Considerable evidence implicates human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma herpesvirus (KSHV), as the necessary etiologic agent of Kaposi's sarcoma (KS). Although the mechanisms of KS pathogenesis by HHV-8 are not well understood, recent evidence suggests that expression of paracrine factors by cells undergoing lytic phase viral replication is important. The HHV-8 chemokine receptor homologue ORF74, a lytic phase gene product, activates several signaling pathways in the absence of added ligand, including NFkB, NF-AT and AP-1, and induces the expression of pro-inflammatory cytokines and cell adhesion molecules. We hypothesize that activation of NFkappaB, NF-AT and AP-1 depends on signaling via the PI-3 kinase-Akt pathway and causes the expression of pro-inflammatory factors, and that chronic dysregulated expression of these factors eventually results in tumor formation. Co-infection with HIV-1 is an extremely strong risk factor for KS development. We hypothesize that the Tat protein of HIV-1 synergizes with ORF74 in activating NFkappaB, NF-AT and AP-1 through the PI-3 kinase-Akt pathway and enhances ORF74-mediated tumorigenesis. The central hypothesis is that Akt is the key mediator of these ORF74-dependent processes. To test these hypotheses, we will characterize ORF74 activation of NFKappaB, NF-AT and AP-1 and induction of pro-inflammatory and anti-apoptotic factors via PI-3 kinase-Akt and will determine whether ORF74-mediated tumorigenesis in a mouse model depends on activation of NFkappaB, NFAT and AP-1 via PI-3 kinase-Akt and GSK-3. We will also determine whether Tat augments ORF74 activation of NFkappaB, NF-AT and AP-1 via PI-3 kinase-Akt and GSK-3 and enhances ORF74 tumorigenesis in mice. These studies should provide valuable insights on the contribution of ORF74 to KS pathogenesis and show a mechanism by which HIV-1 cooperates with HHV-8 in causing KS.
| Guo, Hong-Guang; Pati, Shibani; Sadowska, Mariola et al. (2004) Tumorigenesis by human herpesvirus 8 vGPCR is accelerated by human immunodeficiency virus type 1 Tat. J Virol 78:9336-42 |
