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Article: Chronic Fatigue Syndrome (CFS) associated with Epstein-Barr virus infection.

Good afternoon, I'm a medical student, I'm sick with CFS, and together with my girlfriend, who is already a medical graduate, we've written an article about this disease. Our intention is to share the information we have gathered over the years. The article is in Spanish, but we will soon try to translate it into English, as we do not have a good level of English.

Abstract: Chronic fatigue syndrome or myalgic encephalomyelitis (ME/CFS) is a disease of unknown etiology at present, which appears suddenly in a previously active person and whose onset appears to be related to an acute infection in most cases. Until now, CFS patients have been studied without classification into pathogen subgroups. The Epstein Barr virus (EBV), like other pathogens, is able to generate a functional immunodeficiency acquired through the deficit of expression of class II molecules of the major histocompatibility complex in genetically predisposed individuals. However, some pathogens also succeed in reducing the class I molecules of MHC. This study aims to show how the viral cycle of EBV and its mechanism of immune evasion can generate CFS and what the metabolic and physiological consequences are.

I'm sorry if there are mistakes with the translation.
A greeting,
Manuel Ruiz

EDIT:I attach the article already translated
Article: https://www.safecreative.org/work/1806287515904-sindrome-de-fatiga-cronica-por-virus-de-epstein-barr


  • Síndrome de fatiga crónica por virus de Epstein Barr.pdf
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  • Chronic fatigue syndrome caused by Epstein Barr virus infection.pdf
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Senior Member
United States, New Hampshire
@Manuel, thank you for posting this! :thumbsup: However, when I click on the link or open the file, it is in Spanish. I don't see the translation to English - is there one?

Hi Mary- The PDF is the full paper but I can't get it translated either. I tried google translate but it says the files too big. I guess we'll have to wait for it to be translated.:)


Senior Member
@Manuel, I was unable to sleep last night, so I translated your article a few paragraphs at a time using Google. Spanish translates quite easily into English, and although I find some of the paper hard to understand, that's simply because I'm not a doctor. The language reads well, and I'm sure that people on Phoenix Rising with science and medical backgrounds would understand it. I wasn't able to include your diagrams, but the text is done.

Obviously I won't post it here without your permission. It's a major paper (more than 23,000 words) that must have taken a lot of time and effort to write, especially for someone who is ill with ME/CFS, so of course you want to be happy with the translation. If you would like me to email it to you, or to send you a Dropbox link, just send me a private message.

EDIT: I have now included the diagrams and illustrations.
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Hi, @Moof . Thank you very much for your help.

Translating everything and checking it out, it's going to take me a long time. I was even thinking of paying a medical translation company to do it. I don't know what I'll do in the end.

Meanwhile, I've translated the discussion of the article with a translator. I hope it's understood.


Chronic fatigue syndrome or myalgic encephalomyelitis (ME/CFS) is currently a disease of unknown etiology, which appears suddenly in a previously active person and whose onset appears to be related to an acute infection in most cases. Until now, CFS patients have been studied without classification into pathogen subgroups. The aim of this study is to show how the viral cycle of the Epstein-Barr virus and its mechanism of immune evasion can generate CFS and what the metabolic and physiological consequences are that could be responsible for the symptoms of chronic fatigue.

The EBV expresses at least 44 miRNAs, most of them with unknown function, and two non-coding RNAs (EBERs). EBV-coded miRNAs control the expression of various cellular genes with antiapoptotic functions, but also interfere with innate immune responses and inflammation. Some EBV miRNAs act by suppressing, in infected B lymphocytes, the release of pro-inflammatory cytokines such as IL-12, which resulted in suppression of differentiation of CD4 naive + T-cells to Th1 cells (important antiviral effectors that activate macrophages and NK lymphocytes to kill intracellular pathogens).

Several EBV miRNAs modulate the immune recognition of newly infected B cells (preferably EBV target cells). Viral miRNAs, in infected B cells, control the gene expression of HLA class II and three lysosomal enzymes important for proteolysis and epitope presentation to CD4+ T cells. This allows them to interfere with peptide processing and class II HLA antigenic presentation. As a result of the decrease in HLA II antigenic presentation, the activation of EBV-specific cytotoxic effector CD4+ T cells and the death of infected B cells is reduced.

Also, to avoid detection of EBV-specific CD4 T cells, EBV latent membrane protein 2A (LMP2A) was found to play a critical role in the negative regulation of the expression of class II MHC molecules in infected B cells. Functionally, LMP2A mimics constitutively activated BCR signaling; however, the LMP2A-activated PI3K pathway mediates suppression of HCM class II and CD74 in EBV-infected B cells. Previous studies have revealed that CIITA is a major regulator of the expression of MHC class II and CD74 molecules. They demonstrated that LMP2A mediated the reduction of IUPAC levels by decreasing the expression of PU.1 and E47.

EBV-infected B-lymphocytes generate an IL-10 homologue (vIL-10), encoded by the EBV BCRF1 gene during the prelatent and latent phases.9,17 vIL-10 can act on multiple cell types and inhibit cytokine synthesis in T cells (inhibits production of IL-2 and IFN-g by Th1 cells) and NK.19 cells. This allows the antiviral functions of effector CD4+ T-cells to be suppressed and the NK-cell-mediated death of infected B-cells to be reduced.21 It is also a potent inhibitor of antigenic presentation, reducing the expression of MHC II and the accessory co-stimulation molecules CD80 and CD86 in dendritic cells.

Other miRNAs interfere with the recognition and destruction of EBV-infected cells by CD8+ T cells. First, miRNAs directly target TAP2, negatively regulate the entire TAP complex, and reduce HLA class I allotypes that preferentially have TAP-dependent epitopes. Second, they repress EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8+ T-cells. Third, miRNAs decrease the release of IL-12 by infected B cells, as IL12B is directly suppressed by these miRNAs in infected cells. This repression of IL12B not only can reduce the differentiation of CD4+ T-cells, it can also regulate the functions of effector T-cells, decreasing the activity of CD8+ T-cells specific to EBV.

EBV can infect the CNS through HBMEC infection. This leads to the rupture of the adhesion molecules or narrow BHE bonds, leading to the passage of leukocytes (including EBV-infected B cells) through the capillaries into the surrounding tissue.30 B cells with EBV latent infection are able to release EBERs (two non-coding RNAs). Where the release of EBER1 induces the activation of TLR3 signaling resulting in an increase in proinflammatory cytokines (inflammation is generated in the tissue).

As with EBV infection of HBMEC, infection of epithelial cells of the intestinal mucosa by EBV leads to the breakdown of the narrow junctions of the intestinal barrier, leading to the passage of bacteria and other substances. At the same time, EBV is able to infect plasma cells in the mucosa. Therefore, B cells with latent EBV infection release EBERs. EBER1 activates TLR3 signaling of enterocytes, resulting in the induction of type I IFNs and proinflammatory cytokines. This activation of TLR3 at the intestinal level reduces the activity of the serotonin transporter (SERT) in enterocytes, thus reducing serotonin uptake and causing an increase of extracellular 5-HT in this tissue. This excess serotonin should be collected and transported by platelets, as platelets get 5-HT mainly from the intestine. But the platelets do not get to collect all this excess, as they also express TLR3 as enterocytes. When these receptors are activated by the infection, the serotonin reuptake of these cells decreases. This eventually allows for a buildup of serotonin in the intestinal mucosa. Platelets activated via TLR3 also excrete the content of their granules (dense granules contain serotonin). The serotonin released by platelets would increase vascular permeability and may promote inflammation in tissues where EBV-infected cells are present. All this results in a decrease of 5-HT levels in platelets.

Add that in fasting conditions the 5-HT plasma levels of these patients are the same as those of healthy patients. This occurs thanks to alternative transports that remove free serotonin from the portal blood (prevents excess 5-HT at the intestinal level from reaching the systemic circulation). But in postprandial conditions by further stimulating the release of serotonin (especially with carbohydrate consumption), transport systems are saturated, thus increasing the levels of free 5-HT in plasma, as has been seen in patients with IBS-D, along with an increase in plasma levels of their 5-HIAA metabolite compared to healthy subjects.

In addition, by breaking down the narrow junctions of the intestinal barrier, bacteria and other harmful substances can pass from the lumen into the bloodstream, activating TLR4, which also decreases SERT activity. Activation of the various serotonin receptors would lead to increased intestinal motility, malabsorption problems along with vitamin deficiencies (vitamin A, E, D, K and B12), diarrhea, dysautonomia by communication of the vagus nerve between the enteric and cardiovascular systems, significant increase in wakefulness and a reduction in slow wave sleep along with cognitive problems. In addition to problems with temperature regulation and hormone secretion.

It should be noted that the environmental factor (EBV infection) not only influences the onset of CFS, but also the age at which the primary infection occurs and the genetic susceptibility to this infection. That is, patients with genes from MHC class I and II molecules that are susceptible to developing EBV-related diseases will have difficulty fighting EBV infection. As most of these diseases have numerous polymorphisms of these susceptibility genes, there is a great genetic heterogeneity among patients who develop one of these diseases, which is manifested as a great phenotypic variability among different patients suffering from the same disease. This is because in all vertebrate species the MHC molecules are highly polymorphic. This polymorphism reflects an immune system strategy to prevent the evasion of immune system pathogens. Having different MHC molecules, individuals deal with microbes in a different way, with individuals in a given population being more susceptible and more resistant to a given disease.

For future research, it would be interesting to start classifying patients into subgroups according to the possible pathogens involved based on understanding and focusing on a possible treatment. Rituximab is currently being studied for this disease and the explanation of why it works in some patients and not in others may be due to the type of pathogen involved. On the other hand, common markers must be found based on a diagnosis of the disease. At the metabolic level, it behaves in a similar way to cancer, all the antioxidants (vitamin C, Q10, E....) are reduced to compensate for the high oxidative stress and the appearance of cachexia and constitutional syndrome is common due to the high energy consumption caused by the Warburg effect. In more advanced disease there may be a decrease in the levels of glutamine, cysteine along with high production of urea and glutamate, this could be a marker of severity and a key point to consider based on supplementing them before implementing any therapy. It should be noted that the role of NK is key to viral infection and therefore key to CFS. Above all, it is essential to evaluate which pathogen is involved in the clinical picture, how it circumvents the immune system and therapeutic strategies to reverse the process and return the system to its initial state. For example, in this case Epstein Barr infection, rituximab could be crucial, since the virus acts by generating latency mainly in B cells. So if the infected B-lymphocytes were lysed, we would reduce the Warburg effect and consequently the chronic fatigue, as well as the immunological problems (there would no longer be a deficit of expression of class II molecules of the MHC). But rituximab treatment may have to be given with antivirals, because by immunosuppressing the patient the EBV could reactivate and continue to infect. There is now a more promising treatment without significant adverse effects, Epstein-Barr virus-specific adoptive immunotherapy. Where the death of EBV-infected B cells is achieved by adoptively transferred CD8+ T cells. This treatment has had promising preliminary results in progressive multiple sclerosis due to EBV, with improvements in the patient's symptoms and signs.

For all these reasons, several markers are proposed to be used in patients with CFS post-infection with EBV:

1. Activated T lymphocytes (CD3+, DR+), (CD4+, DR+): A low level of activated T lymphocytes indirectly indicates a decrease in HLA-II antigenic presentation. This decrease in CD4+ DR+ T-lymphocytes can be seen in other EBV-related diseases, such as children with EBV-associated hemophagocytic lymphohistiocytosis.

2. To verify in laboratory the decrease of the antigenic presentation HLA-II on the part of the antigen-presenting cells.

3. Molecular typing of the HLA system: to verify the existence of certain HLA alleles with a predisposition to develop EBV-related diseases.

4. IgG antibodies to nuclear antigen (antiEBNA IgG): presence of a high number, as in multiple sclerosis.

Tests 1 and 2 should be present in most patients with CFS, as other pathogens also evade the immune system in this way. These pathogens are able to generate an acquired functional immunodeficiency through the deficit of expression of class II molecules of the major histocompatibility complex. Although some also manage to decrease the class I molecules of the MHC, as has been mentioned in this article.
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I translated the article as best I could. Also thanks to @Moof ´s help.
If there are any spelling or translation errors that you see, I would be grateful if you would tell me so that I can correct them.
I attach the article in English.


  • Chronic fatigue syndrome caused by Epstein Barr virus infection.pdf
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Summary to better understand the article:

EBV is a herpesvirus that is present in more than 90% of the human population. This percentage includes both healthy people who can fight the virus effectively and those who cannot. Since it is the cause of multiple diseases such as: rheumatoid arthritis, multiple sclerosis, Hodking's lymphoma, Burkitt's lymphoma and other non-Hodking lymphomas. The difference in why some people can fight this infection well and others cannot is in the human leukocyte antigen (HLA) system of each individual.

In humans, the major histocompatibility complex (MHC) is called HLA.
The major histocompatibility complex is a family of genes found in all vertebrates and located in the short arm of chromosome 6 in humans, whose function is the coding of molecules called human leukocyte antigens or histocompatibility antigens (HLA class I molecules and HLA class II molecules), which participate in the presentation of antigens to T lymphocytes allowing the activation of critical processes in the generation of the immune response. In general, MHC (or HLA in humans) makes it possible to distinguish one's own from that of others. Hence, the genes that are most strongly associated with most autoimmune diseases are those of certain HLA molecules, mainly class II, although there are also class I associations. The response to pathogen infections also involves MHC, as they are foreign (not own) antigens.

In virtually all vertebrate species, MHC molecules are highly polymorphic. This polymorphism reflects an immune system strategy to prevent the evasion of immune system pathogens. Having different MHC molecules, individuals deal with microbes in a different way, with individuals in a given population being more susceptible and more resistant to a given disease. Repeated exposure to certain pathogens over the course of evolution may select those individuals who express MHC alleles most suitable for responding to infection. For example, the HLA-B53 allele is associated with resistance to a lethal form of malaria. This allele is very common in individuals in Africa where malaria is abundant, but is not common in places where malaria is not endemic.

These allelic variants (polymorphisms) are normal in the population and by themselves do not determine whether or not an individual will develop the disease (they only increase or decrease the risk of suffering from them); only when they act together and there is also an environmental factor (infection) will the disease develop. Add that it is also influenced by the age at which the infection occurs. There is, therefore, a great genetic heterogeneity among patients who develop a disease (in this case due to an infection by a pathogen), which manifests itself as a great phenotypic variability among different patients suffering from the same disease.

EBV has been associated with multiple sclerosis, but also with a genetic predisposition in the individual. For example, HLA-DR15 and HLA-DQ6 (subtypes of MHC class II molecules) have been shown to increase the probability of developing multiple sclerosis. Both HLA-DR and HLA-DQ are MHC class II molecules. MHC class II molecules: usually present only in antigen-presenting cells (B cells, macrophages, dendritic cells, Langerhans cells), thymus epithelium and activated (but not at rest) T cells.
EBV has been shown to decrease the expression of class II MHC molecules in antigen-presenting cells (especially in B cells), thereby decreasing the activation of T cells and leading to consequences similar to those produced by the disease called bare lymphocyte syndrome (class II MHC deficiency). This, coupled with an individual with genes from MHC class II molecules that are susceptible to developing EBV-associated diseases, will make it difficult to fight EBV infection. And since most of these diseases have numerous polymorphisms of these susceptibility genes, there will be a great genetic heterogeneity among the patients who develop one of these diseases, which manifests itself as a great phenotypic variability among the different patients who suffer from the same disease.

Hence, patients with EBV post-infection CFS have different symptoms. What they all share is a deficit in expression of MHC class II molecules due to the virus and genetic predisposition (HLA-DR15 or HLA-DQ6 for example).
Very good work!!! Congratulations!!! :thumbsup:

I read the summary in English and Spanish, and being Spanish my mother tongue and not being completely bilingual (even much less since I got sick), I think it is completely understandable in English. I am more or less used to reading technical English, but I am a bit more foggy than usual, so when I recover a bit I will try to read both texts and if I see something I can contribute with, I will do it with pleasure.

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gracias, thank you Manuel,
can you speak spanish ?
i live in Germany and i had ME for 13 years. 8 autoimmune disease more , and everything started with EPSTEIN BARR .
German doctors refuse to give me antivirals ( aciclovir, valaciclovir, valtrex)
Its different in Spain ? Could antivirals help i^?
hi @Berzerkerina ,
I'm afraid it's the same in Spain, so I did this work trying to demonstrate how an infection with Epstein-Barr virus, in people with genetic predisposition, can cause CFS. Hence this work can be downloaded by people and shown to their doctors.

Antivirals, in my opinion, could at least help to reduce the progression of the disease and decrease outbreaks.

I have to write in English so that others can understand it, even if I don't have a good level. If you want to ask me privately something in Spanish, I'll be glad to answer it.


Senior Member
Pacific Northwest
@Manuel I read your paper. It is very impressive - you have tied together a lot of topics and the theories show a lot of promise.

Your goal of getting doctors to recognize that EBV is at the root of many patients' problems is great - it likely is for many patients.

The key issue, though, for many patients, is to get doctors to take them seriously and provide adequate diagnostics and treatment.

As a patient, I have brought research articles to doctors - getting them to read them can be another issue entirely. I've been fortunate to see a top ME/CFS specialist and an excellent functional medicine doctor who have run hundreds of tests, in addition to tests run by an immunologist, infectious disease doctors, a rheumatologist, 3 neurologists, etc., likely more than most patients.

My ME/CFS specialist believes EBV is at the root of my issues and prescribed Valcyte, which helped, but I felt inadequate in providing answers to your survey.

My tests don't match up with what you're asking. I have never had a positive EBNA in multiple tests, but have had a positive PCR. I've had T cell panels, B cell panels, CD57 panels, and NK function testing, but don't think I answered your CD3 question with the info you wanted. I've had HLA DQ testing, but not the rest of the HLA sequencing - not sure it's available or that my insurance would cover it. And I have tests for autoimmune POTS and MCAS...

So, I'm wondering if other patients will be able to get those tests done, and more importantly, even if they do, if the results will match up with your theory. Should the list of tests be broader? What's actually needed for patients to get treatment prescribed?

And, is there a bullet point overview or a simplified flow chart (PowerPoint slide?) that illustrates the points in your paper for patients to hand their busy doctors, maybe with an action plan with a list of recommended tests and treatment options on the flip side?

I hope this isn't too impertinent... My thought is just to make your good work more digestible and useful for patients in getting the help they need.;)
Hi @Learner1 .

You're right that I should make a summary so the patients would understand better and I'm on it. But I've been with this article for a long time and wanted to get it out as soon as possible.

About the results you've put in. The antibodies against EBNA I'm asking for are IgG (I forgot to put it in, sorry). Anyone who has been infected with Epstein Barr virus has these positive antibodies. But in our disease (as in multiple sclerosis) I think it's much higher than normal.

The CD3 values you have set are absolute values for CD3 only. What I'm asking for are those CD3 cells that express DR+ (MHC II molecule). In other words, in order for T-lymphocytes to be functional, they must be activated by B-lymphocytes in the secondary lymphoid organs through the antigenic presentation MHC II. These T-lymphocytes express HLA-DR when activated. But due to the decreased expression of class II MHC molecules in antigen-presenting cells (B cells among others) due to EBV infection and genetic predisposition, the activation of these T cells will decrease. In Spain several laboratories do this under the name of CD3+ DR+ activated T-lymphocytes.

The type of HLA that would be of most interest in this case would be HLA-DR, so I mentioned earlier.
These tests, at least in Spain, if you have health insurance and your doctor prescribes it, are not difficult to get.

Another more invasive test is to perform PCR to EBV (does not have to be positive in the blood) on swollen tissue samples, such as the intestinal mucosa or muscle tissue if there is any myopathy. I would use other methods, such as in situ hybridization with a probe that detects EBV-coded RNA (EBER) and is considered the best test for locating latent EBV in tissue samples. O Immuno-FISH combining immunofluorescent staining for surface proteins (using antibodies directly conjugated to fluorochromes) and fluorescent in situ hybridization for EBV DNA. This technique allows simultaneous determination of the type of EBV-infected cells and quantification of the number of EBV copies in the infected cell, which demonstrates that EBV is present not only in B cells (in epithelial cells as well, for example).

I hope I have answered your questions. Thank you very much for your cooperation.

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Senior Member
Northants UK
Yes this is something I thought about myself Manuel as I also have had EBV followed by ME (CFIDS), since the middle of studying for my zoology degree in 1986. I spent ten years undiagnosed, it almost drove me crazy as it affected my brain quite badly, but I survived.

My perspective as a zoologist is that many viruses appear to have evolved convergently to use immunoevasins to attack the same weak points of the human immune system i.e. the antigen flag presentation system is an Achilles heel for us as is the regulation of the innate immune system.

EBV packs a double (at least) whammy and is very common but it is not alone as different viruses use different methods to attack the same immune defences, which may begin to account for the great variability in ME patients and their physical and molecular characteristics. Moreover different pathogens might synergise with each other in the same host.


IMHO the Open Medicine Foundation is our best hope yet for finding and demonstrating the truth about this condition and maybe finding treatments.

I am very interested to see what comes of Ron Davis's research into HLA, and his collaborations with Drs Naviaux on Dauer states and Robert Phair on metabolic traps.

Hi, @boolybooly
Yes, what you say about immunoevasins is included in the article. But it depends, above all, on the HLA system that each individual has, to resist or be more susceptible to these mechanisms of evasion of these viruses. Both cytomegalovirus and herpes zoster also decrease the expression of MHC class II molecules as well as EBV. But I have focused only on EBV, because first you have to classify subgroups by pathogens and see how they evade the immune system each of them. Later, I will try to do the same with other pathogens.

The bad thing about this disease is that by generating a MHC II deficiency, it causes the reactivation of other latent viral infections that the patient has (herpesvirus, Parvovirus B19...) All these reactivated pathogens had been controlled and did not generate any problems until the patient was infected with the pathogen causing his CFS. This indicates that the patient's HLA system predisposes him/her to problems with this particular pathogen (e.g. HLA-DR15 in multiple sclerosis due to EBV infection). That same type of HLA may have problems with more than one pathogen, but it is necessary to classify them one by one and then compare results and classify them.

This MHC II deficiency, in addition to favouring the reactivation of other viruses already present, makes it difficult to defend against other new viral infections. Against bacterial infections it may not affect as much, as B-lymphocytes can generate antibodies directly without collaborating with T-lymphocytes. B cells can directly detect polysaccharides or bacterial lipopolysaccharides by triggering their response. On the other hand, against viral infections if they need to collaborate with T-lymphocytes through MHC II.


Senior Member
Pacific Northwest
The antibodies against EBNA I'm asking for are IgG (I forgot to put it in, sorry). Anyone who has been infected with Epstein Barr virus has these positive antibodies.
You would think so, but this is not always the case. I was absolutely positive I did not have EBV, but with a very high VCA Off snd a positive PCR my doctor, a top ME/CFS specialist said, "I've never seen anyone with your particular combination of labs, but these show you do have it."

Chronic or recurrent EBV can be very tricky to diagnose. See the attached.

The CD3 values you have set are absolute values for CD3 only.
In the US, a major lab, LabCorp, calls it CD3 absolute, which is different than your labs in Spain.


  • serological EBV diagnosis.pdf
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  • deficient EBV response.PDF
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  • EBV diagnosis still challenging.pdf
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  • Realtime EBV PCR l.pdf
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