Herpesvirus-host interactions in neurological diseases: the immunogenetic role of HLA-E

Human herpesviruses (HHVs) comprise nine pathogenic members, including herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, Epstein-Barr virus, human cytomegalovirus, human herpesvirus 6A/B, human herpesvirus 7, and Kaposi's sarcoma-associated herpesvirus. Clinical manifestations of HHV infection can range from asymptomatic cases to a broad spectrum of neurological complications, spanning from acute conditions such as encephalitis to chronic disorders including Alzheimer's disease and multiple sclerosis. By establishing latency and undergoing repeated reactivation, HHVs maintain lifelong interactions with the human immune system and shape host immune responses, exerting considerable impact on nervous system homeostasis. Individual susceptibility to, and outcomes of, HHV-associated neurological disorders depend on multiple factors, including the infecting HHV strain and host genetics. Recent evidence highlights the pivotal role of the human leukocyte antigen E (HLA-E) pathway-a non-classical major histocompatibility complex class I molecule with immunomodulatory functions-in regulating virus-host interactions. Since some HHVs manipulate HLA-E to evade immune recognition, individual variability in this axis may influence neurological outcomes. In this review, we summarize and discuss current knowledge of the role of HLA-E in herpesvirus-associated neurological diseases.