CRITICAL ROLE OF HHV8 ENCODED IRF IN AIDS LYMPHOMAS

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DESCRIPTION: Two major AIDS-associated malignancies are Kaposi sarcoma (KS) and Non-Hodgkin's lymphoma (NHL). Nearly all KS lesions examined contained a novel type of gamma herpes virus HHV-8/KSHV which was also found in a subset of AIDSimmunoblastic lymphomas, pleural effusion lymphomas (PEL). It is assumed that HHV-8 plays a role in the pathogenicity of these diseases. The HHV-8 is a B-cell tropic virus that encodes a number of nonstructural genes encoding homologues of cell regulatory and signaling proteins. It also encodes four open reading frames (ORF) that are homologous to the cellular proteins of the IRF family. The family of IRF proteins represent a group of DNA binding proteins that modulate response to viral infection as well as play a critical role in diverse cellular responses such as apoptosis, homeostasis,maturation of lymphoid cells and function as tumor suppressor genes. The 5q31.3chromosomal deletion containing IRF-1 is often found in leukemia. The investigators have been interested in the role of IRF factors in the virus-mediated transcriptional regulation of IFN and IFN-induced genes and recently, identified a new member of this family (IRF-3) that modulates the growth regulatory and antiviral responses of the other members of the IRF family. The observation that a known pathogenic human herpesvirus, HHV-8, encodes four ORFs homologous to the proteins of the IRF family prompted them to examine the role of vIRF in oncogenesis. Specifically, they plan: (AIM#1) to characterize the vIRF protein; (AIM#2) to determine whether it can modulate host responses to virus- and IFN/cytokine-induced signaling; (AIM#3) to analyze the potential role of vIRF in cell growth and apoptosis; and finally, (AIM#4) to assess in vivo the impacts of vIRF expression to lymphoid tumorigenesis by targeting the expression of vIRF into B-cells in mice. Thus, the results of these studies should allow them to compare the properties of vIRF protein(s) with the cellular IRFs as well as to evaluate its tumorigenic potential in vivo within the B-cell lineage. Lastly, the vIRF transgenic mice may represent an experimental model for future therapeutical studies of AIDS-associated lymphomas.