A review of the role of HHV-6A in multiple sclerosis and HHV-6B in epilepsy

Reactivation of HHV-6 has been implicated in the pathogenesis in multiple sclerosis (MS) and epilepsy. Dunn et al. of the Karolinska Institutet, Stockholm, Sweden, reviewed the literature linking HHV-6A/B to both illnesses.

The role of HHV-6A in MS.  Many lines of evidence link HHV-6A to MS. Viral DNA, mRNA and antigens can be found in plaques, cerebrospinal fluid and in blood, in contrast to healthy controls subjects; levels of viral DNA in blood correlate with disease activity; antibodies to the virus correlate with disease activity and predict relapses; lymphocytes in the blood and spinal fluid of MS patients proliferate in response to HHV-6 antigens; a proinflammatory response is triggered by the virus when it infects the central nervous system; animal models of MS find HHV-6A capable inducing demyelination; at the same time, HHV-6A infection of oligodendrocytes can impair the ability of these cells to remyelinate axons that have been affected by demyelination, as summarized in a recent review (Komaroff).

Led by Anna Fogdell-Hahn, the Karolinska group focuses on other strong evidence linking HHV-6A to MS.  In particular, the review highlights a remarkably large study from the Karolinska Institutet involving over 8,500 MS patients and 7,000 controls which found a very strong association between seropositivity against HHV-6A IEIA antigen (OR = 1.55, P = 9 x 10-22) and increased risk of future MS (OR =2.22, P =2 x 10-5). This was not found for the HHV-6B IEIB antigen (Engdahl 2019). 

The review also highlights the ability of HHV-6A to incorporate host cell proteins into its envelope as it exits an infected cell.  It speculates that the virus, when it infects an oligodendrocyte, could incorporate epitopes from myelin basic protein into its coat, resulting in autoimmunity. Such mechanisms have been seen in human immunodeficiency virus and vesicular stomatitis virus. Further studies should look for a significant host cell-specific protein signature of HHV-6A from human oligodendrocytes.

The role of HHV-6B in epilepsy.  Increased amounts of HHV-6B DNA have been detected in excised hippocampal tissue from patients with mesial temporal lobe epilepsy (MTLE), specifically in astrocytes, compared to hippocampal tissue without MTLE. The ability of HHV-6B to cause neuroinflammation and neuronal hyperexcitability through various mechanisms. The review focused on various epigenetic mechanisms that might be involved.

 One suggested mechanism of latency is through epigenetic mechanisms. There is evidence that HHV-6B affects host cell telomere methylation during an active infection, correlating to DNA integration into host cell telomeres. The group also cited preliminary evidence that HHV-6B also may affect the MAPK kinase signaling pathway, previously shown to be affected in status epilepticus.

Read the full article: Dunn 2020