title: Paradoxical response to prophylactic Didox (N-3, 4 trihydroxybenzamide) treatment in murine cytomegalovirus-infected mice.
abstract: BACKGROUND
  In this study, we investigated the effect of Didox (DX) on the pathogenicity of and host responses to murine cytomegalovirus (MCMV) infection.
  
  
  METHODS
  In vitro efficacy of DX against MCMV was determined using plaque reduction assays. For in vivo studies, mice infected with a sublethal dose (10(4) PFU) of MCMV were treated daily with DX (200 mg/kg) using either a prophylactic or delayed protocol. At predetermined intervals, target organs were removed for histopathology. Cytokine transcription and viral load were performed using real-time PCR. Serum cytokine levels were determined by ELISA, and T-cell markers by real-time PCR.
  
  
  RESULTS
  DX (0.5-50 μM) inhibited MCMV plaque formation in vitro. However, in vivo, prophylactic DX treatment did not decrease viral load and prolonged hepatic proinflammatory cytokine transcription at days 3 and 5 post-infection, which corresponded with more severe histopathological changes observed in the liver. Significant CD8(+) T-cell marker suppression was seen, in accordance with DX-induced inhibition of lymphocyte proliferation observed in vitro. DX prolonged the recovery of MCMV-infected mice when given after infection was established.
  
  
  CONCLUSIONS
  Despite promising MCMV inhibition in vitro, DX had no beneficial effect on MCMV disease in our model and paradoxically had adverse effects when administered prophylactically. The lack of correlation between in vitro activity and in vivo efficacy emphasizes the importance of selecting appropriate antiviral targets and of using animal models when testing new drugs.
authors.affiliation: Department of Internal Medicine, University of California, Davis Health System, Sacramento, CA, USA. Vera.Go@ucdmc.ucdavis.edu
authors.forename: Vera
authors.initials: V
authors.lastname: Go
authors.forename: Yajarayma J
authors.initials: YJ
authors.lastname: Tang-Feldman
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Lochhead
authors.forename: G Raymond
authors.initials: GR
authors.lastname: Lochhead
authors.forename: Cindy Q
authors.initials: CQ
authors.lastname: Yu
authors.forename: Howard L
authors.initials: HL
authors.lastname: Elford
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Inayat
authors.forename: Oliver R
authors.initials: OR
authors.lastname: Oakley
authors.forename: Claire
authors.initials: C
authors.lastname: Pomeroy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D000998:Antiviral Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006877:Hydroxamic Acids; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D017211:Treatment Failure; D019562:Viral Load; D010948:Viral Plaque Assay; D014779:Virus Replication
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D016207:Cytokines; D006877:Hydroxamic Acids; C035419:3,4-dihydroxybenzohydroxamic acid