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Journal of Virology, August 2006, p. 7965-7975, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00689-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Latent Protein LANA Interacts with HIF-1 To Upregulate RTA Expression during Hypoxia: Latency Control under Low Oxygen Conditions

Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, Pennsylvania

Received 5 April 2006/ Accepted 31 May 2006

Hypoxia can induce lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) in primary effusion lymphoma (PEL) cells. However, the molecular mechanism of lytic reactivation of KSHV by hypoxia remains unclear. Here we show that the latency-associated nuclear antigen (LANA), which plays a crucial role in modulating viral and cellular gene expression, directly associated with a low oxygen responder, hypoxia-inducible factor-1 (HIF-1). LANA enhanced not only the transcriptional activities of HIF-1 but also its mRNA level. Coimmunoprecipitation and immunofluorescence studies documented a physical interaction between LANA and HIF-1 in transiently transfected 293T cells as well as in PEL cell lines during hypoxia. Through sequence analysis, several putative hypoxia response elements (HRE-1 to -6) were identified in the essential lytic gene Rta promoter. Reporter assays showed that HRE-2 (–1130 to –1123) and HRE-5 and HRE-6 (+234 to +241 and +812 to +820, respectively, within the intron sequence) were necessary and sufficient for the LANA-mediated HIF-1 response. Electrophoretic mobility shift assays showed HIF-1-dependent binding of a LANA protein complex specifically to the HRE-2, -5, and -6 motifs within the promoter regulatory sequences. This study demonstrates that hypoxia-induced KSHV lytic replication is mediated at least in part through cooperation of HIF-1 with LANA bound to the HRE motifs of the Rta promoter.

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