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.
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.
Toronto General Hospital, Ontario, Canada.
R J
RJ
Fingerote
B M
BM
Cruz
R M
RM
Gorczynski
L S
LS
Fung
H R
HR
Hubbell
R J
RJ
Suhadolnik
G A
GA
Levy
D000227:Adenine Nucleotides / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000096:biosynthesis*; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006524:Hepatitis, Viral, Animal / Q000188:drug therapy / Q000401:mortality; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D006517:Murine hepatitis virus / Q000187:drug effects* / Q000502:physiology; D009841:Oligonucleotides / Q000494:pharmacology*; D009843:Oligoribonucleotides / Q000494:pharmacology*; D018417:Th1 Cells / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D001779:Blood Coagulation Factors; D009841:Oligonucleotides; D009843:Oligoribonucleotides; C091868:Oragen; C045072:macrophage procoagulant activity; C023505:2',5'-oligoadenylate; D007371:Interferon-gamma; D000410:Alanine Transaminase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease