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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079402-03
Application #
6173889
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1998-07-02
Project End
2003-04-30
Budget Start
2000-06-29
Budget End
2001-04-30
Support Year
3
Fiscal Year
2000
Total Cost
$269,170
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Klass, Carmen M; Krug, Laurie T; Pozharskaya, Veronika P et al. (2005) The targeting of primary effusion lymphoma cells for apoptosis by inducing lytic replication of human herpesvirus 8 while blocking virus production. Blood 105:4028-34
Kaiser, William J; Offermann, Margaret K (2005) Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J Immunol 174:4942-52
Pozharskaya, Veronika P; Weakland, Laura L; Zimring, James C et al. (2004) Short duration of elevated vIRF-1 expression during lytic replication of human herpesvirus 8 limits its ability to block antiviral responses induced by alpha interferon in BCBL-1 cells. J Virol 78:6621-35
Krug, Laurie T; Pozharskaya, Veronika P; Yu, Yimin et al. (2004) Inhibition of infection and replication of human herpesvirus 8 in microvascular endothelial cells by alpha interferon and phosphonoformic acid. J Virol 78:8359-71
Pozharskaya, Veronika P; Weakland, Laura L; Offermann, Margaret K (2004) Inhibition of infectious human herpesvirus 8 production by gamma interferon and alpha interferon in BCBL-1 cells. J Gen Virol 85:2779-87
Kaiser, William J; Kaufman, Jonathan L; Offermann, Margaret K (2004) IFN-alpha sensitizes human umbilical vein endothelial cells to apoptosis induced by double-stranded RNA. J Immunol 172:1699-710
Roan, Florence; Inoue, Naoki; Offermann, Margaret K (2002) Activation of cellular and heterologous promoters by the human herpesvirus 8 replication and transcription activator. Virology 301:293-304
Shaw, Renee N; Waller, Edmund K; Offermann, Margaret K (2002) Induction of human herpesvirus 8 gene expression in a posttransplantation primary effusion lymphoma cell line. Leuk Lymphoma 43:631-4
Harcourt, J L; Offermann, M K (2001) Multiple signaling cascades are differentially involved in gene induction by double stranded RNA in interferon-alpha-primed cells. Eur J Biochem 268:1373-81
Harcourt, J L; Hagan, M K; Offermann, M K (2000) Modulation of double-stranded RNA-mediated gene induction by interferon in human umbilical vein endothelial cells. J Interferon Cytokine Res 20:1007-13

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