Paramyxoviridae Use Distinct Virus-Specific Mechanisms to Circumvent the Interferon Response

• Published in: Virology (New York, N.Y.) N.Y.), 2000-04, Vol.269 (2), p.383-390
• Main Authors: Young, D.F., Didcock, L., Goodbourn, S., Randall, R.E.
• Format: Article
• Language: English
• Subjects: Antiviral Agents - therapeutic use; Cell Line; DNA-Binding Proteins - metabolism; Human parainfluenza virus 2; Human parainfluenza virus 3; Humans; interferon; Interferons - therapeutic use; Parainfluenza Virus 2, Human - physiology; Parainfluenza Virus 3, Human - physiology; Paramyxoviridae; Paramyxoviridae - physiology; Paramyxovirus; paramyxoviruses; Promoter Regions, Genetic; Respiratory syncytial virus; Respiratory Syncytial Viruses - physiology; Respirovirus - physiology; Sendai virus; Signal Transduction; Simian virus 5; STAT1; Stat1 protein; STAT1 Transcription Factor; STAT2; Stat2 protein; STAT2 Transcription Factor; Trans-Activators - metabolism; Virus Replication
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1006/viro.2000.0240

STAT1 and STAT2 are cellular transcription factors involved in interferon (IFN) signaling and are thus critical for the IFN-induced antiviral state. We have previously shown that the paramyxovirus Simian Virus 5 (SV5) blocks both type I and type II interferon (IFN) signaling by targeting STAT1 for proteasome-mediated degradation. To determine whether this is a feature common to all Paramyxoviridae, we examined the abilities of SV5, Sendai virus (SeV), human respiratory syncytial virus (RSV), and human parainfluenza viruses types 2 and 3 (hPIV2 and hPIV3, respectively) to block interferon signaling. The results showed that in reporter assays SV5, SeV, and hPIV3 blocked both type I and type II IFN-signaling; hPIV2 blocked type I but not type II IFN-signaling; and RSV failed to block either type I or type II IFN-signaling. In agreement with these results, SV5 and SeV inhibited the formation of the ISGF3 and GAF transcription complexes (essential for type I and type II signaling, respectively). Surprisingly, although hPIV3 inhibited IFN-induction of the ISGF3 complex, GAF complexes were detected in hPIV3-infected cells. hPIV2 also blocked the formation of the ISGF3 complex but not the GAF complex, whereas RSV failed to block the induction of either complex. SV5 was the only virus that caused the degradation of STAT1. Indeed, in SeV- and hPIV3-infected cells STAT1 was phosphorylated on tyrosine 701 (Y701), a characteristic of IFN receptor activation. However, consistent with these viruses blocking IFN signaling downstream of receptor activation, there was a specific reduction in the levels of serine 727 (S727)-phosphorylated forms of STAT1α in SeV- and hPIV3-infected cells. In contrast both (Y701)- and (S727)-phosphorylated forms of STAT1 were detected in hPIV2-infected cells but there was a specific loss of STAT2. Both STAT1 (including Y701- and S727-phosphorylated forms) and STAT2 could readily be detected in RSV-infected cells. Despite not being able to block type I or type II IFN signaling, RSV was able to replicate in human cells that produce and respond to IFN, suggesting that RSV must have an alternative method(s) for circumventing the IFN response. These results demonstrate that, although interference with IFN signaling is a common strategy among Paramyxovirinae, distinct virus-specific mechanisms are used to achieve this end.