Host Genetic Susceptibility and Antiviral Immunity Shape the Pathogenesis and Outcomes of Herpes Simplex Encephalitis

Abstract

Simple Summary Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis worldwide. Even with antiviral therapy, it remains life-threatening and often leaves survivors with severe neurological deficits. Although herpes simplex virus (HSV) infection is extremely common, only a tiny fraction of infected individuals develops HSE, pointing to host factors as key drivers of disease. Recent research has shown that intrinsic antiviral immunity within the central nervous system is critical. Inborn errors affecting the innate immune pathways and downstream molecules (e.g., UNC93B1, TRIF, TRAF3, TBK1, IRF3) impair type I interferon (IFN) production in brain-resident cells, allowing uncontrolled viral replication. Mutations in immune signaling components, such as IFNAR1, IFNAR2, STAT1, and STAT2, further weaken defenses. These genetic insights explain why certain people are vulnerable and open new therapeutic avenues. Future management should combine antiviral drugs with immune-modulating strategies and, potentially, genotype-guided personalized approaches. A clearer understanding of host–virus interactions will improve diagnostics and targeted treatments, ultimately reducing the heavy burden of this devastating disease.