Inhibitory effects of ribavirin alone or combined with human alpha interferon on feline infectious peritonitis virus replication in vitro

Abstract

The antiviral activities of ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide; virazole), either alone or in combination with recombinant human leukocyte (alpha) interferon (rHuIFN-α), were evaluated against feline infectious peritonitis virus (FIPV) in feline kidney-cell cultures. The 50% inhibitory dose (ID₅₀) of ribavirin for uninfected, rapidly dividing cells was ∼17 μg ml⁻¹ whereas the ID₅₀ for FIPV was 2.5 μg ml⁻¹. The therapeutic index (TI) of ribavirin (i.e. the ratio of the minimum cell-toxic dose to minimum virus-inhibitory dose) was 6.8. Although a dose-dependent inhibition of viral infectivity occurred at non-toxic doses, maximum antiviral effects (⩾4 log₁₀ reduction in FIPV) occurred at cytotoxic doses.

When low or moderate doses of ribavirin were combined with either 10 or 100 U of rHuIFN-α ml⁻¹, the resulting antiviral effects were significantly greater than the sum of the observed effects from either ribavirin or rHuIFN-α alone. Significant synergistic interactions with rHuIFN-α occurred at ribavirin doses of 1, 5, 12.5 and 25 μg ml⁻¹. Synergistic combinations of rHuIFN-α and ribavirin produced up to an 80-fold or a 200-fold relative increase in FIPV antiviral activities compared with that produced by equivalent doses, respectively, or ribavirin or rHuIFN-α alone.

In cell growth studies, the addition of either 10 or 100 U of rHuIFN-α ml⁻¹ to test doses of ribavirin did not increase the anticellular effect observed with ribavirin alone; seemingly, the potentiation of ribavirin antiviral activity by rHuIFN-α was independent of any additive cytotoxic effects. Potentially, synergistic combinations of the two antiviral agents in vivo may decrease the therapeutic dose of ribavirin required for inhibition of FIPV and thus reduce drug toxicity.