School of Medicine and Health Sciences Poster Presentations

Title

Human Herpesviruses HHV-6A and 6B Accelerate Clinical and Radiological Disease in an Nonhuman Primate Model of Multiple Sclerosis

Poster Number

26

Document Type

Poster

Publication Date

3-2016

Abstract

Viruses, particularly human herpesviruses, have long been suggested to be an environmental risk factor for the pathogenesis of Multiple Sclerosis (MS). Human herpesviruses HHV-6A and HHV-6B are associated with MS, in addition to several other inflammatory disorders of the central nervous system (CNS). To investigate this viral trigger hypothesis in a nonhuman primate, we asked whether marmosets previously inoculated with HHV6 exhibit an altered disease course of experimental autoimmune encephalomyelitis (EAE) compared to naïve animals. EAE is an well-accepted model of CNS inflammatory demyelination and reflects clinical and radiologic aspects of MS when induced in marmosets.

To mimic a physiologically relevant route of exposure, marmosets were inoculated intranasally with HHV-6A (n=6), HHV-6B (n=4) or uninfected control material (n=6) monthly for four months. Six months after the last viral inoculation, all animals were immunized with white matter homogenate to induce EAE. All animals underwent neurologic exams, in vivo brain MRIs, and peripheral blood (PB) and saliva collection bi-monthly until predetermined clinical endpoints. Upon necropsy, the CNS and other tissues were collected for viral distribution and immunohistochemistry studies.

A subset of marmosets inoculated with HHV6A or HHV6B (HHV6+EAE) mounted antiviral antibody responses and had detectable viral DNA in saliva and PB. Following EAE induction, HHV6+EAE marmosets exhibited accelerated and more aggressive clinical disease compared to controls, with significantly shorter survival times (p=0.01). HHV6+EAE marmosets also had an earlier onset of brain lesions (p=0.04) and mounted earlier and more robust anti-myelin antibody responses.

Following HHV-6 inoculations, there was no detectable increase in serum anti-myelin antibodies, and no evidence of increased T cell responsiveness to myelin antigens, suggesting that a direct mechanism such as molecular mimicry was not underlying the observation of accelerated disease in the virus inoculated marmosets. However, we observed increased cellular immune responses in HHV-6-inoculated marmosets following the viral inoculations. These data suggest that EAE acceleration may have resulted from a more indirect mechanism of inflammatory-mediated blood brain barrier breakdown, possibly due to a viral ‘priming’ of peripheral immune cells.

This study provides an experimental counterpart to the fertile field hypothesis, which puts forth that autoimmune diseases may be induced and/or exacerbated by microbial infections, and provides mechanistic insights into the interplay of viral and autoimmune components, which are believed to be involved in the complex pathophysiology of MS.

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Presented at: GW Research Days 2016

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Human Herpesviruses HHV-6A and 6B Accelerate Clinical and Radiological Disease in an Nonhuman Primate Model of Multiple Sclerosis

Viruses, particularly human herpesviruses, have long been suggested to be an environmental risk factor for the pathogenesis of Multiple Sclerosis (MS). Human herpesviruses HHV-6A and HHV-6B are associated with MS, in addition to several other inflammatory disorders of the central nervous system (CNS). To investigate this viral trigger hypothesis in a nonhuman primate, we asked whether marmosets previously inoculated with HHV6 exhibit an altered disease course of experimental autoimmune encephalomyelitis (EAE) compared to naïve animals. EAE is an well-accepted model of CNS inflammatory demyelination and reflects clinical and radiologic aspects of MS when induced in marmosets.

To mimic a physiologically relevant route of exposure, marmosets were inoculated intranasally with HHV-6A (n=6), HHV-6B (n=4) or uninfected control material (n=6) monthly for four months. Six months after the last viral inoculation, all animals were immunized with white matter homogenate to induce EAE. All animals underwent neurologic exams, in vivo brain MRIs, and peripheral blood (PB) and saliva collection bi-monthly until predetermined clinical endpoints. Upon necropsy, the CNS and other tissues were collected for viral distribution and immunohistochemistry studies.

A subset of marmosets inoculated with HHV6A or HHV6B (HHV6+EAE) mounted antiviral antibody responses and had detectable viral DNA in saliva and PB. Following EAE induction, HHV6+EAE marmosets exhibited accelerated and more aggressive clinical disease compared to controls, with significantly shorter survival times (p=0.01). HHV6+EAE marmosets also had an earlier onset of brain lesions (p=0.04) and mounted earlier and more robust anti-myelin antibody responses.

Following HHV-6 inoculations, there was no detectable increase in serum anti-myelin antibodies, and no evidence of increased T cell responsiveness to myelin antigens, suggesting that a direct mechanism such as molecular mimicry was not underlying the observation of accelerated disease in the virus inoculated marmosets. However, we observed increased cellular immune responses in HHV-6-inoculated marmosets following the viral inoculations. These data suggest that EAE acceleration may have resulted from a more indirect mechanism of inflammatory-mediated blood brain barrier breakdown, possibly due to a viral ‘priming’ of peripheral immune cells.

This study provides an experimental counterpart to the fertile field hypothesis, which puts forth that autoimmune diseases may be induced and/or exacerbated by microbial infections, and provides mechanistic insights into the interplay of viral and autoimmune components, which are believed to be involved in the complex pathophysiology of MS.