Indirect mouse model for the evaluation of potential antiviral compounds: results with Venezuelan equine encephalomyelitis virus.

An indirect mouse model was utilized to evaluate the antiviral activity of several compounds against Venezuelan equine encephalomyelitis (VEE) virus infection in mice. Mice were given various dosages of lysine-stabilized polyriboinosinic acid-polyribocytidylic acid, a tilorone analogue, kethoxal, or mepacrine before and/or shortly after receiving one of several dose levels of attenuated strain TC-83 VEE virus. Twenty-one days later, the same mice were rechallenged intracranially with virulent Trinidad donkey strain VEE virus. Susceptibility to rechallenge was interpreted as evidence of drug effectiveness in completely preventing the initial immunizing virus infection. In contrast, if a drug lacked antiviral effectiveness, the initial attenuated infection stimulated sufficient immunity to protect mice against the virulent rechallenge. Both of the interferon inducers, lysine-stabilized polyriboinosinic acid-polyribocytidylic acid and tilorone analogue 11,567, possessed significant (P < 0.01) antiviral activity based upon this indirect model, whereas mepacrine and kethoxal were inactive. Results using the indirect method were confirmed by using the conventional direct method for evaluating the effectiveness of potentially useful antiviral compounds. The indirect mouse model described should prove useful for studying drug efficacy against certain viruses that are lethal only by intracranial inoculation.