Neuronal reactivation of herpes simplex virus may involve interleukin-6

Interleukin-6 (IL-6) is an inflammatory cytokine produced in many tissues, including the cornea and trigeminal ganglion. IL-6 acts by binding to its specific receptor, stimulating a cascade of signal proteins that induce the transcription factors NF-IL6 and STAT3. These IL-6-induced transcription factors change cellular gene transcription. Neutralization of IL-6 in vivo inhibits herpes simplex virus type 1 (HSV-1) ocular reactivation in mice. There are IL-6 response elements, possible binding sites of the IL-6 induced transcription factors, within the HSV-1 genome. These IL-6 response elements are concentrated in the inverted repeat regions of the genome, occurring in a non-random fashion in the promoters of the LAT and ICPO genes. Viral constructs containing deletions of IL-6 response elements in the LAT promoter region reactivate at a lower frequency compared with similar constructs lacking such deletions. HSV-1 may have evolved to exploit the relationship between a major inflammatory cytokine, IL-6, and conditions favorable for neuronal reactivation and subsequent replication in the epithelium. Exploring the role of IL-6, its receptor, and induced transcription factors in HSV-1 reactivation is a promising new avenue of research into the mechanism of HSV reactivation.