Antiviral activity of biological response modifiers in a murine model of aids. requirement for augmentation of natural killer cell activity and synergy with oral AZT

• Published in: International journal of immunopharmacology 1996-11, Vol.18 (11), p.633-650
• Main Authors: Black, Paul L., McKinnon, Katherine M., Wooden, Sharon L., Ussery, Michael A.
• Format: Article
• Language: English
• Subjects: Acquired Immunodeficiency Syndrome - drug therapy; Acquired Immunodeficiency Syndrome - immunology; Acridines - pharmacology; Acridines - therapeutic use; AIDS; animal model; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antibodies - pharmacology; Antiviral agents; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Asialoglycoproteins - immunology; Biological and medical sciences; biological response modifier(s); Disease Models, Animal; Drug Synergism; Female; G(M1) Ganglioside - immunology; Glucans - pharmacology; Glucans - therapeutic use; Guanosine - analogs & derivatives; Guanosine - pharmacology; Guanosine - therapeutic use; Immunologic Factors - pharmacology; Immunologic Factors - therapeutic use; In Vitro Techniques; interferon inducer(s); Killer Cells, Natural - drug effects; Killer Cells, Natural - physiology; Lymphocyte Depletion; Medical sciences; Mice; Mice, Inbred BALB C; Pharmacology. Drug treatments; Poly I-C - pharmacology; Poly I-C - therapeutic use; Poly U - pharmacology; Poly U - therapeutic use; Pyran Copolymer - pharmacology; Pyran Copolymer - therapeutic use; Rabbits; Rauscher murine leukemia virus; Rauscher Virus - immunology; Specific Pathogen-Free Organisms; Viral Plaque Assay; Zidovudine - pharmacology; Zidovudine - therapeutic use
• ISSN: 0192-0561; 1879-3495
• DOI: 10.1016/S0192-0561(96)00064-1

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 [1,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 GM 1 abolished the antiviral activity of poly [I,C]-LC. Although splenic NK activity was ablated by anti-asialo GM, 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.