Effective treatment of experimental cytomegalovirus-induced encephalo-meningitis in immunocompromised rats with HPMPC

Abstract

Cytomegalovirus (CMV)-induced encephalomeningitis is a dramatic complication in patients with the acquired immunodeficiency syndrome (AIDS) and treatment of this infection remains a major clinical problem. In order to study the pathogenesis and treatment of CMV-induced encephalomeningitis, we experimentally induced intracranial rat CMV (RCMV) infection in rats that were immunosuppressed by total body X-irradiation. CMV infection was monitored by viral plaque assay for estimation of the viral load. CMV-induced pathology, the presence of CMV-infected cells, as well as the presence of T-lymphocytes and monocytes/macrophages were studied by histopathologic and immunohistochemical staining techniques. The meninges showed CMV infection in mononuclear infiltrative cells and in endothelium of small blood vessels 8 days after intracerebral inoculation. This was accompagnied by multiple haemorraghes and inflammatory cell infiltration. The infection and inflammatory response persisted for at least 21 days p.i. Animals were treated with ( S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), hyperimmune serum (HIS) and both DHPG and HIS combined. Treatment with one dosage of HPMPC at 20 mg/kg effectively reduced virus titers. However, all other treatment modalities were not effective. In conclusion, the pathology of RCMV-induced encephalomeningitis in immunocompromised rats closely resembles that of AIDS patients. The infection is effectively treated by HPMPC.