Mismatched double-stranded RNA (polyI-polyC(12)U) is synergistic with multiple anti-HIV drugs and is active against drug-sensitive and drug-resistantHIV-1 in vitro

Although highly active anti-retroviral therapy (HAART) is successful in the treatment of HIV infection, problems with toxicity, drug-resistant variant s, and therapeutic failures have compromised the long-term utility of exist ing combination regimens. Mismatched double-stranded RNA (polyl-polyC(12)U) is an immune modulator with inherent anti-HIV activity. Cell toxicities an d anti-HIV activities of fourteen anti-HIV agents were determined alone and in combination with polyI-polyC(12)U. Combination analyses for anti-HIV ac tivity were performed at three drug ratios. Using Mixed Dose Effect analyse s and the CalcuSyn for Windows software package, combination indeces were d etermined for all drug combinations. In general, polyI-polyC(12)U was syner gistic in combination with abacavir, zidovudine, zalcitabine, didanosine, s tavudine, efavirenz, indinavir, ritonavir, nelfinavir, and amprenavir. It w as synergistic to antagonistic with lamivudine, delavirdine, nevirapine, an d saquinavir. Thus, polyI-polyC(12)U is synergistic with most anti-HIV agen ts at most drug ratios and across most effective concentrations in vitro, a lthough, certain members of each class were exceptions. PolyI-polyC(12)U al one was equally active against wild-type HIV and HIV resistant to nevirapin e, protease inhibitors, or nucleoside analogue reverse transcriptase inhibi tors. These results suggest that polyI-polyC(12)U should be re-evaluated as a potential adjunct therapy in patients who have failed current anti-retro viral therapeutic regimens. (C) 2001 Elsevier Science B.V. All rights reser ved.