Interferon inhibits dengue virus infection by preventing translation of viral RNA through a PKR-independent mechanism.
Previously, we demonstrated that pretreatment of cells with interferon (IFN) alpha + gamma or beta + gamma inhibited dengue virus (DV) replication. In this study, experiments were performed to better define the mechanism by which IFN blocks the accumulation of dengue virus (DV) RNA. Pretreatment of human hepatoma cells with IFN beta + gamma did not significantly alter virus attachment, viral entry, or nucleocapsid penetration into the cytoplasm. The inhibitory effect of IFN was retained even when naked DV RNA was transfected directly into cells, confirming that steps associated with viral entry were not the primary target of IFN action. Biosynthetic labeling experiments revealed that IFN abolished the translation of infectious viral RNA that occurred prior to RNA replication. Subcellular fractionation experiments demonstrated that IFN did not significantly alter the ability of viral RNA to attach to ribosomes. The antiviral effect of IFN appeared independent of the IFN-induced, double-stranded RNA-activated protein kinase (PKR) and RNase L, as genetically deficient PKR- RNase L- cells that were infected by DV retained sensitivity to inhibition by IFN. We conclude that IFN prevents DV infection by inhibiting translation of the infectious viral RNA through a novel, PKR-independent mechanism.
Diamond
M S
MS
Division of Infectious Diseases, University of California, Berkeley, Berkeley, California 94720-7360, USA.
Harris
E
E
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D003715:Dengue / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects* / Q000472:pathogenicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects; D012367:RNA, Viral / Q000235:genetics*; D019892:eIF-2 Kinase / Q000172:deficiency / Q000502:physiology
D000998:Antiviral Agents; D007370:Interferon Type I; D012367:RNA, Viral; D016899:Interferon-beta; D007371:Interferon-gamma; D019892:eIF-2 Kinase