Infection with the human herpesvirus (HHV)-6A may increase the likelihood of having multiple sclerosis (MS), according to a new national study in Sweden.

The research, “Serological response against HHV-6A is associated with increased risk for multiple sclerosis,” was presented by Anna Fogdell-Hahn, PhD, associate professor at the Karolinska Institutet, Sweden, at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) , held in Stockholm Sept. 11-13.

HHV-6 viruses are estimated to infect approximately 80% of people during childhood. Whether these viruses are involved in MS development has remained unclear, but reports have suggested an association with disease onset, MS-related brain lesions, and impaired repair of myelin, the protective layer of nerve fibers.

Now, an international team from Sweden, Germany, Canada, and Japan conducted a large study — called “The Megarun” — to investigate the potential association between HHV-6 and MS development by using a novel serology (blood serum) method.

The serological assay measured antibodies — IgG, the most abundant immunoglobulin class in humans — against the immediate-early protein 1 from HHV-6A (IE1A), and from HHV-6B (IE1B), the two viral strains of HHV-6.

The study included 8,742 MS patients, and 478 individuals assessed prior to disease onset, as well as matched controls for both groups.

Besides statistical analyses to investigate possible correlations with MS, the scientists also conducted genome-wide association tests to explore links with HLA haplotypes, which refers to a set of polymorphisms (gene variants) that tend to be inherited together.

Of note, distinct variants of HLA genes, which code for proteins that help the body distinguish between self and foreign, have been associated with opposite effects on the risk of having MS — protection vs. greater likelihood and younger age at MS onset.

The results revealed that the antibody response against IE1A was significantly associated with both MS and increased risk of developing the disease. In contrast, the IgG response against IE1B did not correlate with such risk in patients with established MS.

“The A variant came out as extremely significant for the MS and pre-MS cohort,” Fogdell-Hahn said, adding that this observation indicates that infection with HHV-6A is present before MS development, and “is therefore a risk factor for having MS.”

Also, the data showed a link on MS risk between the responses against IE1A and the Epstein-Barr virus (EBV), which has been previously associated with greater susceptibility to MS.

“Having both [antibodies against IE1A and EBV] represents a higher risk for MS than having each one of them on their own,” Fogdell-Hahn said.

She also emphasized that the data showed that “MS smokers have higher IE1A IgG levels compared to those who never smoked. This was not observed in controls.”

Results further revealed that the genetic control of the antibody response against HHV-6 — the genes involved in the formation of IgG antibodies targeting HHV-6A and HHV-6B — was located in the HLA region.

A significant interaction was also found between the antibody response against IE1A and two HLA MS risk alleles — DRB1*15:01 and HLA-A*02:01, Fogdell-Hahn noted.

Overall, “a highly significant increase in serological response against the HHV-6a antigen IE1A was found in MS, also before MS onset, and thus HHV-6A IE1A response is a risk factor for MS. In contrast, the response against HHV-6B IE1B was significantly lower in MS, and not detected before disease onset,” Fogdell-Hahn concluded.

The researcher emphasized that interactions with previously well-established risk factors for MS, namely EBV infection and HLA (DR15 allele), “were seen for the HHV-6A IE1A response.”