HSV-1 infections of the prefrontal cortex: regional vulnerability, cellular mechanisms, and neurocognitive consequences.

Herpes simplex encephalitis (HSE), caused by herpes simplex virus type 1 (HSV-1), is the most common cause of sporadic viral encephalitis and remains associated with substantial mortality and long-term neurological morbidity despite effective antiviral therapy. Although HSE is classically characterized by involvement of the medial temporal lobes and limbic system, recent clinical, preclinical and neuroimaging studies highlight involvement of prefrontal cortical regions, including the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC). The functional consequences of HSV-1 associated injury may be particularly relevant to the persistent executive, cognitive, motivational, emotional, and behavioral abnormalities observed in HSE survivors. However, the mechanisms linking HSV-1 infection to prefrontal injury and subsequent neurobehavioral dysfunction remain incompletely defined. This review examines HSV-1 neuropathogenesis through a prefrontal cortical framework, with a focus on the mPFC and OFC, and evaluates potential mechanisms underlying their vulnerability. Current evidence supports a multistep hypothesis for HSV-1-associated injury involving olfactory and trigeminal neural entry, microtubule-dependent axonal transport, dissemination, and potential regional differences in cellular susceptibility. Further, we highlight cellular mechanisms of HSV-1-associated injury, including microglial and NLRP3 inflammasome activation, astrocytic dysfunction, neurovascular unit disruption, neuronal and synaptic injury, and viral immune-evasion mechanisms that facilitate viral persistence and amplify host-mediated injury. Lastly, we integrate these mechanisms with the functional organization of prefrontal-frontal-limbic networks to consider how regional injury may contribute to persistent cognitive and behavioral dysfunction following HSE. The studies discussed here provide a framework for linking HSV-1-associated prefrontal injury to long-lasting cognitive and behavioral sequelae of HSE, while highlighting critical gaps in our understanding of these HSV-driven mechanisms.