Anti-Herpesvirus Action of Isoprinosine

Abstract

Anti-herpesvirus effects of Isoprinosine were found to be condition-dependent in vitro and in vivo. A herpes type 1 strain, grown in primary rabbit kidney cells, was not susceptible to Isoprinosine when cytopathic effect was evaluated, but was modestly inhibited when plaque-forming methocel overlay was used in the same cell line. However, the growth of a herpes type 2 strain was inhibited by Isoprinosine in this system when cytopathic effect was evaluated. Both viruses produced an encephalitis in hamsters after application by corneal abrasion. The encephalitis produced by a 1.5 mean lethal dose of herpesvirus was strikingly suppressed by large doses of Isoprinosine given ad libitum in the drinking water; this protection was not seen, however, at 15 mean lethal doses. Anti-herpes effects of Isoprinosine were suppressed by additional treatment with cortisone, both in tissue culture and in vivo. Isoprinosine, in the absence of virus infection, produced significant effects on the metabolism, structure, and function of brain ribosomes. In vivo, RNA components were labeled more rapidly and gave up their radioactivity more slowly after treatment with Isoprinosine. This enhanced cytoplasmic radioactivity was associated with a loss of incorporated radioactivity located in the nucleus and an increase in radioactivity located in a ribonucleoprotein fraction >4S and <18S. Ribosomes from treated brains gave physical evidence of being more compact (less orthochromic). Isoprinosine treatment increased the incorporation of ["CC]phenylalanine into nascent protein in a cell-free system examining protein synthesis in brain polyribosomes. The addition of the exogenous messenger ribonucleic acid, polyuridylic acid, produced a significant age-dependent inhibition in the incorporation of [IC ] phenylalanine. This inhibition was significantly greater when ribosomes were isolated from animals pretreated with Isoprinosine. These and other observations suggest that the Isoprinosine stimulation of host ribonucleic acid metabolism may be coupled to the production of ribosomes that do not effectively translate exogenous messenger ribonucleic acid.Isoprinosine (methisoprinol, NPT-10381) was first reported by us (8,9), and then by others (4, 17), to exert antiviral activity in vitro and in vivo. In the present study, we determine the conditions that permit a generation of antiviral effects by Isoprinosine against herpes simplex virus in tissue culture systems and in one standard in vivo system, hamster encephalitis.Although the mechanism of antiviral action of Isoprinosine is not yet understood, we have previously reported effects of the drug on the rapid incorporation of RNA and protein precursors into polyribosomes of uninfected and influenza virus-infected monkey kidney cells (8,9), and in uninfected rat brain (7). In the present 'Present address:

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