title: Inhibition of primary effusion lymphoma engraftment in SCID mice by morpholino oligomers against early lytic genes of Kaposi's sarcoma-associated herpesvirus.
abstract: BACKGROUND
  Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with several malignant diseases, including Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease. The objectives of this study were to investigate the use of peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) against KSHV early lytic genes and to assess their efficacy in severe combined immunodeficiency disease (SCID) mice against PEL engraftment. PPMOs are short, single-stranded DNA analogues that contain a backbone of morpholine rings and phosphorodiamidate linkages and have high delivery efficiency into cells.
  
  
  METHODS
  PEL cells were treated with PPMOs against viral interferon regulatory factor 1 (vIRF-1) and expression of vIRF-1 was analysed. PPMOs against vIRF-1 and viral interleukin-6 (vIL-6) were evaluated against PEL cell engraftment in SCID mice. The PPMOs were incubated with BCBL-1 cells and then introduced into the peritoneal cavities of SCID mice, followed by 9 more doses of PPMOs administered at 2-day intervals. At weeks 3 and 9 after BCBL-1 delivery, peritoneal lavage was collected and the ratio of PEL cells among total cells was determined by flow cytometry analysis.
  
  
  RESULTS
  Treatment of PEL cells with PPMOs against vIRF-1 led to a reduction of vIRF-1 expression in a dose-dependent manner. Reduction of vIRF-1 expression resulted in higher levels of cellular interferon regulatory factor 3 and of signal transducer and activator of transcription 1. SCID mice receiving a PPMO against vIL-6 had no engraftment of PEL cells and remained healthy throughout the 120-day study.
  
  
  CONCLUSIONS
  This study showed that PPMOs can be effective antiviral agents against KSHV. Blocking the expression of early lytic genes might be beneficial for the control of KSHV-associated malignant diseases.
authors.affiliation: VA-MD Regional College of Veterinary Medicine, University of Maryland, College Park, MD, USA. zhangyj@umd.edu
authors.forename: Yan-Jin
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Deendayal
authors.initials: D
authors.lastname: Patel
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Nan
authors.forename: Sumin
authors.initials: S
authors.lastname: Fan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000235:genetics; D019288:Herpesvirus 8, Human / Q000187:drug effects / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D060172:Morpholinos / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D050794:STAT1 Transcription Factor / Q000187:drug effects / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000473:pathology / Q000821:virology; D016511:Severe Combined Immunodeficiency / Q000235:genetics; D014162:Transfection; D014764:Viral Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D050835:Interferon Regulatory Factors; D015850:Interleukin-6; D060172:Morpholinos; D050794:STAT1 Transcription Factor; D014764:Viral Proteins; C413486:viral interferon regulatory factors