Adenovirus E1A inhibits IFN-induced resistance to cytolysis by natural killer cells.
Infection of target cells with cytopathic viruses inhibits IFN induction of cytolytic resistance to NK cell-mediated cytolysis [IFN-mediated cytoprotection (IFN-MCP)]. It has been thought that the virally induced inhibition of IFN-MCP is secondary to the shutdown of cellular macromolecular synthesis that accompanies cytopathic virus infections. Group C, adenovirus serotype 5 (Ad5) infection inhibits both IFN-MCP and cellular protein synthesis. This study determined if the Ad5-induced inhibition of IFN-MCP was independent of adenovirus (Ad) infection and secondary only to the expression of the Ad early region 1A gene (E1A). To test this hypothesis, 4-h NK cytolysis assays were performed on IFN-gamma-treated human cells infected with an Ad5 E1A deletion mutant, dl343, or transfected with the Ad5 E1A gene. IFN-MCP was not inhibited by infection with dl343, despite the production of large amounts of both early (E1B, p55) and late (hexon) Ad proteins. In contrast to E1A-negative, parental cell lines, IFN-MCP was blocked in Ad5 E1A-transfected epithelial and fibroblastic cell lines. Genetic mapping studies within the E1A gene demonstrated that expression of only the first exon of E1A was sufficient to inhibit IFN-MCP. DNA sequence homology of E1A genes between different Ad groups (group A, Ad12; group C, Ad5) is limited almost entirely to three conserved regions located within the first exon of E1A. Because IFN-MCP was also blocked in Ad12 E1A-transfected cell lines, expression of one or more of the E1A-conserved regions may be necessary to inhibit IFN-MCP. In summary, the expression of E1A gene products inhibited IFN-MCP independently of virus infection. E1A's inhibition of IFN-MCP has the net effect of promoting the selective NK cell-mediated clearance of Ad-infected or Ad-transformed human cells.
Routes
J M
JM
Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
D017500:Adenovirus E1A Proteins / Q000494:pharmacology*; D000260:Adenoviruses, Human / Q000235:genetics; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005091:Exons; D015870:Gene Expression; D005814:Genes, Viral; D006801:Humans; D066298:In Vitro Techniques; D007372:Interferons / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000276:immunology; D015678:Viral Structural Proteins / Q000235:genetics
D017500:Adenovirus E1A Proteins; D015678:Viral Structural Proteins; D007372:Interferons