Human herpesvirus 8 (HHV-8), the primary etiologic agent of Kaposi's sarcoma (KS), encodes vGPCR, a homologue of the human IL-8 receptor and a member of the G protein coupled receptor (GPCR) family. vGPCR, encoded by HHV-8 open reading frame 74, activates transcription factors including NFkappaB and NF- AT and induces expression of cytokines and cell surface adhesion molecules regulated by these factors. Expression of vGPCR in Tg mice causes KS-like tumors, and we have derived a cell line from one of these tumors that retains expression of vGPCR and tumorigenicity in nude mice. We have previously shown that ritonavir, a protease inhibitor used to treat HIV infection, inhibits NFkappaB activation. Preliminary studies suggest that ritonavir also inhibits NF-AT activation. Ritonavir inhibits tumorigenesis in a nude mouse xenotransplant model using human KS-derived HHV-8-negative cell lines. We propose characterizing the mechanisms of inhibition by ritonavir of vGPCR-mediated signaling and tumorigenesis. These studies will include identifying the signaling pathways through which ritonavir inhibits NFkappaB and NF-AT activation and determining whether inhibition of NFkappaB and/or NF-AT activation by ritonavir inhibits vGPCR-dependent tumorigenesis in nude mice. These studies will show whether ritonavir blocks the activities of HHV-8 vGPCR in vitro and in vivo and whether it has an anti-KS activity independent of its anti-retro viral activity. Consequently, the results may provide a rationale for developing new therapeutic alternatives for KS. The findings could have a more general applicability to other cancers. [unreadable] [unreadable] [unreadable]