Common herpesviruses have differing roles in MS, large study says
Prior infection with CMV linked to lower odds of developing disease
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A study confirmed the known link between a previous infection with the Epstein-Barr virus (shown in this illustration), a common herpesvirus, and MS. (Photo from iStock)
- Multiple sclerosis (MS) risk is significantly linked to prior Epstein-Barr virus infection, a study confirms.
- It also found that cytomegalovirus infection is associated with a modestly reduced risk of developing MS.
- Herpes simplex virus infection shows no significant association with MS development.
Prior infection with the cytomegalovirus (CMV), a type of herpesvirus, was associated with lower odds of developing multiple sclerosis (MS), while herpes simplex virus (HSV) infection showed no significant association with the disease.
That’s according to a study involving data from more than 320,000 individuals in Israel that also confirmed the known link between a previous infection with the Epstein-Barr virus (EBV), another common herpesvirus, and MS.
These findings support a “highly differential, rather than uniform, role that common herpesviruses play in MS,” researchers wrote.
The study, “The association of herpes simplex virus, epstein-barr virus, and cytomegalovirus infections with multiple sclerosis: a large-scale case-control study,” was published in Brain, Behavior, and Immunity by a team of researchers in Israel.
Epstein-Barr virus a leading risk factor for MS
While genetic predisposition plays a role in the development of MS, environmental factors, particularly viral infections, are considered important triggers for the abnormal immune responses that damage certain parts of the brain and spinal cord.
Previous EBV infection has long been recognized as a leading risk factor for MS. However, the impact of other common herpesviruses, such as HSV and CMV, has remained less clear, with previous research producing inconsistent results.
“This ambiguity represents a significant gap in understanding the full spectrum of viral exposures that may modulate MS risk,” the researchers wrote.
In this study, the team used data from a large database to evaluate the potential associations between prior infections with EBV, HSV, and CMV and a later diagnosis of MS and to address limitations of smaller previous studies.
EBV infection linked to 46% higher chance of a subsequent MS diagnosis
The team collected data from the SMC-LHS database, which combines records from Leumit Health Services, an Israeli health maintenance organization, and the Israeli Sheba Medical Center, covering more than 370,000 individuals.
Within this population, the researchers identified all individuals with an MS diagnosis who also received a disease-modifying therapy for MS, a dual criterion intended to increase diagnostic accuracy.
For each MS case, the researchers randomly selected five controls matched for sex, year of birth, socioeconomic status, and follow-up time. A history of HSV infection was identified using diagnostic codes, and EBV and CMV infection was determined by a positive test for antibodies against these viruses.
After excluding people with incomplete data, follow-up data under a year, or conditions similar to MS, 323,399 individuals, including 409 (0.13%) with MS, were included in the final analysis. EBV was the most common infection (30.83%), followed by CMV (25.01%) and HSV (12.39%).
Statistical analyses adjusted for potential influencing factors, including smoking, obesity, and vitamin D deficiency, showed that prior EBV infection was significantly associated with a 46% higher chance of a subsequent MS diagnosis.
Sensitivity analyses using a three-month and a one-year washout period (between infection and MS diagnosis) provided consistent results, “reinforcing the robustness of the associations,” the researchers wrote.
These findings align “with the extensive body of literature that firmly establishes EBV as a leading, and potentially necessary risk factor for MS,” they added.
Earlier study found a protective association between CMV and MS
Previous HSV infection was associated with 19% higher odds of developing MS, but this link failed to reach statistical significance, meaning it could have occurred by chance.
“This study is among the largest to investigate the specific link between HSV and MS with a case-control design and a clinically specific MS case definition,” the team wrote.
A prior CMV infection was linked to a 36% lower MS risk, but this result was not statistically significant. However, when the control group was restricted to individuals with a negative blood CMV test and no positive tests, CMV infection was significantly associated with a 49% lower chance of a subsequent MS diagnosis.
This link remained significant in sensitivity analyses that used a one-year washout period and adjusted for EBV status.
The convergence of these findings from two distinct populations… using different, high-rigor methodologies … substantially strengthens the evidence for a genuine protective role for CMV in MS [development].
The researchers noted that a Swedish case-control study also found a protective association between CMV and MS.
“The convergence of these findings from two distinct populations… using different, high-rigor methodologies… substantially strengthens the evidence for a genuine protective role for CMV in MS [development],” the team wrote.
To explain this result, the researchers hypothesized that previous CMV infection may reduce the immune system’s response to EBV, a form of immune competition between the two viruses, and that chronic CMV infection is associated with substantial commitment of immune resources.
The study “confirmed the dominant and positive association with EBV, provided robust evidence for a null association with clinically documented HSV, and offered validation for the emerging hypothesis that prior CMV infection is associated with modestly reduced MS risk,” the researchers wrote.
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