Paradoxical response to prophylactic Didox (N-3, 4 trihydroxybenzamide) treatment in murine cytomegalovirus-infected mice

• Published in: Antiviral therapy 2011-01, Vol.16 (8), p.1277-1286
• Main Authors: GO, Vera, TANG-FELDMAN, Yajarayma J, LOCHHEAD, Stephanie R, LOCHHEAD, G. Raymond, YU, Cindy Q, ELFORD, Howard L, INAYAT, Mohammed S, OAKLEY, Oliver R, POMEROY, Claire
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic Agents; Antiviral agents; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Proliferation - drug effects; Cells, Cultured; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts - drug effects; Fibroblasts - immunology; Fibroblasts - virology; Herpesviridae Infections - drug therapy; Herpesviridae Infections - immunology; Herpesviridae Infections - virology; Hydroxamic Acids; Liver - cytology; Liver - drug effects; Liver - immunology; Liver - virology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Medical sciences; Mice; Mice, Inbred BALB C; Murine cytomegalovirus; Muromegalovirus - drug effects; Muromegalovirus - growth & development; Muromegalovirus - immunology; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Spleen - cytology; Spleen - drug effects; Spleen - immunology; Spleen - virology; Treatment Failure; Viral Load; Viral Plaque Assay; Virus Replication
• ISSN: 1359-6535; 2040-2058
• DOI: 10.3851/IMP1893

In this study, we investigated the effect of Didox (DX) on the pathogenicity of and host responses to murine cytomegalovirus (MCMV) infection. 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. 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. 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.