) 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 herpesvirus HHV-8/KSHV which was also found in a subset of AIDS immunoblastic lymphomas, pleural effusion lymphomas (PEL). It is assumed that HHV-8 plays a role in the pathogenicity of these diseases. HHV-8 is a B-cell tropic virus that encodes a number of nonstructural genes, including open reading frames (ORFs) that are homologous to the cellular proteins of the IRF family. The IRF proteins represent a group of DNA binding proteins that modulate response to viral infection and play a critical role in diverse cellular responses. We have recently identified two new members of this family (IRF-3 and IRF-7) that functions as a mediator of virus-induced signaling and play a critical role in the induction of early inflammatory genes in infected cells. The observation that a known pathogenic human herpes virus, HHV-8, encodes ORFs homologous to the proteins of the IRF family prompted us to examine the functional properties of these vIRFs. In the proposed application, we plan to focus on two novel HHV- 8-encoded vIRFs, vIRF-2 and vIRF-3, that we have recently cloned. The preliminary characterization of vIRFs show that they encode proteins of 18 and 40-kDa, respectively and are expressed in BCLB-1 cells. The properties of vIRF-2 are distinct from vIRF-1. In the proposed study, we plan (Aim#1) to further characterize the vIRF-2 and vIRF-3 proteins and their interaction with cellular IRFs.
In Aim#2, we will determine whether they can modulate host responses to virus- and IFN/cytokine-induced signaling.
In Aim #3, we will analyze the potential role of the vIRFs in cell growth and apoptosis and analyze the molecular mechanism of these effects. Furthermore we will identify the genes targeted by these vIRFs. We will also analyze the expression of vIRF-2 and vIRF-3 in PEL tumors and Kaposi sarcoma lesions. The results of these studies should allow us to compare the properties of the vIRF-2 and vIRF-3 proteins with vIRF-1 as well as with the cellular IRFs and evaluate the role of vIRFs in AIDS-associated malignancies. Thus, the proposed study will provide functional characterization of vIF-2 and vIRF-3 and will establish the possible contribution of these two vIRFs to AIDS- associated malignancies. Furthermore, the results of this study may provide a new foundation for clinical treatment.
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