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

Herpes simplex encephalitis (HSE), predominantly caused by herpes simplex virus type 1 (HSV-1), is the most common sporadic viral encephalitis worldwide and remains life threatening despite antiviral therapy. Although herpes simplex virus (HSV) infection is highly prevalent, only a minority of individuals develop HSE, highlighting the critical contribution of host-specific factors to disease susceptibility. This review summarizes current knowledge regarding HSE epidemiology, antiviral immunity, genetic susceptibility, and therapeutic advances. Underlying inborn errors of immunity fall into three mechanistic groups: impaired innate immune sensing pathways, including Toll-like receptor 3 (TLR3), retinoic-acid-inducible gene-I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5), and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), which compromise type I interferon (IFN) production in central nervous system (CNS) resident cells; disrupted neuron intrinsic antiviral mechanisms represented by mutations in specific genes (e.g., DBR1, SNORA31, and GTF3A); and defects in other IFN signaling molecules, including interferon-α/β receptor 1 (IFNAR1) and 2 (IFNAR2), as well as signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2), which further weaken antiviral defenses. These findings underscore cell autonomous antiviral responses within the brain and provide insights into the selective vulnerability to HSE. Emerging therapeutic strategies aim to integrate antiviral treatment with modulation of host immune responses and, potentially, personalized approaches based on genetic profiling. In all, we emphasize the pivotal role of CNS-intrinsic immunity and host genetic factors in shaping disease outcomes. A deeper understanding of the interplay between HSV and host defense mechanisms will facilitate the development of improved diagnostic tools and targeted therapies, ultimately reducing the burden of this devastating disease.