Increased IL6 Transcription by HHV8

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DESCRIPTION: (provided by applicant) The human herpesvirus 8 (HHV8) has been associated with three neoplasms: primary effusion lymphoma, Kaposi's sarcoma, and multicentric Castleman' s disease in human immunodeficiency virus (HIV)-related and -unrelated cases. In addition, there is evidence that HHV8 may be present in the bone marrow of multiple myeloma patients. While HHV8 is not ubiquitous in the general population (10-15 percent seroprevalence), evidence of exposure to HHV8 is quite high (60-70 percent) in the homosexual HIV-positive population. One common feature amongst all HHV8-associated neoplasms is that they utilize interleukin 6 (IL-6) as a tumor growth factor. IL-6 may also facilitate HIV infection, as it induces the proliferation of HTV in HIV infected monocytes and CD4-positive T cells. Thus, we initially hypothesized that an HFIV8 encoded protein upregulates IL-6 expression. In preliminary data we successfully demonstrated that the HHV8 latent proteins, latency associated nuclear antigen (LANA) and Fas associated death domain like interferon converting enzyme inhibitory protein (vFLIP), upregulate cellular IL-ti expression. We have shown that LANA transactivates the IL-6 promoter through the API response element, LANA directly binds to the APi response element, and vFLIP functions through activation of the NF-kappaB and APi transcription factors. Furthermore, vFLIP potentiates LANA-induced IL-6 expression and vice versa. In this proposal, our specific aims are: 1. Elucidate the relevant DNA-protein interactions involved in LANA-mediated transactivation of the LL-6 promoter. 2. Identify the protein-protein interactions involved in LANA transactivation of the IL-6 promoter. 3. Establish the importance of vFLIP and LANA in the induction of IL-6 expression as well as proliferation and inhibition of apoptosis in endogenously HHVS-infected cells, and characterize the molecular interactions between vFLIP and LANA that result in their reciprocal potentiation of IL-6 induction. Our long-term objective is to identify the molecular mechanisms involved in HHVS -mediated upregulation of cellular IL-6 production. The identification of the specific domains of LANA or vFLIP that are involved in the augmentation of IL-ti expression might provide a natural target for drug development to inhibit the effects of these proteins in HHV8 infected malignant cells.