Disclosure: Dr Henderson is the president and owner of The Synaptic Space, a neuroimaging consulting firm, president and owner of Dr. Theodore Henderson Inc, and co-owner of Neuro-Luminance Corporation.
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a disorder characterized by marked fatigue, exertion induced malaise, cognitive clouding (or brain fog), impaired academic/work performance, disrupted sleep, and joint/muscle pain. Individually, these symptoms are vague and non-specific; however, in combination the clinical picture is quite reliable. Nevertheless, there is no quantitative test for CFS/ME.
As a result, CFS/ME has been much maligned by the medical community. Patients are often disparaged for being lazy, or dismissed as merely psychosomatic malingerers. As one of my patients said, “The doctor looked at me and said, ‘You’re young! You have no reason to be tired. You just need to exercise more.’ It had taken every bit of strength I had to get out of bed and walk across campus and he wanted me to exercise more. Something was wrong and nobody seemed to care!”
The role of viruses in CFS/ME
In 2015, a consensus review of CFS/ME published by the Institute of Medicine of the National Academies in Washington, DC1 stated that CFS/ME was likely caused by viruses and claimed that the studies supporting cognitive behavioral therapy and graded exercise have been manipulated to exaggerate their benefit.2 The most probable viral culprits were Epstein-Barr virus (EBV), also known as herpes 4, and human herpes virus 6 (HHV6).1,3
Over the last 2 decades, much work has been done on the role of a variety of viruses, particularly those in the herpes family, in persistent neurological, psychiatric, and other disorders. My own work on the role of EBV and HHV6 in CFS/ME in children was published in 2014.4 A recent report from the Mayo Clinic suggests herpes 5 or cytomegalovirus (CMV) may have a role in bipolar disorder.5
The herpes family of viruses are neurotropic and can establish persistent or recurrent infections. Genital herpes (herpes 2) can cause recurrent infections and varicella (herpes 3) can cause an acute infection (chicken pox), which evolves into a chronic infection in neurons. Decades later, when the body becomes stressed or immunocompromised, varicella re-emerges as shingles. Similarly, EBV and HHV6 can become latent or dormant in the body after exposure. Nevertheless, many physicians – in scientific meetings, insurance reviews, disability hearings, and when consulting on individual patients – adamantly deny that EBV and HHV6 may also cause persistent or recurrent infections, let alone infect the brain.
In 2018, a landmark paper examining samples of tissue from a brain bank for evidence of HHV6 infection gave ammunition to end that argument.6 Among the control sample, 22% had HHV6 protein and a larger percentage had HHV6 DNA in neurons. In contrast, among cases with depression, 73% of the cases had HHV6 protein and 87% had HHV6 DNA in neurons.6 Prusty and colleagues shook the ground with this paper. Not only did they find proteins of HHV6 inside brain cells, but confirmed the presence of the virus by a second set of distinct antibodies of different proteins, direct visualization using electron microscopy, and amplification and identification of the DNA of HHV6 inside the neurons of the same brains.
Treating CFS/ME as though it is caused by a virus
Not surprisingly, those who have made a leap in their thinking about CFS/ME have found that treating it like a viral illness yields some success. Lerner and colleagues7,8 showed that treatment with the antiviral valacyclovir reduced symptoms of CFS/ME, as well as antibody titers and cardiac symptoms. Montoya and colleagues found that elevated antibody titers of EBV and HHV6 among patients with CFS/ME predicted a positive response to the antiviral valgancyclovir.9 In my own clinic, I have treated hundreds of patients with antivirals and found about 70% of the cases improve.
As a brief example, a 13 year-old patient began missing school due to fever, fatigue, and sore throat. Multiple tests revealed nothing. She was told it would pass in a few weeks. However, 3 years later, she was still exhausted and unable to attend school. She had bouts of muscle pain, was continuously fatigued, and struggled with profound brain fog. She was tried on multiple antidepressants for presumptive depression, although she denied feeling sad – she just felt tired. Eventually, she came to my clinic. Her fatigue symptoms scales were elevated and she tested positive for EBV, but not HHV6 antibodies. She was started on valacyclovir. After 3 months, she experienced a rapid improvement with renewed energy, mental clarity, and freedom from pain. After 6 months, she returned to school. She completed high school and then went on to a rigorous college program in virology. She has remained on valacyclovir throughout these years and experiences a recurrence of symptoms whenever she stops antiviral therapy.
There is a problem with the claim that EBV, HHV6, HSV1, or CMV are involved in CFS/ME, depression, mania, Alzheimer dementia, or any other disease: supposedly 90-100% of people are infected with HHV6 by age 3,10,11 and HSV1 and EBV reportedly infect a majority of the population.12 How could these ubiquitous viruses cause serious illness in only a small portion of the population?
Firstly, the exposure rates are most likely incorrect. Robinson and colleagues12 allege that 100% of the population has HSV1, but a meta-analysis revealed the global rate was only 67% and rates range from 43% to 91% across regions.13-17 Moreover, longitudinal data showed that the rate of HSV1 in the population has been dropping over time.16,17 In my clinic, I have found that only 41% of patients with CFS/ME, who I test, have antibodies to HSV1 and 47% have antibodies to EBV. The supposedly ubiquitous HHV6 is found in only 70% of my patients. In other words, roughly 59% and 30% of my patients either have not been exposed to HSV1 or HHV6, respectively, or they were exposed, but did not make any antibodies.
Over the years, my findings have been challenged by physicians performing PCR on the blood of my CFS/ME patients and not finding DNA for any herpes viruses. If a patient has HHV6 in the neurons of their brain, where it is happily replicating and spreading via axonal transport, why would you expect to find HHV6 DNA in the blood? Patients with cold sores rarely have signs of HSV1 DNA in their bloodstream and patients with active herpetic lesions of the genitalia rarely have a detectable serum viral load. Prusty and colleagues18 examined the blood of patients with confirmed CFS/ME for HHV6 DNA or RNA. Indeed, no more than 40% showed evidence of HHV6 in the blood. So, how could these viruses cause systemic illness when they are confined to a relatively small number of neurons? To answer that question, I must first explain how mitochondria fit into the picture.
The role of mitochondria in illness and health
A number of disorders show clear evidence of mitochondrial dysfunction, including multiple sclerosis,19 depression,20,21 Alzheimer disease,22 and Parkinson disease.23 Abnormal function of mitochondria is also found in CFS/ME. Changes in mitochondrial structure, reduced ATP production, and increased oxidative stress have been described in CFS/ME.24,25 Patients with CFS/ME are intimately familiar with mitochondrial dysfunction in the form of the amplified fatigue of a “crash” that occurs after they overexert themselves.
This mitochondrial dysfunction manifests clinically in a cardiopulmonary exercise test-retest, where a patient engages in maximal effort exercise on a treadmill or other device while the clinician is measuring oxygen consumption, blood pH, blood lactate levels, and other measures.26 Blood pH and lactate levels are important because they increase when the mitochondria in the muscles cannot keep up with the workload and the muscles switch to anaerobic metabolism.
On day 1, maximal effect exercise is performed, which will usually induce a crash. On day 2, the patient performs a second maximal effort exercise test. Typically, a CFS/ME patient will not be able to reach the same maximal oxygen capacity and will show a lower threshold to switching to anaerobic metabolism on the second day. This cannot be faked: one cannot simply will their blood pH to increase, lactate to build up, and their temperature to paradoxically fall. The patient’s mitochondria are not functioning with a normal capacity. To understand why, we need to understand the innate immune system.
The role of mitochondria in the innate immune system
Mitochondria play a central role in the dance of molecules that serve as our first line of defense against invading viruses – the innate immune system, which provides a nonspecific defense against pathogens.27-29 Bacteria and viruses have a number of conserved or commonly found proteins or nucleic acid sequences, which are recognized by receptors found on mitochondria and other intracellular structures called pattern recognition receptors (PRRs). These PRRs trigger a wide array of molecular signaling pathways, which activate a pro-inflammatory state with increased cytokines and interferons.
Mitochondria, usually depicted as bean or egg shaped distinct bodies, can fuse or split in response to metabolic demands within the cell. They can also split as part of the innate immune response to viruses. Certain viruses including coronaviruses can sabotage this defense mechanism, causing mitochondria to elongate and hyperfuse (Illustration by Taylor Tuteur).
Mitochondria have a vital role in the molecular signaling responsible for this innate response.27-29 Mitochondrial antiviral signaling protein on the outer membrane can strongly bind various PRRs and respond by activating a cascade of second messengers, which induce RNA transcription and cytokine production. Together, these and many other molecules facilitate the increase in reactive oxygen species, pro-inflammatory cytokines and chemokines, and upregulation of interferon, which results in an environment less conducive to viral replication.29
Given that mitochondrial function appears altered in CFS/ME, Prusty and colleagues began unraveling why and how this occurred. HHV6 is capable of integrating into the human chromosome, remaining latent for years. They found that HHV6 is capable of partially reactivating from this integrated state; that is, only a small number of viral proteins are transcribed and no complete virus is made. These few viral proteins have a potent effect on the cell.
Important mitochondrial proteins are downregulated, including those involved in glycolytic pathways, fatty acid oxidation, and other key pathways. Notably, superoxide dismutase 2 expression is decreased, resulting in increases in reactive oxygen species, a common finding in CFS/ME.30 This partial reactivation of HHV6 also leads to lower ATP content and fragmentation of the mitochondria (see Figure), which are less capable of mounting an innate immune response and activate a pro-inflammatory cell danger response (CDR), a generalized response to any menace to the cell. During a CDR, there is a cascade of changes in bioenergetics, redox states, reactive oxygen species, and a shift away from aerobic metabolism and toward a sustained pro-inflammatory state.31
Prusty and colleagues18 incubated naïve cells in the supernatant from cultures of cells in which HHV6 had been partially reactivated. Remarkably, the naïve cells developed fragmented mitochondria and a pro-inflammatory state as though they had experienced HHV6 reactivation themselves, proving that some unknown soluble factor (USF) could induce this state in distant cells. So, the question of how a relatively small number of HHV6 reactivated cells not replicating virus could cause systemic disease throughout the body was now answered.
They then exposed naïve cells to the supernatant of HHV6 reactivated cells, which presumably contained this USF. After 48 hours, they washed off the supernatant and applied fresh media. Then, they exposed the cells to either influenza-A (an RNA virus) or HSV1 (a DNA virus) in an attempt to induce an infection. Shockingly, virtually none of the USF-treated cells became infected. This USF had completely prevented infection by both influenza-A and HSV1, which raises the possibility that USF could prevent infection by other RNA or DNA viruses.18 From the perspective of HHV6, this is a smart move; it protects its home from other viruses that might destroy its host cell.
The investigators then collected sera from patients with confirmed CFS/ME and repeated the experiment. Naïve cells were incubated with patient sera and then washed and given fresh culture media. The fresh media was then infected with influenza-A or HSV1. The number of infected cells was 99% lower among the serum-treated cells compared to controls.18 Neither RNA nor DNA viruses could infect these cells pretreated by serum from patients with CFS/ME.
The significance of these findings is staggering. First, in terms of patients with CFS/ME, it brings some sense to their symptoms. Regardless of whether patients are infected with other herpes viruses, if they have chromosomally integrated HHV6, then this unidentified USF could impair mitochondrial function throughout their body. The consequences would be the familiar symptoms of fatigue, postexertional malaise, etc.
Second, this USF may hold a key to combatting other viruses. If it could be isolated and produced in large quantities, it might serve as a new potent antiviral agent. For example, SARS-CoV, the RNA virus responsible for the SARS epidemic, elongates mitochondria and disrupts the function of mitochondrial antiviral signaling protein.32 SARS-CoV is closely related to the RNA virus COVID-19. Third, this USF induces fragmentation of mitochondria and a pro-inflammatory state in exposed cells. As a result, there may finally be some good news for patients with CFS/ME who have this partial reactivation of HHV6. They may experience cellular protection from both RNA and DNA viruses as a result of this USF.
Third, Prusty and colleagues have laid out the protocol for an assay for CFS/ME, or at least a portion of those affected by this disease. While it is unclear how many CFS/ME patients have chromosomally integrated HHV6 (40% were positive for HHV6 RNA or DNA), the sera of all CFS/ME patients in their study induced viral inhibition. Therefore, this protocol could serve as a new quantifiable, nonsubjective, and therefore inarguable test for CFS/ME, representing a major step forward for the treatment and research in this neglected disease.
Herein, I lay out the proof for several important pieces of the CFS/ME puzzle.
1) HHV6 and HSV1 and therefore likely the other neurotrophic herpes family viruses can invade the brain and replicate there, potentially spreading to many neurons
2) HHV6 can integrate into the human genome
3) HHV6 partial reactivation impairs mitochondrial function, including decreased ATP production and induces a pro-inflammatory state
4) Serum from patients with CFS/ME carry the ability to impede mitochondrial function in naïve cells
5) Serum from patients with CFS/ME may carry some factor that can impart protection from viral infection to naïve cells
6) This protective factor raises exciting possibilities for a new approach to protection from COVID-19
7) The protective factor can be developed into a diagnostic assay for CFS/ME giving the first definitive test for this much beleaguered and neglected disease.
8) A definitive test is the first step to better research, more funding, and greater federal attention to CFS/ME, which affects an estimated 24 million worldwide33-35
1. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. www.ncbi.nlm.nih.gov/books/NBK274235/pdf/Bookshelf_NBK274235.pdf Accessed February 21, 2015.
2. Smith MEB, Nelson HD, Haney E, et al. Diagnosis and treatment of myalgic encephalomyelitis/chronic fatigue syndrome. evidence report/technology assessment No. 219. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-I.) AHRQ Publication No. 15-E001-EF. Rockville, MD: Agency for Healthcare Research and Quality; December 2014. https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/chronic-fatigue_research.pdf. Accessed June 16, 2020
3. Henderson, TA. The role of antiviral therapy in chronic fatigue syndrome. http://www.psychiatryadvisor.com/opinion/the-role-of-antiviral-therapy-in-chronic-fatigue-treatment/article/405424/. Accessed May 17, 2020.
4. Henderson TA. Valacyclovir treatment of chronic fatigue in adolescents. Adv Mind Body Med. 2014 Winter;28(1):4-14.
5. Frye MA, Coombes BJ, McElroy SL, et al. Association of cytomegalovirus and toxoplasma gondii antibody titers with bipolar disorder. JAMA Psychiatry. 2019;76(12):1285-93.
6. Prusty BK, Gulve N, Govind S, et al. Active HHV-6 Infection of cerebellar purkinje cells in mood disorders. Front Microbiol. 2018 Aug 21;9:1955.
7. Lerner AM, Beqaj SH, Deeter RG, et al. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today (Barc). 2002;38(8):549-561.
8. Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007;21(5):707-713.
9. Kogelnik AM, Loomis K, Hoegh-Petersen M, et al. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. J Clin Virol. 2006;37(suppl 1):S33-S38.
10. LevyJ A, Ferro F, Greenspan, DLennette ET. Frequent isolation of HHV-6 from saliva and high seroprevalence of the virus in the population. Lancet 1990;335:1047–1050.
11. Cone RW, Huang ML, Ashley R, Corey L. Human herpesvirus 6 DNA in peripheral blood cells and saliva from immunocompetent individuals. J. Clin. Microbiol. 1992;31:1262–1267.
12. Robinson SR, Dobson C, Lyons J. Challenges and directions for the pathogen hypothesis of Alzheimer’s disease. Neurobiol Aging. 2004;25(5):629-37.
13. Looker KJ, Magaret AS, May MT, et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLoS One. 2015;10(10):e0140765.
14. Khadr L, Harfouche M, Omori R, et al. The epidemiology of herpes simplex virus type 1 in Asia: systematic Review, meta-analyses, and meta-regressions. Clin Infect Dis. 2019;68(5):757-772.
15. Chaabane S, Harfouche M, Chemaitelly H, et al. Herpes simplex virus type 1 epidemiology in the Middle East and North Africa: systematic review, meta-analyses, and meta-regressions. Sci Rep. 2019;9(1):1136.
16. Woestenberg PJ, Tjhie JH, de Melker HE, et al. Herpes simplex virus type 1 and type 2 in the Netherlands: seroprevalence, risk factors and changes during a 12-year period. BMC Infect Dis. 2016;16:364.
17. Bradley H, Markowitz LE, Gibson T, McQuillan GM. Seroprevalence of herpes simplex virus types 1 and 2–United States, 1999-2010. J Infect Dis. 2014;209(3):325-33.
18. Schreiner P, Harrer T, Scheibenbogen C, et al. Human herpesvirus-6 reactivation, mitochondrial fragmentation, and the coordination of antiviral and metabolic phenotypes in myalgic encephalomyelitis/chronic fatigue syndrome. Immunohorizons. 2020;4(4):201-215.
19. Barcelos IP, Troxell RM, Graves JS. Mitochondrial dysfunction and multiple sclerosis. Biology (Basel). 2019;8(2). pii: E37.
20. Kambe Y, Miyata A. Potential involvement of the mitochondrial unfolded protein response in depressive-like symptoms in mice. Neurosci Lett. 2015;588:166-71.
21. Henderson TA, Morries LD. Multi-Watt near-infrared phototherapy for the treatment of comorbid depression: an open label single arm study. Front Psychiatry. 2017;8:187.
22. Reddy PH. Mitochondrial dysfunction in aging and Alzheimer’s disease: strategies to protect neurons. Antioxid Redox Signal. 2007;9(10):1647-58.
23. Vali S, Mythri RB, Jagatha B, et al. Integrating glutathione metabolism and mitochondrial dysfunction with implications for Parkinson’s disease: a dynamic model. Neuroscience. 2007;149(4):917-30.
24. Smits B, van den Heuvel L, Knoop H, et al. Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome. Mitochondrion. 2011;11(5):735-8.
25. Prusty BK, Gulve N, Chowdhury SR, et al. HHV-6 encoded small non-coding RNAs define an intermediate and early stage in viral reactivation. Genom Med. 2018; 5;3:25.
26. Stevens S, Snell C, Stevens J, et al. Cardiopulmonary exercise test methodology for assessing exertion intolerance myalgic encephalomyelitis/chronic fatigue syndrome. Front Pediatr. 2018;4;6:242.
27. Kim SJ, Ahn DG, Syed GH, Siddiqui A. The essential role of mitochondrial dynamics in antiviral immunity. Mitochondrion. 2018;41:21-27.
28. Tiku V, Tan MW, Dikic I. Mitochondrial functions in infection and immunity. Trends Cell Biol. 2020;30(4):263-275.
29. West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol. 2011;11(6):389-402.
30. Prusty, BK, Bohme L, Bergmann B, et al. Imbalanced oxidative stress causes chlamydial persistence during non-productive human herpes virus co-infection. PLoS One 2012;7: e47427.
31. Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014;16:7-17.
32. Shi CS, Qi HY, Boularan C, et al. SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. J Immunol. 2014;193(6):3080-9.
33. Friedman KJ. Advances in ME/CFS: past, present, and future. Front Pediatr. 2019;7:131. doi: 10.3389/fped.2019.00131
34. Estévez-López F, Mudie K, Wang-Steverding X, et al. Systematic review of the epidemiological burden of myalgic encephalomyelitis/chronic fatigue syndrome across europe: current evidence and EUROMENE research recommendations for epidemiology. J Clin Med. 2020;9(5):E1557.
35. Ponting C, Sanchez-Pulido L, Nicoll-Baines K, et al. Analysis of data from 500,000 individuals in UK Biobank demonstrates an inherited component to ME/CFS. https://mecfsresearchreview.me/2018/06/11/analysis-of-data-from-500000-individuals-in-uk-biobank-demonstrates-an-inherited-component-to-me-cfs/. Accessed June 16, 2020.