Circadian clock proteins BMAL1 and CLOCK regulate HSV-1 entry into nerve cells through NECTIN-1

📖 Top 20% JournalOct 17, 2025Virology journal

Circadian clock proteins BMAL1 and CLOCK may control herpes virus entry into nerve cells by affecting NECTIN-1

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

expression in mice's brainstem and hippocampus shows rhythmic patterns that may influence HSV-1 infection.

HSV-1 DNA copy numbers in cells varied in synchrony with NECTIN-1 expression levels.
Overexpression of and significantly increased NECTIN-1 expression.
BMAL1 and CLOCK bind to specific regions in the NECTIN-1 promoter, enhancing its transcriptional activity.
Inhibition of CLOCK activity using CLK8 markedly suppressed HSV-1 infection.

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BACKGROUND: Herpes simplex virus type 1 (HSV-1) is a double-stranded DNA virus that establishes lifelong latency and can cause fatal herpes encephalitis. This study aimed to identify key genes regulating HSV-1 infection and to elucidate the underlying mechanisms.

METHODS: Transcriptomic analyses of the brainstem and hippocampus in mice were conducted to identify clock genes potentially involved in HSV-1 regulation. A serum shock cell model was employed to assess the impact of temporal variations in expression on HSV-1 infection. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to investigate the transcriptional regulatory mechanisms.

RESULTS: NECTIN-1, a primary receptor mediating HSV-1 entry into neurons, exhibited rhythmic expression in both the brainstem and hippocampus of mice. In vitro assays further demonstrated that HSV-1 DNA copy numbers fluctuated in near synchrony with NECTIN-1 expression levels. Overexpression of the core clock factors and CLOCK significantly increased NECTIN-1 expression. Mechanistically, BMAL1 and CLOCK bind directly to E-box-like motifs in the NECTIN-1 promoter region, thereby enhancing its transcriptional activity. Furthermore, pharmacological inhibition of CLOCK using CLK8 markedly suppressed HSV-1 infection.

CONCLUSIONS: Together, our findings reveal a novel mechanism by which the circadian clock modulates HSV-1 entry through rhythmic regulation of the NECTIN-1 receptor. BMAL1 and CLOCK emerge as potential therapeutic targets for circadian-based antiviral strategies.

Key numbers

2.5×

Increase in Expression

Overexpression of in SH-SY5Y cells.

50%

Reduction in Infection

Inhibition rate observed in viral plaque assays with treatment.

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