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7-thia-8-oxoguanosine (TOGuo) is the first reported structure of a family of modified guanosine analogues exhibiting antiviral activity in rodent models. Its spectrum of action includes interferon-sensitive viruses such as alphaviruses, bunyaviruses, corona viruses, flaviviruses, picornaviruses and, to a lesser extent, herpesviruses. Early treatment before or shortly after virus challenge is necessary to protect animals from mortality. The protective effect of TOGuo against Semliki Forest and Punta Toro viruses can be eliminated by co-treatment with antibody to alpha/ beta-interferon. indicating that interferon induction is of prime importance for antiviral activity against these two viruses. Immunological studies indicate that the nucleoside induces alpha-interferon and activates B cells, natural killer cells, antibody-dependent cytotoxic cells and macrophages. TOGuo also has adjuvant activity, since its use in combination with a killed Ll210 leukemia cell vaccine greatly reduced the mortality of mice inoculated with live Ll210 leukemia cells compared with the vaccine used alone. Several related guanosine analogues show similar antiviral and immunoenhancing properties, including 7-methyl-8-oxoguanosine, 7-methyl-8-thioxoguanosine and 7-deazaguanosine. These studies indicate that certain modifications at the 7 and 8 positions of guanosine may confer antiviral and immunostimulatory properties to nucleoside analogues.

Biological response modifiers (BRMs) have particular promise when used in combination with more standard antiviral agents for treatment of viral diseases. Reported here are a series of studies which have used two BRMs in combination with the antiviral drug, ribavirin (l-β-o-ribofuranosyl-1,2,4-triazole-3-carboxamide) in treatment of experimentally-induced phlebovirus (Punta Toro virus) infections in mice. The positive BRMs studied include bropirimine (2-amino-5-bromo-6-phenyl-4[3H]pyrimidinone) given orally at dosages of 25, 50 and 100 mg/kg/day beginning 24 h after virus inoculation. and 7-thia-8-oxoguanosine administered intrapcritoneally at dosages of 6.3, 12.5 and 25 mg/kg/day given 24 and 31 h after virus inoculation. In each experiment. multiple dosages of both BRM and ribavirin were selected to range from ineffective levels to, in certain cases with ribavirin, lethally toxic levels. Ribavirin was always administered orally twice daily for three days starting 24 h after virus inoculation. Both drug combinations were considered synergistic, increasing the therapeutic index compared to either drug used alone, and significantly reducing the evidence of ribavirin toxicity. Efficacy was seen as increased survivors, decreased virus recovery from tissues and blood. and lowered glutamic oxalic and pyruvic transaminase levels in the serum.

Cytokines are attracting increased interest as potential therapies for human immunodeficiency virus (HIV) infections. This attraction has particularly arisen as these cytokines have become more commercially available through recombinant technologies. This review focuses on the effects of these biological response modifiers on preclinical HIV and related retrovirus infections. Cytokines that have particularly been considered for HIV disease control include: interferons -α , -β and -γ, interleukins-2. -3. -4. -6 and -7; tumour necrosis factors -α and -β; and the colony stimulating factors. Efficacy has especially been seen when these cytokines have been used in combination with the more conventional antiviral agents. Due to the many biological functions exerted by cytokines and their interweaving of biological effects with other cytokines, they appear to have the potential to both inhibit as well as enhance viral infections, depending upon how they are used, and caution is therefore urged in their use.