The cell-mediated adaptive immune response to herpes simplex virus type 1 encephalitis: mechanisms and clinical implications.

Herpes simplex virus (HSV) encephalitis is the most frequent cause of sporadic encephalitis globally. Despite the emergence of the antiviral drug aciclovir curtailing mortality, this disease remains a clinical challenge due to its rapid progression and associated neurological sequelae; indicating the urgent requirement for adjunctive neuroprotective treatment options. Recent studies using both human samples and murine models have highlighted how cell mediated immune cells including CD8+, CD4+ and brain tissue-resident memory T cells have the capacity to act as a 'double-edged sword'; both serving to protect the host against HSV encephalitis, but also increasing neuroglial injury by inflammation. Factors which impair cell-mediated immunity may predispose individuals to herpes simplex encephalitis, including defects in viral immune evasion strategies (infected cell protein 47, UL13 kinase), host genetic pre-disposition (toll-like receptor 3 deficiency, lymphotoxin-α deficiency, Rel mutations) and external factors such as stress. Additionally, there is a particular need for clinical vigilance for patients on immunosuppressive treatments which impair cell-mediated immunity, including azathioprine, hydroxychloroquine and methotrexate. Conversely, understanding these molecular mechanisms may provide new insights into the use of immunomodulatory strategies including anakinra, tocilizumab, and the implementation of targeted vaccination. This review summarises the current state of knowledge of how an impaired cell-mediated immune response could promote herpes simplex virus encephalitis, followed by an exploration of the clinical applications and therapeutic interventions which could viably be implemented to ameliorate immune-mediated tissue injury.