Regulation of Kaposi's sarcoma-associated herpesvirus reactivation by dopamine receptor-mediated signaling pathways.

Shaoying Lee, Hongyu Deng, Fuqu Yu, William P Melega, Robert Damoiseaux, Kenneth A Bradley, Ren Sun

School of Dentistry, University of California at Los Angeles, Los Angeles, CA, USA.

Journal of acquired immune deficiency syndromes (1999) 2008 Aug 15

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Kaposi's sarcoma-associated herpesvirus (KSHV) possesses two distinct life cycles, lytic replication and latency. An immediate early viral protein, Replication and transcription activator (RTA), is responsible for the virus switch from latency to active replication. To identify cellular pathways that reactivate KSHV replication, an RTA-responsive viral early promoter, PAN, coupled with an enhanced green fluorescent protein (EGFP) reporter was delivered into a KSHV latently infected B cell line. Five different chemical libraries with defined cellular targets were screened for their ability to induce the PAN promoter as an indication of lytic replication. We identified seven chemicals that disrupted latency in KSHV latently infected B cells, five being N-acyl-dopamine derivatives. We showed that these chemicals reactivate KSHV through interacting with dopamine receptors, and that KSHV utilizes dopamine receptors and the associated PKA and MAP kinase pathways to detect and transmit stress signals for reactivation. Our study identified two cellular signaling pathways that mediate KSHV reactivation and provided a chemical genetics approach to identify new endogenous activators with therapeutic potential against herpesvirus associated malignancies.

Citation

Shaoying Lee, Hongyu Deng, Fuqu Yu, William P Melega, Robert Damoiseaux, Kenneth A Bradley, Ren Sun. Regulation of Kaposi's sarcoma-associated herpesvirus reactivation by dopamine receptor-mediated signaling pathways. Journal of acquired immune deficiency syndromes (1999). 2008 Aug 15;48(5):531-40