Hit-hit and hit-run: Viruses in the playing field of multiple sclerosis

Viruses have been major players in the search for the cause of multiple sclerosis (MS). In support of the viral theory is the predominance of CD8+ T cells and class-I major histocompatibility complex in lesions, the powerful therapeutic effects of β interferons, the ease of inducing demyelination in experimental models following virus challenge, and the documented examples of several human demyelinating diseases conclusively demonstrated to be of viral origin. We propose two hypotheses of how viruses may cause MS. In the "Hit-Hit" hypothesis, the virus persists or may be reactivated in the central nervous system (CNS). Injury is the result of direct viral damage and by an attempt of the immune response to clear the infectious agent. In the "Hit-Run" hypothesis, virus infects the periphery but never enters the CNS. The virus sets up an abnormal immunologic milieu for subsequent autoimmunity. In both scenarios, knowing the inciting virus would be expected to eliminate disease if the population were vaccinated to prevent infection. In the treatment of patients with fully established disease, the Hit-Hit hypothesis would require that antiviral agents enter the CNS and stop replication. In the case of the Hit-Run hypothesis, treatment of patients with established disease with antiviral agents would be futile.