A molecular and cellular model to explain the differences in reactivation from latency by herpes simplex and varicella–zoster viruses

There are marked similarities in the biological properties of the human neurotropic herpesviruses herpes simplex virus type 1 (HSV–1) and varicella–zoster virus (VZV), including their ability to establish lifelong latent infections in human peripheral sensory ganglia (PSG). Despite this, their patterns of reactivation are quite different: HSV–1 reactivations occur many times during a lifetime, they are localized to the cutaneous distribution of a single sensory nerve, they are not associated with sensory symptomatology and their frequency decreases with age. VZV recurrence on the other hand is usually a single event which tends to appear with advancing age, its cutaneous eruption involves an entire dermatome and is usually extremely painful. To help explain these differences, we have formulated a model based on current knowledge of the molecular and cellular basis of latent infection in the nervous system. We suggest that the amount of latent viral DNA and RNA in the latently infected tissue (higher with HSV–1), the cellular location of latent virus (neuronal in HSV–1, probably non–neuronal in VZV), the presence or absence of viral replication in the PSG during reactivation together with the host immune response, are all key determinants of the clinical expression of viral reactivation