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Journal of Virology, May 2008, p. 4235-4249, Vol. 82, No. 9
0022-538X/08/$08.00+0     doi:10.1128/JVI.02370-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Latent Gene vFLIP Inhibits Viral Lytic Replication through NF-{kappa}B-Mediated Suppression of the AP-1 Pathway: a Novel Mechanism of Virus Control of Latency{triangledown}

Feng-Chun Ye,1,2,6 Fu-Chun Zhou,1,2,6 Jian-Ping Xie,1,2 Tao Kang,1,2,7 Whitney Greene,1,2 Kurt Kuhne,1,3 Xiu-Fen Lei,1,2,6 Qui-Hua Li,1,3 and Shou-Jiang Gao1,2,3,4,5,6,7*

Tumor Virology Program, Greehey Children's Cancer Research Institute,1 Departments of Pediatrics,2 Microbiology and Immunology,3 Molecular Medicine,4 Medicine,5 Cancer Treatment and Research Center, 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 2 November 2007/ Accepted 19 February 2008

Kaposi's sarcoma-associated herpesvirus (KSHV) latency is central to the evasion of host immune surveillances and induction of KSHV-related malignancies. The mechanism of KSHV latency remains unclear. Here, we show that the KSHV latent gene vFLIP promotes viral latency by inhibiting viral lytic replication. vFLIP suppresses the AP-1 pathway, which is essential for KSHV lytic replication, by activating the NF-{kappa}B pathway. Thus, by manipulating two convergent cellular pathways, vFLIP regulates both cell survival and KSHV lytic replication to promote viral latency. These results also indicate that the effect of the NF-{kappa}B pathway on KSHV replication is determined by the status of the AP-1 pathway and hence provide a mechanistic explanation for the contradictory role of the NF-{kappa}B pathway in KSHV replication. Since the NF-{kappa}B pathway is commonly activated during infection of gammaherpesviruses, these findings might have general implications for the control of gammaherpesviral latency.

* Corresponding author. Mailing address: Tumor Virology Program, Greehey 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

{triangledown} Published ahead of print on 27 February 2008.

Journal of Virology, May 2008, p. 4235-4249, Vol. 82, No. 9
0022-538X/08/$08.00+0     doi:10.1128/JVI.02370-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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