HSV-1 reactivation as an emergent property of neuronal stress: implications for traumatic brain injury.

Herpes simplex virus type 1 (HSV-1) establishes lifelong latency in neurons, with reactivation driven by multiple molecular, cellular, and systemic stressors. While several individual mechanisms of reactivation have been well characterized, there are potentially other unresolved vulnerabilities that drive HSV-1 reactivation. Traumatic brain injury (TBI) has emerged as a potential trigger of HSV-1 reactivation and represents a complex and clinically relevant perturbation that disrupts neuronal homeostasis, immune surveillance, and inflammatory signaling, processes that are also central to HSV-1 latency and reactivation. However, the mechanisms linking TBI to HSV-1 reactivation remain poorly understood.In this review, we examine whether known mechanisms of TBI-induced cellular stress overlap with pathways implicated in HSV-1 latency and reactivation. We synthesize shared mechanisms, including stress signaling, neuroinflammation, and immune dysregulation during TBI that may create conditions permissive for HSV-1 reactivation in the injured brain. This integrated perspective reframes TBI as a context in which established drivers of HSV-1 reactivation converge and may increase reactivation susceptibility.We propose that HSV-1 reactivation is an emergent property of dysregulated neural systems and that TBI may engage many of these processes. In this framework, viral reactivation is inseparable from the broader neuronal and systemic context in which it occurs. This perspective highlights the importance of integrating neural state, injury, and immune dynamics into models of HSV-1 latency and reactivation. Advancing this multidimensional view will be critical for developing therapeutic strategies that not only suppress viral reactivation but also address neuroinflammation following brain injury.