A CDK-4EBP1 signaling axis drives HSV-1 replication and underscores a druggable pathway for potent antiviral intervention.

Herpes simplex virus type 1 (HSV-1) poses a persistent public health challenge, particularly due to the emergence of drug-resistant strains and the limited efficacy of current monotherapies. Through an unbiased multi-omic approach, we identify a previously lesser-known viral strategy in which HSV-1 hijacks cyclin-dependent kinase (CDK) signaling to disrupt host cell cycle and translational control, specifically via the eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). Targeted knockdown of CDKs confirmed their critical role in mediating 4EBP1 dephosphorylation during infection. Mechanistic evaluation of BX795, a previously known modulator of the 4EBP1 pathway, revealed an alternative route of translational repression mediated through CDKs. To further support this conclusion, we demonstrated that a distinct small-molecule CDK inhibitor, GW8510, exhibits potent antiviral activity against HSV-1 and functions as a true mechanistic analog of BX795. Together, these findings uncover a previously unrecognized CDK-4EBP1 regulatory axis exploited by HSV-1 and identify GW8510 as a promising candidate for host-directed antiviral intervention.IMPORTANCEHerpes simplex virus type 1 remains a major clinical burden, and resistance to existing therapies underscores the need for alternative strategies. This study reveals a mechanism by which HSV-1 regulates host cell cycle and translation control through cyclin-dependent kinase signaling and the 4E-binding protein 1 pathway. By revealing that pharmacological inhibition of this pathway suppresses viral replication, we identify a host-directed therapeutic approach that circumvents challenges associated with viral resistance to the current drugs. The demonstration of potent antiviral activity by GW8510, a small-molecule cyclin-dependent kinase inhibitor, establishes a promising foundation for translational development and highlights the potential of targeting host regulatory networks to combat viral infection.