Gamma-herpesviruses such as Kaposi’s sarcoma herpesvirus (KSHV) and Epstein–Barr virus (EBV) establish lifelong latent infections and contribute to virus-associated cancers. A central feature of latency is the persistence of the viral genome as an episome tethered to host chromatin by the viral protein LANA, forming distinct nuclear bodies (NBs). While these structures are essential for maintaining latency, the host mechanisms supporting their formation and stability remain largely undefined.

We identified heat shock factor 2 (HSF2) as a novel host regulator of gamma-herpesvirus latency. Proteomic analysis in infected cells revealed significant overlap between HSF2 and LANA interactomes, with shared partners enriched in DNA replication and chromatin segregation pathways. Imaging and biochemical assays confirmed HSF2’s direct interaction with LANA and its localization within NBs. Depletion of HSF2 led to NB disruption and a marked reduction in viral genome copies in physiologically relevant cell models. Importantly, the role of HSF2 is conserved across tumor types, as similar effects were observed in EBV-positive gastric cancer cells. Our recent published work (Cutrone et al. 2025) has shown that HSF2 influences chromatin accessibility at key viral promoters, promoting basal lytic gene expression and lowering the threshold for lytic reactivation. These findings support a model in which HSF2 acts as a guardian of herpesviral infection, balancing structural genome maintenance with transcriptional control.

Together, these insights position HSF2 as a central controller of viral processes essential for persistence and oncogenesis and a promising target for antiviral cancer therapy.