Viruses have been heavily researched for their role in triggering the development and progression of many autoimmune diseases, including multiple sclerosis (MS). When a viral infection occurs, the immune system is turned on and attacks cells that are infected. However, the viruses may also infect immune cells, leading to autoimmune diseases. Additionally, some viruses may stay in the body and lay dormant (not active), and their later reactivation can trigger further autoimmunity.

Viruses known to contribute to the development of MS include Epstein-Barr virus, human herpesvirus 6, and cytomegalovirus. Although they may play a role, viruses do not single-handedly cause MS. It’s believed that several factors combine to contribute to MS, including genetics and other environmental factors.

Epstein-Barr Virus

Epstein-Barr virus (EBV) is a well-known trigger for MS. EBV infection is common in children, and they typically do not show any symptoms. When teenagers and young adults are infected, 30 percent to 40 percent of cases will result in infectious mononucleosis, a known risk factor for developing MS. Nearly all people with MS have been infected with EBV.

EBV infects B cells, which are specialized immune cells responsible for making antibodies. B cells play an important role in the development and progression of MS. Memory B cells are a specialized subset of B cells that remember infections, so that the next time a virus enters the body, the B cells know to attack it. Unfortunately, these memory B cells may contain dormant EBV, which can cause another infection. They may also tell the other cells in the immune system to attack the myelin (a type of fatty tissue that surrounds and protects nerves throughout the body) or other healthy tissues.

In the brains of people with MS, EBV-infected B cells group together to form clusters near lesions. In these clusters, the B cells communicate with T cells, specialized immune cells that attack and kill infected or damaged cells. EBV antigens (particles recognized by the immune system) look very similar to myelin — this phenomenon is known as molecular mimicry. Some T cells may recognize myelin as EBV and attack it, leading to neurological damage.

Disease-modifying therapies (DMTs) used to treat MS target both T and B cells in hopes of slowing the damage caused by these cells in the immune system.

Cytomegalovirus

Cytomegalovirus (CMV) is a common viral infection that can affect people of any age. In the United States, almost 1 in 3 children will be infected by age 5, and more than half of adults will be infected by age 40. Once a person is infected with CMV, they have it for life. The virus may reactivate at a later time. Most people do not know they are infected because their immune systems can fight the virus. However, people with weakened immune systems can experience symptoms and develop more serious health issues.

Recent research has shown that there may be opposing roles for CMV infection in the development and progression of MS. One multiethnic study found that previous infection with CMV was associated with a lower risk of developing MS or its precursor, clinically isolated syndrome (CIS), in Hispanic people, but not in Black or white individuals.

However, other research points to CMV infection as a risk factor for developing MS. In animal models of MS, CMV has been shown to cause immune cells to attack myelin in a similar way to EBV through molecular mimicry. In humans, CMV DNA and antibodies have been found at higher levels in people with MS compared to healthy controls.

These opposing findings highlight the need for further research on the role of CMV in the development and progression of MS.

Human Herpesvirus 6

Human herpesvirus 6 (HHV-6) is a virus closely related to CMV, and it comes in two forms: HHV-6A and HHV-6B. Around 95 percent of adults have been infected with HHV-6 at some point in their lives. Although symptoms are possible, most people are asymptomatic.

Studies have found that the levels of HHV-6 DNA are higher in the brains of people with MS compared to levels in healthy controls. Specifically, higher levels are seen in demyelinated plaques (lesions) in the brain. Researchers have also found that 20 percent of people with MS have oligoclonal bands — proteins called immunoglobulins (also known as antibodies) that indicate inflammation in the central nervous system (CNS) — against HHV-6. This finding supports the hypothesis that HHV-6 infection within the CNS is involved in the development and progression of MS.

Human Endogenous Retroviruses

Human endogenous retroviruses (HERVs) are pieces of viral DNA that have been inserted into human DNA. These pieces are passed down through family members and make up around eight percent of the human genome. HERVs are noninfectious and cannot make new viruses, but some can still trigger immune responses.

HERVs are thought to be involved in the development of MS. In 1997, researchers discovered an endogenous virus in people with MS, known as MSRV. MSRV was found in their blood and cerebrospinal fluid (CSF) at high levels compared to healthy controls and people with other neurological disorders. Notably, MSRV-associated proteins had accumulated in demyelinated neurons in people with MS.

HERV-related proteins are known to activate immune responses and cause neurotoxicity in several ways. Glial cells, which are found in the brain and CNS, may produce neurotoxic chemicals if HERV proteins are present. The production of neurotoxic chemicals can trigger an immune response against neurons and other healthy tissues, especially oligodendrocytes, which make myelin. This leads to the demyelination seen in people with MS.

Varicella-Zoster Virus

Varicella-zoster virus (VZV), more commonly known as chickenpox, is a viral infection that often occurs in young children under the age of 10. After infection, the virus can remain dormant in the nervous system for decades. Zoster, or shingles, can occur in adults if the virus becomes active again. Varicella is a herpesvirus.

Many people with MS have previously had chickenpox, and its viral DNA can be found in immune cells and CSF. Interestingly, this viral DNA is only seen during the transient stage of MS relapse and then disappears after recovery. One study took blood samples from 89 healthy controls and 82 people with relapsing-remitting MS (RRMS) to look for viral DNA and antibodies against VZV. Approximately 25 percent of the MS group tested positive for viral DNA in their blood, compared to 3 percent in controls. However, more than 90 percent of both the healthy and MS groups had VZV antibodies, meaning that they had been exposed to the virus at some point in their lives.

There seems to be evidence for the role of VZV in the development of MS, but other studies have found no relationship between the two. A similar study looked at the blood and CSF of 54 people with MS for VZV and other viruses. All samples tested negative for any herpesvirus DNA, suggesting that VZV does not play a role in the development of MS. These studies highlight the need for further research on how VZV infection may lead to MS.

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