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Journal of Virology, June 2006, p. 5371-5382, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02299-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Modulation of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by MEK/ERK, JNK, and p38 Multiple Mitogen-Activated Protein Kinase Pathways during Primary Infection

Hongyi Pan,1,2 Jianping Xie,1,2 Fengchun Ye,1,2 and Shou-Jiang Gao1,2,3,4,5,6,7*

Tumor Virology Program, Children's Cancer Research Institute,1 Departments of Pediatrics,2 Microbiology and Immunology,3 Medicine,4 Molecular Medicine,5 San Antonio Cancer Institute, The University of Texas Health Science Center, San Antonio, Texas,6 Tumor Virology Group, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China7

Received 1 November 2005/ Accepted 20 March 2006

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma, a dominant AIDS-related tumor of endothelial cells, and several other lymphoproliferative malignancies. While activation of the phosphatidylinositol 3-kinase-protein kinase C-MEK-ERK pathway is essential for KSHV infection, we have recently shown that KSHV also activates JNK and p38 mitogen-activated protein kinase (MAPK) pathways during primary infection (J. Xie, H. Y. Pan, S. Yoo, and S.-J. Gao, J. Virol. 79:15027-15037, 2005). Here, we found that activation of both JNK and p38 pathways was also essential for KSHV infection. Inhibitors of all three MAPK pathways reduced KSHV infectivity in both human umbilical vein endothelial cells (HUVEC) and 293 cells. These inhibitory effects were dose dependent and occurred at the virus entry stage of infection. Consistently, inhibition of all three MAPK pathways with dominant-negative constructs reduced KSHV infectivity whereas activation of the ERK pathway but not the JNK and p38 pathways enhanced KSHV infectivity. Importantly, inhibition of all three MAPK pathways also reduced the yield of infectious virions during KSHV productive infection of HUVEC. While the reduction of infectious virions was in part due to the reduced infectivity, it was also the result of direct modulation of KSHV lytic replication by the MAPK pathways. Accordingly, KSHV upregulated the expression of RTA (Orf50), a master transactivator of KSHV lytic replication, and activated its promoter during primary infection. Furthermore, KSHV activation of RTA promoter during primary infection was modulated by all three MAPK pathways, predominantly through their downstream target AP-1. Together, these results indicate that, by modulating multiple MAPK pathways, KSHV manipulates the host cells to facilitate its entry into the cells and postentry productive lytic replication during primary infection.

* Corresponding author. Mailing address: Tumor Virology Program, Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229. Phone: (210) 562-9030. Fax: (210) 562-9014. E-mail: gaos{at}uthscsa.edu.

Journal of Virology, June 2006, p. 5371-5382, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02299-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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