[SCAN] The Cellular Circuit Hacker: How an Oncogenic Virus Rewires the Host Epigenome

Title: The Cellular Circuit Hacker: How an Oncogenic Virus Rewires the Host Epigenome

Speaker: Colin McVey

From: Structural Virology Lab, ITQB NOVA

Abstract: Pathogens across all kingdoms of life—from plants to humans—must continuously evolve strategies to commandeer host cellular machinery. For Kaposi’s sarcoma-associated herpesvirus (KSHV), lifelong persistence relies on establishing a "stealth" latent phase inside the host nucleus. To maintain this state, the virus deploys a master-regulator protein called LANA. Far from being a simple physical anchor for the viral DNA, LANA acts as a highly modular "cellular circuit hacker" that physically rewires the host's epigenetic landscape to ensure its own survival.

Our previous structural work revealed the chemical basis for this hijacking: LANA uses precise structural mimicry to plug directly into the host's MLL1 methyltransferase complex, forcing the deposition of active transcription marks on the viral genome. Now, we are turning our attention to how LANA intercepts a critical upstream gatekeeper—the host deubiquitinase USP7—to control the delicate chemical balance of histone ubiquitination and methylation (the H2Bub1/H3K4me3 axis).

 Because these higher-order viral-host chromatin assemblies are highly flexible, they have long defied classical X-ray crystallography.

However, the recent explosion in AlphaFold's predictive capabilities has sparked a fundamental rethink in how we can tackle KSHV chromatin biology. Driven by these AI breakthroughs, our laboratory has just embarked on a major methodological pivot toward integrative single-particle Cryo-EM. Although this structural transition is in its infancy, it provides the technological leap necessary to finally visualize the LANA-orchestrated viral chromatin architecture linked to nuclear body formation and virus-induced malignancies. By converging

AlphaFold3 predictions, multi-nucleosome arrays, and chromatin, our goal is to translate these elusive, highly flexible molecular machines into tangible, large-complex drug targets, paving the way for novel precision therapies.

SCANs are weekly seminars that happen every Wednesday at noon by in-house researchers and invited speakers at ITQB NOVA.