Herpes Simplex Virus 1 Induces Brain Inflammation and Multifocal Demyelination in Cotton Rats Sigmodon Hispidus (1920)

Objective: This work was conducted to explore possible association between Herpes Simplex Virus 1 (HSV-1) infection and multifocal CNS demyelination. Background: Demyelinating CNS disorders like multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) have been difficult to study and treat due to the lack of understanding of their etiology. Numerous cases point to the link between HSV infection and multifocal CNS demyelination in humans, however, convincing evidence from animal models has been missing. Design/Methods: Cotton rats Sigmodon hispidus, animals with high translational value for human health, were infected with HSV-1 via lip abrasion. Neurologic symptoms, brain histopathology, and viral presence in the lip, trigeminal ganglia, and brain were monitored. Results: HSV-1 caused multifocal CNS demyelination and inflammation in cotton rats. Remyelination occurred shortly after demyelination, but could be incomplete, resulting in “scars” or “shadow” plaques. Virus was detected sequentially in the lip, trigeminal ganglia, and the brain of infected animals. Brain pathology developed primarily on the ipsilateral side of the brainstem, in the cerebellum, and contralateral side of the forebrain/midbrain. Neurologic symptoms, including head tilt, reduced whisker touch, and defective blink responses, were detected at the time of maximal viral load in the brain and could be representative of the brainstem/cerebellum dysfunction. Most animals recovered from neurologic defects. The timing of recovery correlated with the timing of CNS remyelination. Immunization of cotton rats with a split HSV-1 vaccine protected animals against viral replication and brain pathology. Conclusions: This work demonstrates for the first time a direct association between infection with HSV-1, a ubiquitous human pathogen generally responsible for facial cold sores, and multifocal brain demyelination in an otherwise normal animal host. Our results suggest that lip HSV-1 infection may be associated with a subset of demyelinating CNS disorders characterized by the brainstem/cerebellum involvement, and that vaccination against HSV-1 may help to prevent these disorders. Disclosure: Dr. Boukhvalova has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sigmovir Biosystems, Inc. Dr. Boukhvalova has received compensation for serving on the Board of Directors of Sigmovir Biosystems, Inc. Dr. Boukhvalova holds stock and/or stock options in Sigmovir Biosystems, Inc. which sponsored research in which Dr. Boukhvalova was involved as an investigator. Dr. Boukhvalova has received research support from Sigmovir Biosystems, Inc. Dr. Mortensen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SIGMOVIR BIOSYSTEMS, INC.. Dr. Mortensen has received research support from SIGMOVIR BIOSYSTEMS, INC.. Dr. Mbaye has nothing to disclose. Dr. Lopez has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with SIGMOVIR BIOSYSTEMS, INC.. Dr. Lopez has received research support from SIGMOVIR BIOSYSTEMS, INC.. Dr. Kastrukoff has nothing to disclose. Dr. Blanco has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sigmovir Biosystems, Inc. Dr. Blanco has received compensation for serving on the Board of Directors of Sigmovir Biosystems, Inc. Dr. Blanco holds stock and/or stock options in Sigmovir Biosystems, Inc. which sponsored research in which Dr. Blanco was involved as an investigator. Dr. Blanco has received research support from Sigmovir Biosystems, Inc.