Distinctive roles for 2',5'-oligoadenylate synthetases and double-stranded RNA-dependent protein kinase R in the in vivo antiviral effect of an adenoviral vector expressing murine IFN-beta.
To evaluate the anti-HSV-1 mechanisms of murine IFN-beta in ocular infection, mice were transduced with an adenoviral vector expressing murine IFN-beta (Ad:IFN-beta). Ocular transduction with Ad:IFN-beta resulted in enhanced survival following infection with HSV-1. The protective effect was associated with a reduction in 1) viral titer, 2) viral gene expression, 3) IFN-gamma levels, and 4) the percentage of CD8(+) T lymphocyte and NK cell infiltration in infected tissue. Expression of IFN-beta resulted in an elevation of the IFN-induced antiviral gene 2',5'-oligoadenylate synthetase (OAS1a) but not dsRNA-dependent protein kinase R (PKR) in the cornea and trigeminal ganglion (TG). Mice deficient in the downstream effector molecule of the OAS pathway, RNase L, were no more sensitive to ocular HSV-1 compared with wild-type controls in the TG based on measurements of viral titer. However, the efficacy of Ad:IFN-beta was transiently lost in the eyes of RNase L mice. By comparison, PKR-deficient mice were more susceptible to ocular HSV-1 infection, and the antiviral efficacy following transduction with Ad:IFN-beta was significantly diminished in the eye and TG. These results suggest that PKR is central in controlling ocular HSV-1 infection in the absence of exogenous IFN, whereas the OAS pathway appears to respond to exogenous IFN, contributing to the establishment of an antiviral environment in a tissue-restricted manner.
Al-Khatib
Khaldun
K
Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Williams
Bryan R G
BR
Silverman
Robert H
RH
Halford
William
W
Carr
Daniel J J
DJ
D015088:2',5'-Oligoadenylate Synthetase / Q000502:physiology*; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology; D000287:Administration, Topical; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D005260:Female; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D018259:Herpesvirus 1, Human / Q000276:immunology; D016899:Interferon-beta / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016849:Keratitis, Herpetic / Q000201:enzymology / Q000276:immunology / Q000401:mortality / Q000628:therapy; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008164:Luminescent Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D016019:Survival Analysis; D012668:Trigeminal Ganglion / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000276:Adjuvants, Immunologic; D000998:Antiviral Agents; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D016899:Interferon-beta; D007371:Interferon-gamma; D019892:eIF-2 Kinase; D015088:2',5'-Oligoadenylate Synthetase