A 2',5'-OLIGOADENYLATE ANALOG INHIBITS MURINE HEPATITIS-VIRUS STRAIN-3 (MHV-3) REPLICATION IN-VITRO BUT DOES NOT REDUCE MHV-3-RELATED MORTALITY OR INDUCTION OF PROCOAGULANT ACTIVITY IN SUSCEPTIBLE MICE

Exposure of inbred mice to murine hepatitis virus strain 3 (MHV-3) causes a strain dependent spectrum of disease symptoms which correlates with induction of procoagulant activity (PCA) by macrophages. Previous studies have demonstrated a role for interferons in resistance to MHV-3 infection. These cytokines have both antiviral and immunoregulatory effects which may be crucial for MHV-3 resistance. One of their antiviral effects is the ability to induce 2',5'-oligoadenylate (2-5A) synthetase leading to activation of the latent endoribonuclease RNase L. Once activated, RNase L degrades ssRNA thereby inhibiting viral-induced protein synthesis. These studies were undertaken to determine the effects of Oragen 0004 (Oragen), an RNase L activating 2-5A analogue, on MHV-3 replication and induction of PCA in vitro and on the course of MHV-3 infection in susceptible BALB/cJ mice in vivo. Oragen inhibited MHV-3 replication in peritoneal macrophages derived from resistant A/J and susceptible BALB/cJ mice in a dose-dependent fashion. Concentrations of Oragen greater than 110 mu g/2 x 10(6) macrophages decreased viral replication by greater than 89% in peritoneal macrophages in vitro obtained from both BALB/cJ and A/J mice and by 86% in livers from MHV-3-infected mice in vivo. However, Oragen failed to inhibit induction of PCA following in vitro exposure of BALB/cJ mice-derived peritoneal macrophages to MHV-3 and failed to prevent the development of fulminant hepatitis in BALB/cJ mice in viva. Thus, these studies demonstrate clearly that induction of 2-5A synthase and inhibition of viral replication is not sufficient to prevent MHV-3-related hepatocellular injury, and these data further support the role of PCA in the pathogenesis of MHV-3 infection.