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The Surprising Long COVID And EBV Connection

Decorative microscope photo of EBV particles

Mononucleosis Is Caused By The Epstein-Barr Virus

It is estimated that 95% of the world’s adult population is currently infected with the virus that causes mononucleosis, the Epstein-Barr Virus. However, most of the world’s population never displayed symptoms of the symptomatic infection known as mononucleosis. 

That’s because EBV is known as a latent virus, meaning once the immune response controls EBV’s initial cell-destroying (lytic) infection, the virus enters a new dormant stage called EBV latency. EBV latency persists in the individuals’ memory B cells for the rest of their lives.

This can have devastating consequences later in life. 

Epstein-Barr Virus and Chronic Disease

What virus do you think causes the most disease on the planet? You might be thinking it is SARS-CoV-2, the etiological agent causing long COVID. Maybe it’s HIV the virus that causes AIDS. But what if we told you that the Epstein-Barr Virus (EBV) ranks near the top?

Don’t take this the wrong way, we are not trying to minimize the pain and suffering of those with long COVID or those who succumb to COVID-19. We are simply trying to convey how EBV is one of the most destructive viruses to human health that few people know about (unless you’re suffering from an EBV-related illness).

So, why is EBV so destructive to human health?

Well, it’s not because EBV is a lethal virus upon infection. In fact, 95% of the world’s adult population between the ages of 40 and 69 is predicted to be infected with EBV, most of which were asymptomatic infections in childhood (1).

The fact that EBV has a high rate of morbidity is because it increases your odds of developing chronic inflammatory diseases, autoimmune diseases, and cancer later in life. The association with EBV and the following diseases is attributed to EBV reactivation. These chronic diseases include, but are not limited to, the following:

  • Nasopharyngeal Carcinoma
  • Hodgkin’s Lymphoma
  • Rheumatoid Arthritis
  • Burkitt’s Lymphoma
  • Multiple Sclerosis
  • Type 1 Diabetes
  • Celiac Disease
  • Sjogren’s
  • ME/CFS
  • Lupus
  • POTS

The scientific community recently discovered a new chronic disease that should be added to this list: long COVID.

While EBV reactivation is one of several factors associated with the development of long COVID, some would argue that this new found correlation (in a subset of patients), makes EBV one of the more destructive viruses known to science.

EBV Reactivation Predicts Long COVID

Amid the global pandemic, discoveries have emerged that could change the way we understand long COVID and its underlying causes. Studies suggest that during the early stages of a SARS-CoV-2 infection, the reactivation of EBV was found to predict the future onset of long COVID2. But what exactly is EBV, and why is its reactivation so significant?

What Is EBV?

Epstein-Barr Virus is a member of the herpesvirus family and is best known for causing infectious mononucleosis (mono), also known as glandular fever (3). Once inside the body, EBV can infect antibody-producing B cells and epithelial cells (3).

A healthy immune system causes the virus to enter a dormant state called latency (4). However, certain triggers, such as chronic activation of the HPA axis (stress), other infections (like COVID-19), immunosuppressants, and a weakened immune system, can cause the virus to reactivate (5). Viral reactivation stimulates the production of viral gene products, expressed from a circular ring of DNA inside the host cell’s nucleus, stimulating EBV production. 

The production of new EBV virions causes the B cell’s lytic (cell rupture) destruction. The EBV viral particles are released from the ruptured B cell, infecting more uninfected B cells and epithelial cells.

ID: cartoon image of a circular ring of DNA, the EBV geneome, laying dormant inside of a B cell known as EBV latency.

Can EBV Reactivation Contribute to Long COVID?

During the pandemic, researchers conducted a study involving uninfected participants who were later exposed to COVID-19 (2). Blood samples were collected at various intervals:

  • one-week post-infection
  • two weeks post-infection
  • two to three months post-infection

     

The results were striking. Fourteen percent of COVID-19 patients had detectable levels of EBV antigens in their blood one week after infection. By two weeks post-infection, the virus was no longer detectable, suggesting that COVID-19 had caused EBV reactivation, but the immune system forced the virus back into latency (2). But was this brief EBV reactivation associated with the development of the disease?

EBV Reactivation and Long COVID Symptoms

The data revealed a strong association between EBV reactivation and three long COVID symptoms: fatigue, memory deficits, and a persistent mucus cough. The odds of developing these symptoms increased by 150% to 250% in those with reactivated EBV2. As a control, reactivation of another common latent virus in humans, cytomegalovirus (CMV) was quantified following a SARS-CoV-2 symptomatic infection. However, CMV reactivation was not detected under these circumstances (2). This suggests that COVID-19 facilitates EBV reactivation but not CMV reactivation. More studies are required to understand the perceived specificity of EBV reactivation.

Further studies supported this work as a significant percentage of long COVID patients had evidence of recent EBV reactivation (6,7).

Specifically, in one retrospective cohort study, 66.7% of long COVID patients had unusually high anti-EBV antibody titers, suggesting recent EBV reactivation (6). In contrast, only 10% of COVID-19 recovered participants without long COVID showed signs of EBV reactivation. Another study involving 280 participants found that EBV reactivation was most strongly associated with long COVID fatigue and neurocognitive dysfunction (7).

Preventing EBV Reactivation During Repeated SARS-CoV-2 Infections

Preventing repeated SARS-CoV-2 infections is ideal regardless of whether you have long COVID or not. This is especially true for those with long COVID that might be caused by EBV reactivation.

Chronic EBV reactivation would not only increase your susceptibility to developing a more severe form of Long COVID, but it might also increase your susceptibility to developing those as mentioned earlier chronic inflammatory and autoimmune diseases.

EBV Treatments

There is no licensed drug to prevent EBV reactivation. However, there are many repurposed drugs, vitamins, dietary constituents, and supplements that have been found to reduce EBV reactivation.

The table below lists different drugs found to limit EBV reactivation in patients and/or in vitro (cell culture). The following however is not intended to be medical advice. Please consult with a healthcare professional to learn if one of these medications or supplements is right for you. For more information about the drug, please review the cited peer-reviewed literature.

EBV Inhibitor

Mechanism of Action

Anti-herpes drugs

 

Aciclovir

Inhibitor of herpesvirus DNA polymerase needed for EBV replication (8).

Ganciclovir/valganciclovir

Preferential inhibitor of herpesvirus DNA polymerase (9).

Omaciclovir

Inhibitor of DNA polymerase leading to limited DNA chain elongation (10).

Maribavir

Maribavir is an oral benzimidazole L-riboside which inhibits EBV protein kinases (11).

Cidofovir

Cidofovir diphosphate selectively inhibits viral DNA polymerase (12,13).

Other Drugs

 

Cimetidine

Histamine H2 receptor antagonist inhibits Tregs (suppressor T cells), inhibits cellular proliferation, inhibits adhesion and angiogenesis (14-18).

Zidovudine

Thymidine analogue that induces the lytic gene expression of EBV forcing the virus out of latency to kill the cancer cell it resides in. Not used to prevent EBV reactivation (19-21).

Valpromide

An HDAC inhibitor that prevents the expression of immediate-early EBV genes, BZLF1 and BRLF1 needed for EBV reactivation (22).

JQ1

JQ1 inhibits the growth of EBV+ nasopharyngeal cancer cells; is proapoptotic (kills infected cells), antiproliferative and enhances the radiological sensitivity of EBV+ cancer cells (23,24).

Artesunate

Inhibition of immediate-early genes needed for EBV reactivation (25,26).

Vitamins

 

Vitamin C

Inhibition of EBV reactivation in human lymphoblastoid cells. Killing of EBV+ Burkitt lymphoma cells and EBV-transformed cells in cell culture (27-29).

Vitamin D

Direct inhibition of enveloped viruses like EBV. Upregulation of antimicrobial peptides LL-37 and human β-defensin. LL-37 may disrupt EBV’s viral envelope (30-35).

Retinoic acid

Negative regulator of EBV gene BZLF1 and thus inhibits EBV lytic cycle. Irreversibly inhibitions EBV-transformed B lymphocytes (29,36-39).

Dietary Constituents and Supplements

 

Resveratrol

Inhibition of the EBV lytic cycle through effects on multiple molecular targets such as inhibiting lytic EBV proteins Rta, Zta, and EA-D also reduces EBV production (40-42).

Luteolin

Inhibition of promoter activity of EBV immediate-early genes, BRLF1 and BZLF1. Reduces genomic instability and suppresses tumorigenicity of EBV (43-48).

Apigenin

Inhibition of EBV BRLF1 and BZLF1 activity used to convert viral DNA to RNA (49).

Astragalus extract

Inhibition of expression of BZLF1, BRLF1 and EA-D during the EBV lytic cycle (50).

Epigallocatechin-3-gallate

Downregulation of LMP1. Inhibition of EBV-induced B-lymphocyte transformation via suppression of RelA acetylation, which reduces inflammation in the infected cell (51-53).

Delta-9-tetrahydrocannabinol (THC)

THC inhibits replication of γ-herpesviruses. Mechanism is poorly understood (54).

L-arginine

Suppression of EBV replication through enhancement of iNOS and nitric oxide (55).

Sulforaphane

Inhibition of transactivation of Rta, but not Zta (56).

Curcumin

Enhanced apoptosis-mediated inhibition of proliferation of EBV-transformed lymphoblastoid cell line. Inhibition of BZLF1 transcription (57-59).

Baicalein

Inhibition of EBV+ NPC through repression of activity of EBNA1 Q-promoter (60).

(+)-Rutamarin

Cellular topoisomerase II catalytic inhibitor, disrupting EBV DNA replication and DNA processing (61,62).

Drugs In Exploration

 

Dipyridamole

An FDA-approved drug to treat blood clots was found to inhibit nucleoside uptake by EBV (needed for EBV DNA replication) (63).

Histone Deacetylase (HDAC) Inhibitors

An array of HDAC inhibitors made EBV-infected cells more sensitive to the anti-herpes drug ganciclovir. See Ghosh, et al for the complete list (64).

XBP-targeting Drugs

 

Tenofovir alafenamide (TAF)

TAF is also used to treat HIV and was found to inhibit the incorporation of dATP into the EBV DNA template (65).

Tenofovir disoproxil fumarate (TDF)

Used clinically for HIV, TDF is a safe drug that was found to inhibit expression of lytic genes (65).

 

 

See the image below to learn more about the name of each drug target and what role they play in EBV lytic cycle. EAD, early antigen D; EBI2, EBV-induced 2 gene; EBNA1, EBV nuclear antigen 1; EBV, Epstein-Barr virus; HCMV, human cytomegalovirus; NPC, nasopharyngeal carcinoma; iNOS, inducible nitric oxide synthase, Rta and Zta are genes involved in lytic destruction of infected cells. BZLF1 and BRLF1 are gene products important in the EBV lytic phase.Table adapted from Kerr, J. Clin. Pathol. 2019 (4).

EBV Drug Targets Defined

Having a difficult time interpreting the different drug mechanisms from the table above because you’re not an expert on EBV pathophysiology? We created this image to explain what the various drug targets are and their role in EBV biology. We also color coded the name and description of each drug target so you can visualize what stage of the EBV lytic cycle the gene regulates.

ID:

Conclusion

We do not want you to live in fear of any virus. Especially EBV. We hope the information in this guide provides you with a piece of mind and helps you limit any future EBV reactivation that might be occurring in your body.

After all, limiting EBV reactivation following repeated SARS-CoV-2 infections, or any future immunosuppressive events such as chronic stress, might not only help prevent your long COVID from becoming worse but also prevent the onset of future autoimmune or chronic inflammatory diseases associated with EBV reactivation.

Smiling caucasian male scientist with short brown hair, fair skin, and brown eyes.

Written By

Matthew Menendez, Ph.D.

Director of Science Communication, Brain Inflammation Collaborative

Dr. Menendez has a passion for empowering patients navigating complex chronic diseases. Through innovative educational strategies, he bridges the gap between cutting-edge research and real-world understanding, helping individuals advocate for better care, access timely treatments, and reclaim their quality of life. 

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