isatoribine-anhydrous and Disease-Models--Animal

We employed the Rauscher murine leukemia virus (RMuLV) as a murine retrovirus model of AIDS, to test biological response modifiers (BRM) and antiviral agents for potential therapeutic activity against the human immunodeficiency virus (HIV). We examined the relationship between the augmentation of natural killer (NK) cell activity and antiviral efficacy of a series of BRM, most of which are known inducers of interferon, in this model. Poly [I,C]-LC, MVE-2, and CL 246,738, but not Ampligen, soluble glucan, or 7-thia-8-oxoguanosine, consistently produced antiviral activity. In addition, the combination of suboptimal doses of oral 3'-azido-3'-deoxythymidine (AZT) (in drinking water) and poly [I,C]-LC produced a synergistic antiviral effect. With all the BRM tested, a consistent pattern emerged, namely that antiviral activity always correlated with the augmentation of splenic NK cell activity in infected animals. For instance, poly [I,C]-LC boosted NK activity much more in infected mice treated therapeutically (treatment initiated after infection) than prophylactically (treatment initiated before infection), and it had greater antiviral activity therapeutically than prophylactically. For the BRM tested, antiviral activity did not occur without augmentation of NK activity in infected mice. In contrast, augmentation of NK activity in uninfected mice bore no relationship to antiviral activity. Furthermore, elimination of NK cells by treating mice with anti-asialo GM1 abolished the antiviral activity of poly [I,C]-LC. Although splenic NK activity was ablated by anti-asialo GM1, serum interferon levels were not affected by this treatment. These results point to a causal connection between the augmentation of NK cell activity and the antiviral efficacy of these BRM in this murine AIDS model. NK cells thus appear to play a key role in resistance to this retrovirus, as has been suggested for HIV.

Topics: Acquired Immunodeficiency Syndrome; Acridines; Animals; Antibodies; Antiviral Agents; Asialoglycoproteins; Disease Models, Animal; Drug Synergism; Female; G(M1) Ganglioside; Glucans; Guanosine; Immunologic Factors; In Vitro Techniques; Killer Cells, Natural; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Poly I-C; Poly U; Pyran Copolymer; Rabbits; Rauscher Virus; Specific Pathogen-Free Organisms; Viral Plaque Assay; Zidovudine

A novel thiazolopyrimidine nucleoside, 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (7-thia-8-oxoguanosine), was evaluated for antiviral activity in rodent models, and at 50-200 mg/kg prevented death in mice inoculated intraperitoneally (i.p.) with Semliki Forest, San Angelo, and banzi viruses when administered i.p. before virus challenge. Similarly, the nucleoside was effective against an intranasal challenge of rat coronavirus in suckling rats, with activity present when treatment started as late as 4 h after virus inoculation. Protection was observed against herpes type 1 and murine cytomegalovirus (both inoculated i.p.) infections, and encephalitis induced by intracerebral inoculation of a human coronavirus in mice. Friend leukemia virus splenomegaly was more severe in drug-treated animals than in placebos. This immune modulator is promising for the treatment of animal and human diseases.

Topics: Adjuvants, Immunologic; Animals; Antiviral Agents; Disease Models, Animal; Female; Guanosine; Mice; Pregnancy; Rats; Rats, Inbred F344; Semliki forest virus; Togaviridae Infections; Virus Diseases