ATF1 Restricts Human Herpesvirus 6A Replication via Beta Interferon Induction

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Human herpesvirus 6A (HHV-6A) is a lymphotropic virus linked to neuroinflammatory diseases.
• The role of transcription factors binding to cAMP response elements (CREs) in HHV-6A replication is not fully understood.

Purpose of the Study:

• To investigate the function of the CREB transcription factor family in HHV-6A replication.
• To elucidate the mechanism by which CREB transcription factors regulate HHV-6A viral gene expression and replication.

Main Methods:

• Analysis of CREB1 and activating transcription factor 1 (ATF1) phosphorylation during HHV-6A infection.
• Creation of CREB1 and ATF1 knockout (KO) cell lines to assess viral replication.
• Transcriptome sequencing (RNA-seq) to analyze gene expression changes in ATF1-KO cells.
• Intervention with beta interferon (IFN-β) in ATF1-KO cells.

Main Results:

• HHV-6A infection increased phosphorylation of CREB1 and ATF1.
• Knockout of CREB1 or ATF1 enhanced HHV-6A gene expression and replication, with ATF1-KO showing a greater increase.
• In ATF1-KO cells, innate immune sensors and IFN-β-related genes were downregulated.
• IFN-β treatment of ATF1-KO cells significantly reduced viral yields, indicating reduced IFN-β levels contributed to enhanced replication.

Conclusions:

• ATF1 is activated during HHV-6A infection and acts as a restriction factor for viral replication.
• ATF1-mediated restriction of HHV-6A replication is dependent on the induction of IFN-β.
• This study highlights the role of ATF1 in innate viral immunity and the importance of IFN-β in regulating HHV-6A replication and pathogenesis.