Molecular mechanisms of viral infections: the role of cellular transport proteins and cell cycle regulators in virus-host interactions

Respiratory infections with influenza A virus (IAV) cause substantial global morbidity, while herpes simplex virus type 1 (HSV 1) infects over 60% of the population and can lead to severe systemic disease in newborns and immunocompromised individuals. Increasing antiviral resistance highlights the need for alternative strategies, including drug repurposing and host directed therapies targeting cellular pathways exploited by viruses. This study examines how viral infections affect intracellular trafficking and cell cycle regulation. Histone deacetylase 6 (HDAC6), which destabilizes microtubules through α tubulin deacetylation, was investigated for its role in IAV replication. Both proteasomal degradation–based inhibition and genetic knockout of HDAC6 reduced IAV replication without impairing cell viability. Rab GTPases, key regulators of vesicular transport, are also targeted by viruses. HSV 1 depends on Rab6 mediated transport of glycoproteins from the Golgi to the plasma membrane, followed by endocytosis into Rab5 and Rab11 endosomes for secondary envelopment. Treatment with the procaine derived compound ProcCluster® disrupts this process, causing glycoprotein accumulation in endosomes and reducing viral replication. The protein phosphatase 2A (PP2A) is involved in various pathways, including cell cycle regulation, cell proliferation, and DNA damage response (DDR). In particular, the regulatory B-type subunit PR130 controls ATM phosphorylation and its downstream CHK2, as well as the cell cycle regulator p21. HSV-1 infection induces the activation of ATM and has developed mechanisms to induce dysregulation of the cell cycle by arresting host cells in the S phase. Accordingly, pharmacological and genetic modulation of the ATM and the p21-CDK2 signalling components affects viral replication. Overall, the findings support further exploration of host directed antiviral strategies targeting intracellular trafficking or DDR pathways.