Seminars

Gammaherpesviruses (γHVs) including Epstsein-Barr virus (EBV) establish life-long persistent infections in B lymphocytes through latency, contributing to various malignancies. While viral persistence is a hallmark of γHVs, the molecular mechanisms governing the maintenance of latency remain incompletely understood. This study reveals two distinct molecular mechanisms of γHV latency: the innate immune regulator NLRC3 and non-canonical DNA/RNA structures called G-quadruplexes (G4s).

Using murine gammaherpesvirus 68 (MHV-68) as a model, we identified that NLRC3 functions as a negative regulator of viral latency. We discovered a reciprocal regulatory circuit where the viral protein LMP1 suppresses NLRC3 to promote persistence, while NLRC3 targets LMP1 for proteasomal degradation to disrupt latency. Parallel investigations into G4 structures revealed their dynamic role during the transition between latency and reactivation. Notably, pharmacological stabilization of G4s significantly inhibited viral replication, suggesting these structures as promising therapeutic targets.

Together, these findings highlight a complex virus-host interplay involving both cellular modulators and genomic architecture. This dual-pronged approach provides novel insights into the molecular mechanisms of viral persistence and identifies potential strategies for treating γHV-associated malignancies.