and may regulate HSV-1 nerve-cell entry by rhythmically increasing the receptor.
Evidence
Mouse brain transcriptomics, serum-shocked cell infection assays, overexpression, luciferase reporter assays, ChIP, and CLOCK inhibition showed rhythmic NECTIN-1 expression, HSV-1 DNA variation near NECTIN-1 timing, BMAL1/CLOCK promoter binding, and CLK8 suppression of infection.
Caveat
The antiviral implication is based on mouse tissue analyses and cell models, with no clinical test of circadian timing or BMAL1/CLOCK-targeted HSV-1 therapy.
Simplified
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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