Viruses in Chronic Progressive Neurologic Disease

Herpesviruses are implicated as triggers of disease onset and progression in several major classes of human central nervous system (CNS) inflammatory disorders, including multiple sclerosis (MS), encephalitis, and epilepsy. Viral associations with these diseases, especially MS, are longstanding and somewhat debated. Human herpesvirus 6 (HHV-6) in particular plays an unclear role, as a ubiquitous virus acquired in early childhood, and one for which animal models have been challenging to establish. We investigated the HHV-6 viruses in patients with virally-associated CNS disorders and controls, in addition to nonhuman primate models of primary infection, with or without the subsequent induction of an immune-mediated CNS demyelinating disease. Following the development and characterization of a multiplex digital PCR assay, we demonstrate increased HHV-6A and HHV-6B coinfection in MS patients, as well as enriched viral detection in select CNS regions from patients with epilepsy and encephalitis. Using a marmoset model to investigate clinical, immunological and radiological outcomes of HHV-6A and HHV-6B primary infections, we noted biological and clinical differences between the two viruses, and between intravenous and intranasal routes of inoculation. We extended this model to compare the outcomes of an experimentally-induced CNS inflammatory demyelinating disease in animals previously inoculated with HHV-6 to animals that had not been exposed to virus. We demonstrate that asymptomatic intranasal viral acquisition accelerated and exacerbated subsequent CNS inflammatory disease through i) CNS infection and ii) peripheral immune activation, both of which may promote blood brain barrier permeability and enhance CNS inflammatory processes. Taken together, these clinical and pre-clinical data support the association of HHV-6 with neuroinflammation and lend further rationale for prophylactic or therapeutic anti-viral intervention in patients affected by acute or chronic neuroinflammatory conditions.

Author

• Leibovitch, Emily

Language

• en

Keyword

• Human herpesvirus 6
• experimental autoimmune encephalomyelitis
• CNS disease
• neuroinflammation
• Multiple Sclerosis
• marmoset

Date created

• 2017

Type of Work

• Dissertation

License

• All rights reserved

Rights statement

• In Copyright

Degree

• Ph.D.

Advisor

• Leitenberg, David
• Jacobson, Steven

Committee Member(s)

• Colberg-Poley, Anamaris
• Gaillard, William

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/b5644r691