Clearance of a Persistent Human Enterovirus Infection of the Mouse Central Nervous System by the Antiviral Agent Disoxaril

Abstract

Enteroviruses can cause persistent central nervous system (CNS) infections in agammaglobulinemic individuals. Because these infections are rarely cured by passive administration of antibody, a chemotherapeutic approach would be advantageous. In this study, the efficacy of the antienterovirus (and antipicornavirus) drug disoxaril was demonstrated in a murine model of persistent enterovirus infection. Disoxaril is a hydrophobic antiviral compound that blocks picornavirus uncoating. The W-2 strain of human poliovirus type 2 (PV2) persists in the CNS of immunosuppressed mice and causes late paralysis. Mice were inoculated intracerebrally with PV2, immunosuppressed with cyclophosphamide, and treated intragastrically with disoxaril at 50, 100, or 200 mg/kg per day in two divided doses beginning on postinfection day 20. At 200 mg/kg per day, disoxaril significantly decreased the incidence of clinical disease, i.e., paralysis and death. Assays for virus revealed more rapid clearance of virus from the CNS in the drug-treated group. No drug-associated toxicity was observed. Residual isolates of virus were not drug-resistant, suggesting that the appearance of drug resistance during prolonged treatment may not be a clinical problem.

Selective inhibitors of picornavirus replication

“…[62][63][64] Arildone or disoxaril in combination with other known picornavirus inhibitors mostly demonstrated synergistic activities in vitro as well as in mice. [65][66][67][68] Mechanism of action studies with HRV-2 and poliovirus revealed that disoxaril and analogues prevented viral uncoating.…”

Antiviral Therapy for Enteroviruses and Rhinoviruses

“…Infected animals develop flaccid limb paralysis as a result of infection and intragastric administration of a capsid-inhibitor agent is capable of preventing the development of paralysis (Woods et al, 1989;. Adult mice can be infected intracranially with poliovirus and protected from development of paralysis by oral administration of capsid-inhibitor agents (Buontempo et al, 1997;McKinlay & Steinburg, 1986;Jubeit et al, 1989). Similarly, coxsackievirus B3 can infect adult mice result-ing in myocarditis with involvement of multiple organ systems (Klingel et al, 1996); again, a capsid function inhibitor has been shown to be orally effective in markedly reducing viral titres in all organs tested and preventing death of the mice in this latter model system (Pevear et al, 1999).…”

Picornavirus inhibitors

“…The W-2 strains of poliovirus type 2 can cause persistent infections in the CNS of immunosuppressed mice. Disoxazil treatment of these mice significantly decreased the incidence of disease and induced a rapid clearance of the virus from the CNS (Jubelt et al, 1989). Unfortunately, side effects appear in patients when high oral doses of this compound are given .…”