title: Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor confers resistance to the antiproliferative effect of interferon-alpha.
abstract: BACKGROUND
  Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a 442 amino acid polypeptide-designated viral interferon regulatory factor (vIRF) that displays homology to members of the interferon regulatory factor (IRF) family that bind to consensus interferon sequences and transactivate cellular genes that can modulate growth inhibition. Studies were conducted to determine whether vIRF affects the growth suppression mediated by interferon-alpha (IFN-alpha) in a human B lymphocyte cell line.
  
  
  METHODS
  The human B lymphocyte cell line Daudi, which is sensitive to the antiproliferative effects of IFN-alpha, was stably transfected to express vIRF, and the proliferative response of vIRF expressing cells to IFN-alpha was compared with controls. The effect of vIRF on IRF- 1 transactivation was analyzed by co-transfection of an IFN-alpha-responsive chloramphenicol acetyltransferase reporter and expression plasmids encoding IRF-1 and vIRF. Electrophoretic mobility shift assays were conducted to determine whether vIRF interferes with the DNA binding activity of IRF-1.
  
  
  RESULTS
  Daudi human B lymphocyte cells expressing vIRF were resistant to the antiproliferative effects of IFN-alpha, whereas wild-type Daudi or Daudi cells transformed with vector DNA were growth inhibited by IFN-alpha. The activation of an interferon-responsive reporter by IFN-alpha or IRF-1 was repressed by expression of vIRF. IRF-1 DNA binding activity was unaffected by vIRF, and vIRF alone did not bind to the interferon consensus sequence.
  
  
  CONCLUSIONS
  These studies revealed that vIRF functions to inhibit interferon-mediated growth control of a human B lymphocyte cell line by targeting IRF-1 transactivation of interferon-inducible genes. Since KSHV is a B lymphotropic herpesvirus associated with two forms of B lymphocyte neoplasms, these effects of vIRF likely contribute to B cell oncogenesis associated with KSHV infection.
authors.affiliation: Howard Hughes Medical Institute, University of Michigan Medical Center, Department of Internal Medicine, Ann Arbor 48109-0650, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Flowers
authors.forename: S P
authors.initials: SP
authors.lastname: Flowers
authors.forename: G J
authors.initials: GJ
authors.lastname: Nabel
mesh_terms: D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000737:chemistry*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology*; D016899:Interferon-beta / Q000235:genetics; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016898:Interferon-alpha; C494258:Irf1 protein, mouse; D009856:Oncogene Proteins, Viral; D010750:Phosphoproteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D016899:Interferon-beta