Latent Infection of the Central Nervous System (CNS) and the 'Inside-Out' Model of Multiple Sclerosis (MS) (P1.158)

OBJECTIVE: To determine if CNS infection with Herpes simplex 1 (HSV-1) results in 'spontaneous molecular reactivation' without the development of recurrent immune mediated CNS demyelination BACKGROUND: The nature of the initial trigger in MS - cytodegenertion (inside-out) or primary autoimmune attack (outside-in) remains controversial. Recently, Stys and colleagues argued in favour of a primary cytodegenerative mechanism as the initiating event with a convolution between progressive cytodegeneration and a variably primed immune system explaining the differences in clinical presentation (Nat Rev Neuro 2012). Previously, we provided evidence that viral infection in the CNS could act as the initiating event with recurrent immune mediated CNS demyelination resulting from acute and spontaneous molecular reactivation of HSV-1 in the CNS combined with an anti-viral T-cell immune response in the periphery of EAE susceptible mouse strains. DESIGN/METHODS: To determine if HSV-1 DNA is present in the brains of BALB/c mice, a strain not developing recurrent demyelination after infection, solution phase PCR was performed during the intermediate (week 10) and late (week 25) stages of infection. Immunohistochemistry studies were performed to identify latently infected CNS cells expressing viral proteins without the development of infectious virus - spontaneous molecular reactivation. RESULTS: Using solution phase PCR, HSV-1 DNA was identified in the brains of BALB/c mice at week 10 and 25 PI. CNS cells, stained with anti-HSV antibody, were identified in BALB/c mice during the intermediate stage of infection and when infectious virus could not be identified - consistent with spontaneous molecular reactivation. CONCLUSIONS: This study provides support for 'spontaneous molecular reactivation' of HSV-1 in BALB/c mice without associated immune mediated CNS demyelination. The results raise the possibility that latent viral infections of the CNS could fulfill the role of a primary cytodegenerative mechanism in an inside-out model of MS. Study Supported by: