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) cau ses a strain dependent spectrum of disease symptoms which correlates w ith 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 antivi ral effects is the ability to induce 2',5'-oligoadenylate (2-5A) synth etase leading to activation of the latent endoribonuclease RNase L. On ce activated, RNase L degrades ssRNA thereby inhibiting viral-induced protein synthesis. These studies were undertaken to determine the effe cts of Oragen 0004 (Oragen), an RNase L activating 2-5A analogue, on M HV-3 replication and induction of PCA in vitro and on the course of MH V-3 infection in susceptible BALB/cJ mice in vivo. Oragen inhibited MH V-3 replication in peritoneal macrophages derived from resistant A/J a nd susceptible BALB/cJ mice in a dose-dependent fashion. Concentration s of Oragen greater than 110 mu g/2 x 10(6) macrophages decreased vira l replication by greater than 89% in peritoneal macrophages in vitro o btained 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 ma crophages to MHV-3 and failed to prevent the development of fulminant hepatitis in BALB/cJ mice in viva. Thus, these studies demonstrate cle arly that induction of 2-5A synthase and inhibition of viral replicati on is not sufficient to prevent MHV-3-related hepatocellular injury, a nd these data further support the role of PCA in the pathogenesis of M HV-3 infection.