Epstein-Barr Virus: Genetic Risks, Reactivation, and Chronic Illnesses

Key takeaways: 
~ Epstein-Barr Virus (EBV) infects most people worldwide, remains in the body for life, and can reactivate under certain conditions.
~ EBV is linked to mononucleosis, several cancers, and autoimmune diseases like MS, lupus, and Sjögren’s syndrome.
~ Genetics play a key role in who gets severe EBV symptoms and related diseases, with specific gene variants increasing risk.
~ EBV reactivation is associated with chronic illnesses such as ME/CFS and Long Covid, especially after immune stress or infection.

What is Epstein-Barr Virus?

Epstein-Barr virus (EBV) is a type of human herpesvirus and is one of the most common viruses we are exposed to. It’s estimated that 90% of people have been infected with the Epstein-Barr virus at some point in their lives. Once you’ve been infected, the virus sticks around for the rest of your life.

Mono (mononucleosis) is caused by an EBV infection during the teen or early adult years. When someone gets EBV at other ages, such as during early childhood, the symptoms can be mild, like a brief cold, or completely asymptomatic.

EBV was discovered in a biopsy of cells from Burkitt’s lymphoma in 1964 by Dr. Anthony Epstein. Further studies over the next two decades established EBV as a cause of specific types of cancer, including lymphomas, throat cancer, and some stomach cancers.[ref][ref]

More recently, researchers have found that EBV infection and reactivity are connected to several autoimmune diseases, ME/CFS (chronic fatigue syndrome), and possibly long Covid.

EBV Lifecycle: Sticking around forever?

Epstein-Barr virus is a double-stranded DNA virus surrounded by a nucleocapsid and a lipid envelope. It primarily infects B cells, which are a type of white blood cell, and epithelial cells lining your throat, nose, stomach, and intestines.

Cell entry:
In epithelial cells, neuropilin 1 (NRP1) is important in how the virus gains entry to the cell. When NRP1 is decreased, the infection is suppressed, and when NRP1 is increased, the infection is enhanced. For B cells, the virus enters through interaction with the CD21 or CD35 receptors on the surface of the cell, along with HLA class II receptor fusion.[ref]

Lytic phase:
The lytic cycle is the primary infectious phase of viral reproduction. The Epstein-Barr virus enters epithelial cells, such as the lining of the throat and nose, and replicates rapidly. The replicated virus then buds off and leaves the epithelial cells. It is taken up by B cells in the immune system.[ref]

Latency:
In the latent phase, the virus DNA becomes circular and isn’t actively replicating in the B cells. This creates a reservoir for the virus to remain in a latent, inactive form in B cells for life. The viral DNA remains in the nucleus of B cells, but it is methylated (turned off) so that it isn’t replicating.[ref]

Reactivation:
While EBV stays latent, or dormant, in B cells for most people, it can be reactivated in some people in specific circumstances. The lifelong persistence and then periodic reactivation in a small percentage of people is why EBV is continuously present in the human population.[ref]

EBV-Associated Diseases:

In addition to causing certain types of lymphomas and nasopharyngeal cancers, Epstein-Barr virus infection and reactivation are associated with several diseases. The genetic variants that increase susceptibility will be covered in the Genotype Report section below.

Mononucleosis:

While ~90% of adults carry antibodies to the Epstein-Barr virus that causes mono, less than 30% of people actually get the symptoms of mono. The immune response and age at which you encounter the virus make a huge difference in who gets mono and how sick you get.

If you get the Epstein-Barr virus as a teen or young adult, you are much more likely to have mono from it. Symptoms of mono include fever, sore throat, fatigue, enlarged spleen, swollen lymph nodes, and sometimes a rash. Mono usually lasts for 2-4 weeks, but the fatigue can continue for a month or more.[ref]

Genetic susceptibility to mono:

Twin studies, one way of determining the heritability of a condition,  show that identical twins are twice as likely to both have mono as compared to fraternal twin siblings.[ref]

A study found that certain HLA polymorphisms increase the risk of mono when getting EBV as a teen or adult.[ref] Interleukin 10 (IL-10) is produced during inflammation as a way to keep the inflammatory system under control. Variants in the IL10 gene were shown in a study to be protective against Epstein-Barr infection.[ref]

More on the genetic variants that increase susceptibility to mono in the Genotype Report section below.

Reactivation of Epstein-Barr Virus:

The reactivation of the Epstein-Barr virus moves it from a latent, or dormant, infection to an actively replicating virus. Reactivated EBV is implicated as having a causal role in several autoimmune diseases, a couple of types of uncommon cancers, in ME/CFS and long Covid, and possibly in COPD.

Let’s take a look at how and why the virus can be reactivated, and then go into the connections with autoimmune diseases and ME/CFS.

Triggers of EBV reactivation:
The reactivation of EBV is regulated by different signalling pathways and can occur under certain conditions, such as hypoxia (lack of oxygen), B-cell receptor activation, ROS inducers, and exposure to certain lab chemicals. In addition, stress, immunosuppression, and certain medications can reactivate the virus. Certain bacteria, including Aggregatibacter actinomycetemcomitans, an oral bacterium associated with periodontitis, and H. pylori, can also trigger reactivation.[ref]

The reactivation cascade starts with the expression of two of the viral proteins: Zta and Rta. These two proteins then promote and boost the transcription of the other viral proteins for replicating the viral genome.

There’s a lot of research specific to the Zta and Rta proteins, looking at how our human immune system keeps them from getting activated, and also looking for ways to stop those proteins once activated. There’s also research on how to target those proteins as a way of targeting epithelial cancers.[ref]

The latent viral genome is methylated, which means that a methyl group is attached to the DNA to keep it from being translated. The CAF-1  protein complex is involved in the methylation of EBV to keep it latent, and low levels of CAF-1 are associated with EBV reactivation in Burkitt lymphoma cells. Interferon-γ-inducible protein 16 (IFI16) is also involved in keeping EBV from being reactivated.[ref][ref] IFI16 is also involved in the body’s response to Covid. [ref]

Epstein-Barr and Autoimmune Diseases:

Autoimmune disorders are characterized by the body’s immune system attacking its own cells. Epstein-Barr virus is associated in epidemiological studies with several autoimmune diseases. Research points to multiple possible mechanisms through which EBV increases autoimmunity, including lytic reactivation, immune evasion, and molecular mimicry.[ref]

Sjögren’s Syndrome:
Sjögren’s Syndrome is an autoimmune disease that usually involves a dry mouth, but it can also involve joint and muscle pain, severe fatigue, and skin issues for some people. Epstein-Barr virus infection usually occurs in the salivary glands, and for most people, the epithelial cells of the salivary glands are a reservoir for the latent virus. In Sjögren’s patients, salivary gland biopsies often show increased levels of EBV and viral reactivation. The salivary gland epithelial cells also have been shown to express high levels of the HLA-DR antigens, indicating that Sjögren’s could be due to persistent EBV with an ineffective T cell response against it.[ref]

Lupus:
There’s also an increase in risk of Lupus with IgAa levels for a specific viral protein in EBV. CD40 variants affect susceptibility to lupus in conjunction with EBV.[ref]

Multiple Sclerosis:
Multiple Sclerosis (MS) is a disease involving inflammation and demyelination of neurons in the brain and spinal cord. There is quite a bit of research showing that EBV likely plays a causal role in MS, at least for most MS patients.

A study involving US Army personnel found that the individuals who converted to Epstein-Barr seropositivity (showing they had been infected) were at a 32-fold risk of MS diagnosis compared to Army personnel who were seronegative for EBV.[ref]

Genetic susceptibility to MS and EBV:
In looking at the antibody to EBV antigens, patients with MS have an altered immunological response to it.[ref] The strongest genetic risk factor for MS is having the HLA-DRB1*15:01 serotype, and that HLA type interacts with the EBV antibodies differently. Research also shows an altered anti-EBV T cell response in patients with MS.[ref]

More studies have been done on the link between having had mono and later developing multiple sclerosis.  Studies have found that those with the HLA-DRB1*1501 are at a higher risk of multiple sclerosis, especially if they have had mono.[ref]

Epstein-Barr reactivation in ME/CFS and Long Covid:

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a chronic, disabling disease that affects approximately 1% of the general population. The disease involves fatigue that doesn’t improve with sleep and is often worsened by physical or mental activity. For many with ME/CFS, the onset is preceded by a viral infection, but for some, the initiating event is a physical trauma.

Chronic fatigue syndrome was first theorized to be due to Epstein-Barr infection back in the 1960s. Since then, other viral triggers have also been investigated, such as cytomegalovirus or HHV. Studies show that a subset of people with ME/CFS have elevated EBV antibodies or are positive for EBV reactivation. It is theorized that the changes to B cell and T cell responses due to EBV are a cause of ME/CFS. [ref][ref][ref]

Long Covid or PASC (post-acute sequelae of Covid) involves symptoms, such as fatigue, POTS, brain fog, post-exertional malaise, and shortness of breath, that continue for more than 4 weeks after a Covid infection. For a subset of long Covid patients, there is reactivation of Epstein-Barr virus, which may be a driving factor in the fatigue, etc. In patients hospitalized for severe Covid, reactivation of EBV was found in 82% of the patients. A review of 40 studies on viral reactivation in Covid patients showed that Epstein-Barr virus was the most common, along with cytomegalovirus and HHV-1. [ref][ref] [ref]

Genetic susceptibility to EBV:

Genetic variants interact with EBV in a couple of ways.  Rare mutations related to a decreased immune response, called inborn errors of immunity, are linked to an increased risk of having severe mono.

Interestingly, a 2024 study showed that a variant in the IL-27 receptor (IL27R gene) caused more severe symptoms of active EBV infection, but the same mutation also prevented the reactivation of the virus as a cause of lymphoma or other cancers.

Lifehacks:

The million-dollar question is, what can you do about EBV reactivation? Below are some possible ways to address it, but keep in mind that the research studies here are mostly in cells or animals and not placebo-controlled clinical trials.

Be sure to talk with your doctor if you need medical advice before starting any supplements.

Testing for reactivation:

Your doctor can order EBV testing for you, or you can order the blood tests on your own in many places. (How to order your own blood tests)

Here are some of the terms used in testing for EBV reactivation:[ref][ref]

EBV nuclear antigen (EBNA): A test for antibodies to EBNA. These antibodies are found 2-4 months after the initial, primary infection and then usually last for the rest of your life. It’s a marker for having had EBV at some point in your life.

Viral capsid antigen (VCA) IgM:  The VCA IgM antibodies will show up early on in an EBV infection and may be present during reactivation.

Viral capsid antigen (VCA) IgG: The IgG antibodies present later after the acute infection and can be an indication of reactivation.[ref]

Early antigen (EA): The early antibodies appear in the first three to six months after you get infected with EBV. You may not need this test if you are looking for reactivation.

Supplements that may help: