zeta} (PKC-{zeta}) were recruited as upstream mediators of the HHV-8-induced ERK pathway. Anti-HHV-8 gB-neutralizing antibodies and soluble {alpha}3ß1 integrin inhibited the virus-induced signaling pathways. Early kinetics of the cellular signaling pathway and its activation by UV-inactivated HHV-8 suggest a role for virus binding and/or entry but not viral gene expression in this induction. Studies with human {alpha}3 integrin-transfected Chinese hamster ovary cells and FAK-negative mouse DU3 cells suggest that the {alpha}3ß1 integrin and FAK play roles in the HHV-8 mediated signal induction. Inhibitors specific for PI 3-kinase, PKC-{zeta}, MEK, and ERK significantly reduced the virus infectivity without affecting virus binding to the target cells. Examination of viral DNA entry suggests a role for PI 3-kinase in HHV-8 entry into the target cells and a role for PKC-{zeta}, MEK, and ERK at a post-viral entry stage of infection. These findings implicate a critical role for integrin-associated mitogenic signaling in HHV-8's infection of target cells and suggest that, by orchestrating the signal cascade, HHV-8 may create an appropriate intracellular environment to facilitate the infection.

* Corresponding author. Mailing address: Department of Microbiology, Molecular Genetics and Immunology, The University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160. Phone: (913) 588-7043. Fax: (913) 588-7295. E-mail: bchandra{at}kumc.edu.

Journal of Virology, January 2003, p. 1524-1539, Vol. 77, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.2.1524-1539.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cheshenko, N., Liu, W., Satlin, L. M., Herold, B. C. (2005). Focal Adhesion Kinase Plays a Pivotal Role in Herpes Simplex Virus Entry. J. Biol. Chem. 280: 31116-31125 [Abstract] [Full Text]  


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