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The polyoma virus T antigen interferes with interferon-inducible gene expression
X Weihua1, S Ramanujam, D J Lindner
1Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Abstract:
Murine polyoma virus (MPyV) is a small DNA virus that induces tumors in multiple tissues of infected host. In this investigation, we show that cell lines derived from wild type virus-induced breast tumors are resistant to the growth inhibitory action of interferon beta (IFN-beta). Furthermore, replication of heterologous viruses such as vesicular stomatitis virus and encephalomyocarditis virus was not inhibited by IFN-beta in these cells. This effect was due to inhibition of IFN-stimulated gene expression by viral T antigen. Activation of IFN-stimulated gene factor 3 was inhibited in cells derived from a tumor induced by wild-type MPyV but not those from a mutant that lacks the pRB binding site of the large T antigen. Similarly IFN-gamma-inducible gene expression was also inhibited in cells transformed by wild-type virus. The levels of components of IFN-stimulated gene factor 3 and signal transducing Janus tyrosine kinases were comparable between the cells transformed by the wild-type and mutant viruses. The viral large T antigen bound to Janus tyrosine kinase 1 and inactivated signaling through IFN receptors. Thus, these studies identify a mechanism of viral resistance to IFN action.
Insights
Murine polyoma virus (MPyV) infection confers resistance to interferon beta (IFN-beta) by inhibiting IFN-stimulated gene expression. The viral T antigen inactivates signaling through IFN receptors, revealing a novel viral immune evasion mechanism.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Murine polyoma virus (MPyV) is a DNA virus known to induce tumors.
- Interferon beta (IFN-beta) is a key antiviral cytokine.
- Viral infections can develop mechanisms to evade host immune responses.
Purpose of the Study:
- To investigate the mechanism by which MPyV-induced tumor cells resist IFN-beta.
- To determine the role of viral T antigen in this resistance.
- To elucidate how MPyV interferes with interferon signaling pathways.
Main Methods:
- Generation and characterization of MPyV-induced tumor cell lines.
- Assays for IFN-beta sensitivity and heterologous virus replication.
- Analysis of IFN-stimulated gene expression and signaling pathways (e.g., ISGF3, JAK-STAT).
- Western blotting and co-immunoprecipitation to assess protein interactions.
Main Results:
- MPyV-induced tumor cell lines exhibited resistance to IFN-beta's growth inhibitory effects.
- Replication of other viruses was also not inhibited by IFN-beta in these cells.
- Viral T antigen was found to inhibit IFN-stimulated gene expression and ISGF3 activation.
- Wild-type MPyV T antigen, but not a mutant lacking the pRB binding site, caused this inhibition.
- MPyV T antigen directly bound to Janus tyrosine kinase 1, inactivating IFN receptor signaling.
Conclusions:
- MPyV employs its large T antigen to actively suppress interferon signaling.
- This suppression involves direct interaction with Janus tyrosine kinase 1, blocking IFN receptor pathways.
- These findings reveal a novel mechanism of viral immune evasion against interferon action.