Co-infection of HHV-6A and EBV results in a 6.7 fold increased risk of developing multiple sclerosis

The increased risk occurred only in adults who were infected with EBV after their teenage years, and had elevated EBNA-1 antibodies.

Swedish investigators led by Peter Sundström of the Karolinska Institute collaborated with the German Cancer Center to report more evidence of the synergistic interaction between HHV-6A and EBV infection in the pathogenesis of multiple sclerosis (MS). The team utilized carefully selected samples from Swedish repositories as well as an assay developed by the German Cancer Center to confirm a previous study that found an association with HHV-6A immediate early antibodies (HHV-6A IE1), but not HHV-6A late antibodies or HHV-6B early or late antibodies (Engdahl 2019).

Since multiple sclerosis was first described, investigators have speculated that it was triggered by viral infection. Yet one putative viral trigger after another could not be confirmed.

In 1995, it was first suggested that HHV-6 (unclear if -6A or -6B) might be a trigger (Challoner 1995), and considerable evidence since then has supported that possibility  Serologic studies as well as studies of HHV-6A nucleic acid and antigen in the brain of people with MS have indicated that HHV-6A also may be one trigger of MS (Leibovitch 2018, Komaroff 2021).

Over the past 30 years, increasing evidence also has linked Epstein-Barr virus (EBV) to MS, in paradoxical ways.  Early infection (before early teens) with EBV, like infection with cytomegalovirus (CMV), seems to protect against a person developing MS.  In contrast, a large epidemiologic study found a greatly increased risk of subsequent MS among people in whom the primary infection with EBV occurred during and after their late teens (Bjornevik 2022).  A subsequent study demonstrated molecular mimicry between an EBV-antigen and a molecule expressed in MS plaques, suggesting a mechanism by which EBV might be a trigger for MS (Lanz 2022).

Increasing evidence of possible synergy between EBV and HHV-6A also has emerged in the past decade:

The new study further implicates both EBV and HHV-6A as triggers of MS.  The Swedish and German team assessed antibody levels to all nine human herpesviruses in the serum of 670 cases of MS in the years before they developed MS, and in 670 non-MS controls matched by sex, age of sampling, and birthdate.

The team found that:

  • EBV-EBNA-1-Ab positivity was significantly higher in cases (p<0.001)
  • HHV-6-IE1A-Ab positivity also was significantly higher in cases (P<0.001)
  • The combination of high antibody levels to both EBV-EBNA-1 and HHV-6A-greatly increased the likelihood of an individual later developing MS: odds ratio 6.7
  • These strong associations to both EBV and HHV-6A were seen only in people whose primary infection with EBV occurred in their late teens and older
  • No significant associations were seen between those with high levels of antibody to any other human herpesviruses—alone or in combination with elevated antibodies to EBNA-1—except for an inverse association between MS and antibody levels to CMV, as has been found in several previous studies
  • A strong association in the older people was seen with high antibody levels to EBNA-1 even when antibody levels to HHV-6A-IE1A were not elevated
  • No association was found between MS and antibodies to HHV-6B

The results are summarized in Figure 1.

The novel bead-based multiplex serological assay for HHV-6A immediate early antibodies identifies actively replicating HHV-6A. The investigators note that the assay has not yet been thoroughly validated.  However, its predictive power now has been demonstrated in several studies.

This study provides further support for a possible synergy between EBV and HHV-6A in triggering MS.  This synergy could plausibly be explained by earlier reports that EBV-infected B cells can be infected by HHV-6A (which primarily targets T cells), and that coinfection of B cells by both viruses leads to increased expression of EBV antigens (Cuomo 1995).

Read the full article: Grut 2024