Document 0356
 DOCN  M9550356
 TI    A 2',5'-oligoadenylate analogue 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.
 DT    9505
 AU    Fingerote RJ; Cruz BM; Gorczynski RM; Fung LS; Hubbell HR; Suhadolnik
       RJ; Levy GA; Toronto General Hospital, Ontario, Canada.
 SO    J Gen Virol. 1995 Feb;76 ( Pt 2):373-80. Unique Identifier : AIDSLINE
       MED/95146978
 AB    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 micrograms/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 vivo. 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.
 DE    Adenine Nucleotides/*PHARMACOLOGY  Alanine Aminotransferase/BLOOD
       Animal  Antiviral Agents/*PHARMACOLOGY  Blood Coagulation
       Factors/*BIOSYNTHESIS  Endoribonucleases/METABOLISM  Enzyme Activation
       Female  Gastroenteritis Virus, Murine/*DRUG EFFECTS/PHYSIOLOGY
       Hepatitis, Viral, Animal/DRUG THERAPY/MORTALITY  Interferon Type
       II/BIOSYNTHESIS  Mice  Mice, Inbred BALB C
       Oligonucleotides/*PHARMACOLOGY  Oligoribonucleotides/*PHARMACOLOGY
       Support, Non-U.S. Gov't  Th1 Cells/IMMUNOLOGY  Virus Replication/*DRUG
       EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).