Human herpes virus 8 (HHV8) is a recently identified gamma herpes virus that is associated with and most likely the etiologic agent of both Kaposi's sarcoma (KS) and primary effusion lymphomas. These conditions occur primarily in patients infected with HIV, suggesting that immunosuppression, cytokine dysregulation, or other factors associated with HIV infection may be important factors in the pathogenesis of these diseases, perhaps by altering the host-viral interaction in latently infected cells. The HHV8 genome encodes vIRF, a gene product that has homology to the interferon regulatory factor (IRF) family of transcription factors, a group of related transcription factors that regulate expression of interferon and other antiviral, immunomodulatory and growth regulatory genes. The investigators have demonstrated that vIRF inhibits responses to type I and type II interferons and blocks IRF-1-mediated transcription. This suggests that vIRF joins a number of viral proteins that specifically target components of the host antiviral responses and could further compromise the immunologic status of patients who are already compromised by infection with HIV. Furthermore, IRF-1 is a tumor suppressor gene, and vIRF may contribute to the malignant transformation of HHV8 infected cells in part by inhibiting IRF-1 function. The investigators will investigate the mechanism(s) by which vIRF alters interferon responses and affects gene transcription. They will examine the sensitivity of specific IFN-responsive genes to inhibition by vIRF. They have demonstrated that the inhibition of IRF-1-regulated transcription by vIRF is not a consequence of competition for DNA binding, indicating that the mechanism differs from the competition for binding to the IRF site that occurs in response to IRF2. The investigators have determined that the transactivation domain of IRF-1 is targeted by vIRF, and they propose to refine their analysis of elements within IRF-1 that are affected by vIRF. They will also determine whether the elements in vIRF that are responsible for inhibition of IFN responses are the same or distinct from those that inhibit IRF-1-mediated responses. They will identify and characterize proteins that are involved in vIRF-mediated inhibitory responses. They will extend their studies from in vitro systems to KS lesions and primary effusion lymphoma cells using reagents generated in their laboratory. These studies should offer insight into the mechanism of action by which HHV8-encoded vIRF subverts host antiviral responses and contributes to malignant transformation in HIV infected patients.
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