Immunomodulatory Strategies in Herpes Simplex Virus Encephalitis

Abstract

Herpes simplex virus 1 (HSV-1) can be responsible for life-threatening HSV encephalitis (HSE). The mortality rate of patients with HSE who do not receive antiviral treatment is 70%, with most survivors suffering from permanent neurological sequelae. The use of intravenous acyclovir together with improved diagnostic technologies such as PCR and magnetic resonance imaging has resulted in a reduction in the mortality rate to close to 20%. However, 70% of surviving patients still do not recover complete neurological functions. Thus, there is an urgent need to develop more effective treatments for a better clinical outcome. It is well recognized that cerebral damage resulting from HSE is caused by viral replication together with an overzealous inflammatory response. Both of these processes constitute potential targets for the development of innovative therapies against HSE. In this review, we discuss recent progress in therapy that may be used to ameliorate the outcome of patients with HSE, with a particular emphasis on immunomodulatory agents. Ideally, the administration of adjunctive immunomodulatory drugs should be initiated during the rise of the inflammatory response, and its duration should be limited in time to reduce undesired effects. This critical time frame should be optimized by the identification of reliable biomarkers of inflammation.

Keywords: encephalitis; herpes simplex virus; immune response; immunomodulatory drugs.

FIG 1

Signaling pathways involved in the recognition of HSV. Viral glycoproteins are sensed by TLR2 located at the cell surface, whereas the abundant CpG motifs present in the viral dsDNA are recognized by endosomal TLR9. Both TLR2 and TLR9 signal through the MyD88/TAK1 pathway to activate NF-κB and AP-1. In the cytosol, viral dsDNA also induces the synthesis of cGAMP by cGAS, which activates the STING/TRIF/TRAF3 signaling pathway. Intermediate dsRNA produced during viral replication is recognized by endosomal TLR3 or cytosolic RIG-I and Mda5 sensors that signal, respectively, through TRIF/TRAF3 or IPS-1/TRAF3 pathways to activate IRF3 and IRF7. Activated NF-κB, AP-1, or dimers of IRF3 and IRF7 induce the production of type I IFNs (IFN-α/β) and proinflammatory cytokines. IFN-α/β bind to the IFNAR receptor, and the signal is transduced to JAK-1 and TYK-2, which phosphorylate STAT1 and STAT2, respectively. The complex of phosphorylated STAT1 and STAT2 heterodimerizes with IRF9 and translocates to the nucleus to induce the transcription of interferon-stimulated genes.

FIG 2

Hypothetical management of patients suffering from HSE with acyclovir and adjunctive corticosteroid therapy. At admission, a clinical evaluation of the patients should be performed together with laboratory testing of the cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electroencephalography (EEG). The level of production of a reliable biomarker of inflammation in the CSF or serum should be determined. Empirical intravenous acyclovir should be initiated pending results of CSF and MRI testing and continued for 14 to 21 days if the PCR is positive. Adjunctive corticosteroid therapy should be started later, during the rise of the inflammatory response, and should be limited in time to prevent undesired effects. This combined therapy should reduce both the viral load (dotted blue line) and the excessive inflammatory response (dotted red line) and result in less damage to the brain.