Understanding a Herpes Virus' Relationship to Autoimmune Multiple Sclerosis

Claude P. Genain, M.D.

University of California, San Francisco

Funded in September, 2003: $300000 for 3 years
LAY SUMMARY . ABSTRACT . FINDINGS . SELECTED PUBLICATIONS .

ABSTRACT

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Understanding a Herpes Virus's Relationship to Autoimmune Multiple Sclerosis

Human herpesvirus 6 (HHV6) is a recently discovered, ubiquitous herpes virus with particular tropism for the central nervous system (CNS), salivary glands, and immune cells. Of the 2 known strains of HHV6, the B strain causes exanthema subitum (roseola) in young children. Pathogenicity of the A strain and the consequences of exposure to this variant are unknown.

There has recently been a considerable amount of interest regarding the possible association of HHV6 with multiple sclerosis (MS), based on the detection of HHV6 DNA in the brain, cerebrospinal fluid, or serum of affected individuals, antibody reactivity to viral antigens, and findings of elevated levels of CD46 (the receptor for HHV6). As with many other candidate viruses however, a direct link between infection with HHV6 and MS is lacking. Greater than 95% of the general population is infected with this virus by age 2, and HHV6 is known to persist in CNS and other organs. HHV6 commonly re-infects healthy subjects throughout their adult life without adverse consequences. Thus, a causal relationship between HHV6 infection and MS that occurs at a much lower prevalence, if present, must require additional factors of pathogenicity that are only present in restricted populations.

This proposal is based on the novel finding that common marmosets, a species of New World primates that is prone to develop an MS-like immune-mediated CNS illness after immunization with myelin antigens, can be infected with HHV6. A "two-hit" infection with HHV-6A appears to result in neurological deficits and pathologically, CNS inflammatory demyelination similar to human MS. Affected animals appear to develop immune reactivity to myelin antigens, indicating the possibility that mechanisms of mimicry may be involved in pathogenesis. CNS viral persistence and/or replication can also be demonstrated, suggesting direct toxicity to CNS glial cells or neurons.

The proposed research will consolidate these observations in marmosets and establish the requirements in exposure to HHV6 viruses for appearance of CNS autoimmune demyelinating disease (e.g., single or repeated exposure, variant A vs. variant B). Mechanistic studies using all laboratory and immunological methods relevant to marmoset EAE pathogenesis will be applied to understand the cause of CNS autoimmunity and the pathway(s) of tissue damage following exposure to HHV6. Longitudinal studies of reactivity to myelin antigens and to HHV6, and viral persistence/replication in relation to time-course of disease will be examined. Sophisticated neuropathological, molecular, and immunohistochemical techniques will be employed to characterize CNS inflammatory infiltrates, cytokine production, and oligodendrocyte and neuronal pathology. Possible cytotoxicity of lymphocytes from HHV6-infected animals towards antigen-sensitized targets and capacity for immune viral clearance or neutralization will be explored.

We will also examine whether disease phenotype depends on exposure to live, as opposed to inactivated, HHV6, which should allow us to dissect the respective pathophysiological contributions of direct cytotoxicity and molecular mimicry. Time permitting, we will also extend this research to investigate whether exposure to HHV6 can modulate the phenotypic expression of EAE in the marmoset model, a question that is highly relevant to the notion that viral infections are generally thought to be triggers for MS attacks and/or worsening progression. These experiments will be carried out in an outbred primate species with close phylogenic similarity to humans. The work is expected to prove a causal link between HHV6 and autoimmune demyelination. Markers of HHV6-induced pathology that could be used clinically may be discovered.

These results will lay the foundations for future work that may provide a comprehensive understanding of the pathogenesis of HHV6-mediated autoimmune demyelination, an essential step towards rational virus-specific therapeutic intervention in MS.

FINDINGS

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Lay Results:
Multiple sclerosis (MS) is a disease where the immune system attacks the patient’s own brain and spinal cord, which produces destruction of the myelin insulating the nerve cells and a blockade of electrical conduction. The cause of MS is not known. Some believe that it occurs in childhood, by infection with environmental agents such as viruses. It has been difficult to prove this association, because MS is usually diagnosed in young adults in their 20’s. In our study we have shown that a common childhood virus, called human herpesvirus 6 (HHV6), causes MS in the marmoset (a small monkey used for MS studies). The virus causes death of myelin-making cells and nerve cells when it persists in the brain. The immune attack against the myelin is only a second step that follows weeks or months later. This is the first proof of a human virus causing MS, even if it is in an experimental animal. It is important because now scientists can study how this complication happens, discover blood tests to find young persons at risk, and attempt to find ways to stop the MS process early.

Scientific Results:
Human herpesvirus 6 (HHV6) has been tentatively associated with autoimmunity in humans, especially multiple sclerosis (MS). Direct evidence of association between exposure to HHV6, a ubiquitous virus, and MS has been lacking. We have demonstrated that in common marmosets, exposure to HHV6 variant A (HHV6-A), is followed by a neurological disease with relapsing remitting course, and neuropathology that mimics MS (perivascular inflammatory demyelinating plaques). Disease did not occur to date, following exposure to HHV6-B (the agent causing roseola in children). We observed virus persistence in the central nervous system, and apoptosis of glial cells in the vicinity of lesions. Preliminary observations in animals with chronic disease indicate that autoimmunity to myelin proteins is delayed, and appears secondary to clinical disease. In vitro, HHV6-A, and not HHV6-B, is capable of inducing apoptosis in human glial cell and neuronal cell lines. These results are the first direct evidence of a link between HHV6-A and an experimental disease mimicking human MS.  The model systems created are a foundation not only to study mechanisms by which HHV6-A infection can lead to MS, but also to develop causative therapies.

SELECTED PUBLICATIONS

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Gardell J.L., Dazin P., Islar J., Menge T., Genain C.P., and Lalive P.H.  Apoptotic effects of Human Herpesvirus-6A on glia and neurons as potential triggers for central nervous system autoimmunity.   J Clin Virol. 2006 Dec;37 Suppl 1:S11-6.