Viral interferon regulatory factors decrease the induction of type I and type II interferon during rhesus macaque...

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus and rhesus macaque rhadinovirus (RRV), express viral homologs of cellular interferon regulatory factors (IRFs), known as vIRFs.
• The precise role of vIRFs during the initial stages of viral infection remains incompletely understood.

Purpose of the Study:

• To investigate the function of RRV vIRFs during de novo infection.
• To determine the impact of vIRFs on host interferon responses.

Main Methods:

• Generation of a recombinant RRV lacking all eight vIRFs (vIRF-ko RRV) using a bacterial artificial chromosome clone.
• Infection of primary rhesus fibroblasts and peripheral blood mononuclear cells (PBMCs) with WT(BAC) RRV and vIRF-ko RRV.
• Quantification of type I (IFN-α/β) and type II (IFN-γ) interferon induction.
• Assessment of IRF-3 activation and nuclear localization.

Main Results:

• vIRF-ko RRV infection led to earlier and increased induction of type I and II interferons compared to wild-type RRV.
• Plasmacytoid dendritic cells produced higher levels of IFN-α in response to vIRF-ko RRV infection.
• Wild-type RRV infection inhibited the nuclear accumulation of phosphorylated IRF-3, a key step in type I interferon induction.

Conclusions:

• RRV vIRFs actively suppress interferon induction at the transcriptional level during de novo infection.
• vIRFs likely exert their inhibitory effect by interfering with the activation and nuclear translocation of IRF-3.