ANTIVIRAL ACTIVITY OF BIOLOGICAL RESPONSE MODIFIERS IN A MURINE MODELOF AIDS - REQUIREMENT FOR AUGMENTATION OF NATURAL-KILLER-CELL ACTIVITY AND SYNERGY WITH ORAL AZT

We employed the Rauscher murine leukemia virus (RMuLV) as a murine ret rovirus 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 th e augmentation of natural killer (NK) cell activity and antiviral effi cacy of a series of BRM, most of which are known inducers of interfero n, in this model. Poly [I,C]-LC, MVE-2, and CL 246,738, but not Amplig en, soluble glucan, or 7-thia-8-oxoguanosine, consistently produced an tiviral 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 infect ed animals. For instance, poly [I,C]-LC boosted NK activity much more in infected mice treated therapeutically (treatment initiated after in fection) than prophylactically (treatment initiated before infection), and it had greater antiviral activity therapeutically than prophylact ically. For the BRM tested, antiviral activity did not occur without a ugmentation of NK activity in infected mice. In contrast, augmentation of NK activity in uninfected mice bore no relationship to antiviral a ctivity. Furthermore, elimination of NK cells by treating mice with an ti-asialo GM(1) abolished the antiviral activity of poly [I,C]-LC. Alt hough splenic NK activity was ablated by anti-asialo GM(1), serum inte rferon levels were not affected by this treatment. These results point to a causal connection between the augmentation of NK cell activity a nd the antiviral efficacy of these BRM in this murine AIDS model. NK c ells thus appear to play a key role in resistance to this retrovirus, as has been suggested for HIV. (C) 1997 International Society for Immu nopharmacology.