Reactive Oxygen and Reactive Nitrogen Species in Herpesvirus Infections: Mechanisms, Clinical Implications, and Therapeutic Opportunities

Significance: Herpesvirus infections are highly prevalent in the human population, causing a broad spectrum of diseases ranging from mild to severe that affect numerous tissues, although most infections remain asymptomatic. These viruses establish lifelong infections through latency and may reactivate at different frequencies, with or without clinical symptoms. To counteract microbial infections, host cells have evolved molecular mechanisms that interfere with viral replication, including the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Recent Advances: ROS and RNS are not merely antimicrobial products but also regulators of pathogen gene expression, immune modulation, and cell fate decisions, with excessive production leading to oxidative stress and cellular damage, among other effects. Notably, many viruses, including herpesviruses, modulate ROS and RNS production in infected cells to promote viral replication and evade the host immune response. Critical Issues: In this review, we examine the complex interplay between ROS, RNS, and herpesvirus infections. The available literature suggests (i) that herpesviruses from all three subfamilies exploit ROS and RNS as molecular switches for viral replication and immune evasion, (ii) that the specific ROS and RNS species and pathways hijacked by these viruses differ by subfamily, creating distinct and targetable redox vulnerabilities, and (iii) that antioxidant interventions selectively restoring physiological redox balances could represent efficacious antiviral strategies. Future Directions: Highlighting emerging therapeutic strategies that modulate redox balance to control viral replication and disease progression, this review underscores the need for mechanistic and controlled clinical studies to validate virus subfamily-tailored, redox-based antiviral approaches. Antioxid. Redox Signal. 00, 000–000.