Virus-host interactome reveals host cellular pathways perturbed by tick-borne encephalitis virus infection.

Tick-borne encephalitis virus (TBEV) poses an increasingly significant threat to public health. Building on our previous TBEV-host interactome study, we further refine the virus-host interaction network and show that multiple viral proteins, including prM, NS1, NS2B3, NS4A, and NS5, are associated with modulation of diverse host cellular pathways, including innate immune responses, autophagy, ribosomal biogenesis, homologous recombination, and cell cycle regulation. Notably, TBEV infection is associated with a modest but reproducible accumulation of host cells in the G0/G1 phase. Mechanistically, NS5 interacts with the histone acetyltransferase P300 and correlates with increased P16 expression and reduced CDK4 levels, consistent with G0/G1 cell-cycle arrest. Similar alterations were observed in TBEV-infected brain organoids. Pharmacological inhibition of P300 or activation of CDK4 attenuated virus-induced cell cycle changes and reduced viral RNA and protein levels. These findings provide valuable insights into TBEV pathogenicity and hold promise for antiviral drug development.