Best treatment for multiple sclerosis may be antivirals

The best treatment for multiple sclerosis (MS) might be antivirals that target the Epstein-Barr virus. Pharmaceutical companies are now being called on to develop such drugs after researchers studied the immune responses of people with and without the condition.

“There aren’t good Epstein-Barr virus drugs currently available, but they can be developed,” says Michael Levy at Harvard Medical School. “That might be the most useful specific therapy for MS in the future.”

MS is caused by an immune attack on myelin, a fatty sleeve that wraps around nerves. The loss of myelin reduces their ability to transmit signals and can cause a wide range of symptoms, including muscle weakness. Drugs that suppress the immune system can slow the progression of the condition.

There is strong evidence that the Epstein-Barr virus (EBV), which causes mononucleosis, or glandular fever, is also the cause of MS. “I think most MS researchers now would agree that EBV plays a major role in the development of the disease,” says team member Kjetil Bjornevik at the Harvard T.H. Chan School of Public Health.

But exactly how remains a mystery. Almost everyone is infected with EBV during their childhood or teen years. It mainly infects immune cells known as B-cells, where it can remain dormant for the rest of a person’s life. But in some cells, the virus can reactivate.

The big question is why only around 1 in 1000 people develop MS when nearly everyone gets EBV. This suggests there is something different about the immune response to EBV in people who go on to develop MS, says team member Natalia Drosu at Massachusetts General Hospital. “Our question for this study was: in people with MS, what parts of EBV does the immune system respond to? And do those responses look different from people who don’t have MS?”

The team focused on immune cells known as CD4 T-cells, which circulate in the body. Although these aren’t the cells that directly attack myelin, there are multiple lines of evidence suggesting they play a role in MS, says Drosu.

The team found that, in 30 people with MS, most of the CD4 T-cells targeting EBV were specifically targeting viral proteins produced when the virus is actively replicating, rather than the proteins associated with its dormant stage. What’s more, people with MS produced twice as many of these cells, on average, as 30 people without the condition.

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The researchers then looked at T-cells in 60 people with MS before and after they began drug treatments that reduce their number of B-cells. They found these treatments reduced the T-cell response to EBV almost to the levels seen in people without MS.

In addition, the team found low levels of EBV in the saliva of these people before they were treated to reduce their number of B-cells, which shows that the virus was replicating in their bodies. After treatment, viral levels dropped below detectable levels in most people.

The thinking has been that B-cells help drive the harmful immune response in people with MS, says Levy, and this is why drugs that reduce B-cell levels are effective. But the results suggest these drugs also work by eliminating B-cells infected with EBV, he says, thereby reducing the immune response caused by active viral replication. “We’re thinking that depleting B-cells is also depleting the reservoir of the Epstein-Barr virus.”

If so, targeting EBV directly with antivirals might be just as effective as B-cell-depleting drugs, but without the undesirable side effects of treatments that weaken the immune system, such as an increased risk of infections. “I think a lot of patients would prefer a specific drug,” says Bjornevik. “If we can show that an antiviral had a similar effect as the most effective MS drugs, I think there will be a big market for that drug.”

Another approach already being trialled for treating MS is using modified immune cells called CAR T-cells. While existing drugs merely reduce B-cell levels, CAR T-cells can temporarily eliminate them altogether. Dozens of people with MS have gone into remission after CAR-T treatment, says Levy.

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But EBV might linger in some other cell types and reinfect B-cells as they slowly recover in the years after the CAR T-cell treatment, he says. “Then we would need the antivirals… so we just have to wait and see.” CAR T-cells can also have serious side effects, says Bjornevik, so antivirals could be safer as well.

There are also vaccines against EBV under development. “If people don’t get infected with EBV, their risk of MS would be virtually zero,” says Drosu. “So I think vaccines are [a] very promising strategy to eradicate MS.”

But 1000 people would have to be vaccinated to prevent just one case of MS, Levy points out, so it isn’t clear if EBV would be justified for preventing MS alone. However, EBV causes many other problems, including a number of cancers, and has also been linked to other autoimmune conditions, such as lupus and rheumatoid arthritis.