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.