Modulation of the Host Response to Tacaribe Arenavirus Infection in AG129 Mice by MY-24

MY-24 is a new antiviral compound recently shown to protect immunocompromised mice from lethal challenge with Tacaribe virus (TCRV). Tacaribe virus is incapable of causing disease to humans, but is closely related to the highly pathogenic New World arenaviruses that cause often-fatal viral hemorrhagic fever syndromes. Remarkably, MY-24 prevents mortality without reducing virus burden in the circulation or tissues. To investigate the mechanism by which MY-24 protects AG129 mice against Tacaribe virus infection, we first characterized the natural history of disease in the model with an emphasis on host immune response and blood vessel function to establish the best times to evaluate the effects of MY-24 treatment on host immune responses believed to contribute to disease severity and fatal outcome. We found that viral replication in the blood and in various tissues precedes an overzealous immune response that may lead to the destabilization of the blood vessels and increased fluid leakage believed to contribute to fatal shock associated with severe cases of hemorrhagic fever. We also found slightly reduced virus titers in certain tissues from MY-24-treated mice, suggesting that there may be a weak antiviral effect; however, TCRV was not cleared from lung, spleen, brain or kidney in recovering animals out to 40 days post-infection, indicating the establishment of a chronic infection infection in mice that are able to survive the initial challenge. Neutralizing antibodies do not appear to play a major role in the antiviral effect of MY-24, whereas reductions in several key factors that cause inflammation in mice treated with MY-24 may serve to reduce fluid leakage caused by Tacaribe virus infection