ANTIVIRAL AND IMMUNOMODULATING INHIBITORS OF EXPERIMENTALLY-INDUCED PUNTA-TORO VIRUS-INFECTIONS

A major component of a US Army Medical Research and Development Comman d-supported program to discover and develop new drugs for the treatmen t of Rift Valley fever, sandfly fever, and Crimean-Congo hemorrhagic f ever has been to study candidate test materials against hepatotropic i nfections of C57BL/6 mice induced by the related but less biohazardous Punta Toro virus (PTV). The effects of 75 compounds, some of which we re considered immunomodulators in their primary mechanism of activity, were studied in the PTV infection model. Of these, ribavirin, ribamid ine, ribavirin 2',3',5'-triacetate, tiazofurin, tiazofurin-5'-monophos phate, tiazofurin-2',3',5'-triacetate, selenazofurin, pyrazofurin, 3-d eazaguanine, and 3-deazaguanosine were considered significantly inhibi tory, acting against the infection by a direct antiviral (non-immunomo dulatory) fashion. These compounds had therapeutic indices (TI) rangin g from greater than or equal to 5 to 65, using increased survivors as the evaluation parameter. Immunomodulators considered significantly in hibitory to this infection were poly (ICLC), ampligen, human recombina nt interferon-alpha-A/D, MVE-1, MVE-2, AM-3, AM-5, mannozym, bropirimi ne, CL246,738, phenyleneamine, and 7-thia-8-oxoguanosine. Utilizing in creased survivor numbers as measure of activity, these inhibitors had TI ranging from greater than or equal to 16 to 1000. Other antiviral e ffects exerted by the active compounds included reduction of hepatic i cterus, lowered serum glutamic oxaloacetic and pyruvic acid transamina ses, and inhibition of recoverable serum and liver virus titers. The a ctive immunomodulators were significantly effective when therapy was i nitiated as late as 48 h after virus inoculation, at a time when clini cal signs of the PTV disease were being manifested in the animal.