Does a virus help to trigger MS?



People have long wondered whether a virus might be responsible, at least in part, for causing multiple sclerosis. In 1958, people with MS asked their physicians to administer a rabies vaccine, in the hopes that it would neutralize a rabies virus that was believed to be involved in MS (British Medical Journal 1958;1:7–9). As we now know, that belief was mistaken.



More to han 50 years later, we have a much better handle on what viruses—and other factors— may be involved in MS, and how they may trigger or contribute to the disease.



Why look to a virus?

We know something in the environment triggers MS. For example, the identical twin of someone with MS, who shared virtually all the same genes, has only a one in four chance of developing the disease, suggesting that factors other than genetics are involved.



Another reason is that data from epidemiological studies (studies that analyze the geographical, socioeconomic, genetic and other factors that may contribute to who gets MS) suggest that exposure to an infectious agent may be involved in triggering the disease. And immune system proteins that are typically found in the spinal fluid of people with nervous system diseases that are known to be reactions to viruses are also found in the spinal fluid of 90 to 95 percent of people with MS.



That said, researchers have yet to pinpoint a single virus as the trigger for MS. Several viruses have been studied, but proving a cause-and-effect relationship between any virus and MS requires many research steps. One of these steps is to show that the virus is in the body before MS develops. We also need to show—and this is the most difficult step—that the virus actually causes the disease, and is not just happening alongside the disease.



Certainly, the virus that has come the longest way on this road is the Epstein-Barr virus.



The case for Epstein-Barr



Epstein-Barr virus (EBV) is known to cause infectious mononucleosis and other disorders. Most everyone has been exposed to EBV, though not everyone develops an illness from it. Key studies from Alberto Ascherio, MD, DrPH, and his team at the Harvard School of Public Health, have made EBV the front-runner for a virus involved in MS.

• Dr. Ascherio and colleagues examined stored blood serum samples that had been collected from several large groups of individuals who were then followed for the occurrence of MS. Antibodies (immune proteins that indicate a person has been exposed) to EBV were significantly higher in people who eventually developed MS than in control



Researchers are investigating the role of a virus, pictured here, in MS.

samples of people who did not get the disease (JAMA 2001; 386:3083; JAMA 2005;293:2496; Archives of Neurology 2006;63:839).

• The group also identified 305 cases of definite or probable MS in electronic databases of the U.S. Army and Navy. For each case, they obtained up to three blood samples (the earliest and latest available, as well as a third interim sample) from each person, and compared MS development and EBV infection in each case with two people who did not

have MS. MS risk increased significantly following

EBV infection. They found evidence that EBV preceded MS—the first step toward showing a causal relationship

(Annals of Neurology

2010;6:324).

• The team also has investigated

how EBV may interact with genes or other risk factors in the development of MS. They reported that people who had a specific immune- related gene and high levels of antibodies to EBV in

the blood serum were nine times more likely to develop MS than those without that gene and with low levels of viral antibodies (Neurology 2008;70:1113–18). In another study population, they showed that current

or previous smokers with the highest levels of EBV antibodies were 70 percent more likely to develop MS than those with neither risk factor (Neurology 2010; 74:1365).

These studies provide intriguing evidence that EBV plays some role in MS, although that role is still unclear.

Dr. Ascherio is now funded by the National MS Society and the National Institutes

of Health to evaluate blood samples and data from more than 1,600 people who were followed since displaying early symptoms of possible MS. His team is evaluating the effects of vitamin D levels, EBV infection and cigarette smoking on whether these early symptoms eventually turn into MS and how rapidly they do so.

HHV-6 and MS

Human herpes virus 6 (HHV- 6) has also been tagged for possible involvement in MS, specifically with triggering exacerbations. Steve Simpson, PhD, and colleagues at the Universities of Tasmania and Melbourne examined HHV-6 antibody levels in blood serum samples taken from 145 people with MS, who were followed for three years.

The results, published earlier this year, show that HHV-6 antibodies were associated with a higher risk of relapse. Also, antibody levels were nearly three times higher in women with progressive MS. Although the findings need to be confirmed, the team suggests that tracking HHV-6 antibodies may help

to predict the clinical course of MS (Multiple Sclerosis 2012;18:799).

Taking virus research deeper

Advances in technology are helping MS researchers look

for viral clues. John Kriesel, MD, and his colleagues at the University of Utah received a grant from the Society to use novel genetics technology to determine the presence of a virus that has not yet been associated with MS—the hepatitis G virus. “Subtractive sequencing” is a powerful new technology that allows researchers to detect millions of different RNA molecules in a single specimen. RNA, or ribonucleic acid, is

the chemical that delivers the instructions from a gene to a cell. In subtractive sequencing, investigators can subtract human RNA, leaving thousands of nonhuman, possibly disease- causing, RNAs.

Dr. Kriesel’s team applied subtractive sequencing to brain specimens taken from people who had MS during their lifetimes, and specimens from controls without MS. Although the hepatitis G virus was found in just one sample, the team concluded that this is a powerful new tool for revealing novel viruses that may not yet have been associated with MS (PLoS ONE 2012;7:331886).

Others are investigating the idea that perhaps it’s not a virus itself that causes MS, but some immune response triggered by viruses. Stephen Miller, PhD, at Northwestern University, led a team funded by the Society to investigate why some strains of mice infected with Theiler’s murine encephalomyelitis virus (TMEV) develop an MS-like disease, but others do not.

The results are intriguing.

In mice bred to be susceptible to the disease, the immune response led them to produce “Tregs”—a type of immune cusually known for suppressing the immune attack in MS.

In these mice, however, Tregs actually interfered with the anti-virus response, lessening its effectiveness, while mice that lacked the Tregs couldfight off the virus (Journal of Autoimmunity 2011;36:142). The team is exploring its findings further, as they shed new light on how an immune attack may result from viral infection.

Raising the bar

When researching viruses and other risk factors, it’s important to study large numbers of people for a long time. Emmanuelle Waubant, PhD (University of California at San Francisco),

is leading a nationwide study

in which 640 children who

have early MS or are at high

risk for the disease are being followed for four years to determine how viruses and

other environmental and genetic risk factors make children susceptible to developing MS. Their results will be compared with those from 1,280 children without MS. The five-year,

$3.2 million grant from the NIH is based on data collected by the Society’s Network of Pediatric Centers of Excellence, which showed that in children, certain viruses were associated with MS risk (Neurology 2011;76:1989–1995).