TY - JOUR
T1 - Effect of deficiency of the double-stranded RNA-dependent protein kinase, PKR, on antiviral resistance in the presence or absence of ribonuclease L
T2 - HSV-1 replication is particularly sensitive to deficiency of the major IFN-mediated enzymes
AU - Khabar, Khalid S.A.
AU - Dhalla, Mohammed
AU - Siddiqui, Yunus
AU - Zhou, Amin
AU - Al-Ahdal, Mohammed N.
AU - Der, Sandy D.
AU - Silverman, Robert H.
AU - Williams, Bryan R.G.
PY - 2000/8/5
Y1 - 2000/8/5
N2 - Control of viral replication by interferon (IFN) is thought to be principally mediated by the 2',5'-oligoadenylate synthetase (OAS)/RNAse L, double-stranded dependent protein kinase (PKR), and myxovirus resistance protein (Mx) pathways. In this study, we monitored the constitutive and IFN- induced antiviral activity in mouse embryo fibroblasts lines derived from mice with targeted disruption of either PKR or PKR/RNAse L genes. At high multiplicity of infection (moi = 10), the absence of PKR had no effect on replication of vesicular stomatitis virus (VSV) but moderately enhanced encephalomyocarditis virus (EMCV) growth and greatly increased replication of herpes simplex virus-1 (HSV-1). Replication of EMCV, HSV-1, and VSV was modestly higher in PKR(-/-) RNAse L(-/-) fibroblasts when compared with control cells. Although the antiviral action of IFN-α was unaffected by the absence of PKR, IFN action was significantly impaired in the double knockout cells but was dependent on the stage of the virus cycle. At early stages, it appeared that anti-EMCV and anti-HSV-1 action of IFN-α was significantly compromised, although weak residual antiviral activity was seen. The action of IFN-α against VSV was specifically compromised at a late stage of virus replication. The results showed that PKR is an important mediator in constitutive resistance against HSV-1 and that RNAse L is also necessary for the full antiviral activity of IFN against a variety of viruses. These results supported the existence of novel pathways aimed toward specific stages of the virus life cycle.
AB - Control of viral replication by interferon (IFN) is thought to be principally mediated by the 2',5'-oligoadenylate synthetase (OAS)/RNAse L, double-stranded dependent protein kinase (PKR), and myxovirus resistance protein (Mx) pathways. In this study, we monitored the constitutive and IFN- induced antiviral activity in mouse embryo fibroblasts lines derived from mice with targeted disruption of either PKR or PKR/RNAse L genes. At high multiplicity of infection (moi = 10), the absence of PKR had no effect on replication of vesicular stomatitis virus (VSV) but moderately enhanced encephalomyocarditis virus (EMCV) growth and greatly increased replication of herpes simplex virus-1 (HSV-1). Replication of EMCV, HSV-1, and VSV was modestly higher in PKR(-/-) RNAse L(-/-) fibroblasts when compared with control cells. Although the antiviral action of IFN-α was unaffected by the absence of PKR, IFN action was significantly impaired in the double knockout cells but was dependent on the stage of the virus cycle. At early stages, it appeared that anti-EMCV and anti-HSV-1 action of IFN-α was significantly compromised, although weak residual antiviral activity was seen. The action of IFN-α against VSV was specifically compromised at a late stage of virus replication. The results showed that PKR is an important mediator in constitutive resistance against HSV-1 and that RNAse L is also necessary for the full antiviral activity of IFN against a variety of viruses. These results supported the existence of novel pathways aimed toward specific stages of the virus life cycle.
UR - http://www.scopus.com/inward/record.url?scp=0033911420&partnerID=8YFLogxK
U2 - 10.1089/107999000414835
DO - 10.1089/107999000414835
M3 - Article
C2 - 10926208
AN - SCOPUS:0033911420
VL - 20
SP - 653
EP - 659
JO - Journal of Interferon and Cytokine Research
JF - Journal of Interferon and Cytokine Research
SN - 1079-9907
IS - 7
ER -