EBV III: HERV’s, Treatment Studies, Summary

The Epstein Barr Virus Series on Phoenix Rising

Since EBV reactivation commonly occurs in healthy people but rarely produces symptoms a finding of EBV reactivation is not necessarily a cause for alarm. But could EBV reactivation be more likely to cause harm in ME/ CFS patients than others?

Some researchers suggest that while many of the pathogens found in ME/ CFS patients do not cause ME/ CFS they may make its underlying problems worse. A recent study indicates EBV could possibly accelerate disease pathology in some people by activating retroviral elements in our DNA (Sutkowski et. al.  2004).  It turns out that a significant portion of our DNA (up to 8%) is composed of old degraded and mutated retroviruses that have managed to insert themselves into our genome. Although most are inactive some may not be…… Could the EBV reactivation present in some chronic fatigue syndrome (ME/ CFS) patient’s be turning on the retroviral elements in their DNA?

The EBV/Endogenous Retrovirus (HERV) Connection?

The Sutkowski  study found that EBV produces proteins which are able to reactivate a portion of a human endogenous retrovirus K18 (HERV-K18) that produces a ‘superantigen’. Superantigens are proteins produced by viruses or bacteria that are able, by binding to a certain spot on T-cells, to provoke unusually large T-cell responses. The herpesvirus family is one of three viral families (hesperviridae, retroviridae, rhadboviridae) able to produce superantigens. Dr. De Meirleir has suggested that the RNase L fragmentation and immune system activation in CFS could be due to HERV activation.

Since the proteins (LMP-2A, LMP-1) that activate the superantigen are associated with EBV’s latent phase they are presumably, since EBV is in the body for life, always present. This was a laboratory study – we don’t know under what conditions EBV is able to do this is the body – but it presents the potential for a great deal of immune disruption. .

Since the HHV-6 herpesvirus is also able to reactivate EBV one could envision the following chain reaction; HHV-6 reactivates EBV which reactivates HERV (which causes T/NK cell suppression, immune dysfunction, etc. Some researchers believe an undiagnosed HHV-6A infection could cause many of the problems in CFS.

As yet here is no evidence it is happening in ME/ CFS. We should know more about HERV-K18 and CFS pretty soon – both the NIH and the CFIDS Association of America are funding studies  examining HERV – K18 activity in ME/ CFS

Treatment Studies

Treatment studies and reports provide the most convincing evidence that EBV infection plays a significant role for at least some chronic fatigue syndrome patients.

An antiviral therapy trial that resulted in much decreased symptoms and increased energy and improved ventricular functioning for about 2/3rds of ME/ CFS patients at 18 months suggests an EBV associated cardiomyopathy may be important in some patients (Lerner et. al. 2002a).

A 2007 study by Dr. Lerner found that long-term use of Valacyclovir (> 1year) in EBV positive patients resulted in reduced EBV VCA IgM antibodies, significantly improved heart functioning (sinus tachycardias,abnormal cardiac wall motion) and progressive improvement functioning overall. Dr. Lerner reported that ‘patients resumed normal activities’.

A small 2006 valganciclovir study of patients with increased IgG titers to EBV and HHV-6 found that nine of 12 patients with severe long-term disability returned to normal functioning. A follow-up larger trial – which has not been published – did not have markedly positive effects. The trial has reportedly been extended to 12 months to determine if longer antiviral treatment will show results. Several doctors including Dr. Peterson and Dr. Lerner have indicated that long-term antiviral treatments are often necessary to show significant results.

A recent study may explain why long time antiviral therapy may be necessary (Hoshino 2009). It found that Valacyclovir reduces cell to cell reinfection but does not effect EBV infected cells. Since cell to cell reinfection is the chief means EBV has of maintaining itself in the body very long term antiviral therapy could reduce EBV infection rates simply by allowing infected B cells to die off over time without being replaced.

Rituximab and EBV

A 2009 case study featuring an B-cell depleting anticancer drug called methotrexate stirred the EBV pot considerably (Fluge and Mella 2009). A chronic fatigue syndrome patient had developed severe fatigue, headaches, sleep disturbances, concentration problems, and severe muscle and skin pain. etc. after coming down with infectious mononucleosis 10 years earlier. Following chemotherapy for Hodgkin’s lymphoma she unexpectedly demonstrated a significant improvement from her chronic fatigue syndrome symptoms. For four to five months she was able to walk for long distances pain free, etc.after which her pain and symptoms gradually recurred. Stem cell therapy successfully treated me recurrence of the Hodgkins lymphoma but did not positively affect her chronic fatigue syndrome symptoms.

She and two other ME/CFS patients with infectious mononucleosis onset were later treated with the B-cell depleting drug Rituximab. Interestingly none of the patients tested positive for active EBV infection using standard serological or PCR techniques. All had high IgG titers and zero IgM titers.

Two experienced dramatic improvement six weeks (and one 26 weeks) after a single Rituximab injection after which their symptoms slowly returned. Follow up injections produced a similar result. The authors of the study postulated that  reduced antibody or auto-antibody production was responsible for their improvements – suggesting that ME/CFS may have an autoimmune component that is possibly driven by a chronic B-cell infection (eg EBV or another virus).  No problematic side effects were reported. The authors are reportedly engaging in further studies.

The Rituximab case study suggests a possible duo treatment regime for post infectious mononucleosis ME/CFS patients.

Summary

It appears that we are not nearly done examining EBV’s role in ME/ CFS. The Dubbo studies (and others) have indicated that about 10% of patients with infectious mononucleosis come down with ME/CFS. Why this happens is still unclear but may have to do with a slightly slower immune response that enables EBV to strike more quickly and virulently.

Epstein-Barr virus in chronic fatigue syndromeThe Dubbo researchers believe the initial EBV infection is resolved but others disagree. Both Dr. Glaser and Dr. Lerner believe that the immune system is able to stop EBV replication but is unable to shut it down completely. Dr. Glaser believes the chronic production of enzymes produced early in EBV’s life cycle triggers an immune response that is the symptoms present in ME/ CFS. Dr. Lerner believes a chronic herpesvirus infection is damaging the hearts of a subset of”ME/CFS patients.

Dr. Lerner’s treatment trials suggest long term antiviral therapy may be very helpful for a subset of patients. A small  but successful trial of the B-cell depleting drug Rituximab in infectious mononucleosis onset ME/CFS patients potentially adds an intriguing tool to physician toolkit’s.

EBV may be well adapted to attack ME/CFS patients. Several studies indicate that ME/ CFS patients often experience increased stress levels prior to their becoming ill, and EBV targets a part of the immune system (B lymphocytes) that are activated during periods of chronic stress. EBV also appears adapted to thrive during a pronounced Th2 cytokine (anti-inflammatory) response  which some researchers believe is prevalent in chronic fatigue syndrome.

The ongoing Dubbo studies, an NIH funded study by Dr. Taylor, Dr. Montoya’s and Dr. Lerner’s research and the exciting Rituximab study should keep the EBV/ME/ CFS interaction in the news.

The Phoenix Rising website and most of the articles in it are created by a layman. It is not a substitute for a physician and is for informational uses only.

REFERENCES

Cacioppo, J., Kiecolt-Glaser, J., Malarkey, W., Laskowski, B., Rozlog, L., Poehlmann, K., Burleson, M. and R. Glaser. 2001. Autonomic and glucocorticoid associations with the steady state expression of latent Epstein-Barr virus.  Hormones and Behavior 42, 32-41.

Cameron, B., Bharadwaj, M., Burrows, J., Fazou, C., Hickie, French, R., Khanna, R. and A. Lloyd. 2006. Prolonged Illness after infectious mononucleosis is associated with altered immunity but not with increased viral load. Journal of Infectious Diseases 193, 664-671.

Fluge, O and Mella, O. Clinical Impact of B-cell depletion with the anti-CD20 antibody Rituximab in chronic fatigue syndrome, a case series.
BMC Neurology, 2009, 9:28.

Glaser, R., Padgett, D., Litsky, M., Baiocchi R., Yang, E., Chen, M., Yeh, P., Klimas, N., Marshall, G., Whiteside, T., Herberman, R., Kiecolt-Glaser, J., and M. Williams. 2005. Stress-associated changes in the steady-state expression of latent Epstein-Barr virus; implications for Chronic Fatigue Syndrome and cancer. Brain, Behavior and Immunity 19: 91-103.

Hollsberg P, Kusk M, Bech E, Hansen HJ, Jakobsen J, Haahr S. 2005. Presence of Epstein-Barr virus and human herpesvirus 6B DNA in multiple sclerosis patients: associations with disease activity. Acta Neurol Scand.;112(6):395-402.

Hoshino Yo, Katano D, et. al. Long-term administration of valacyclovir reduces the number of EBV infected cells. Journal of Virology, published online September, 2009.

Jones, J., Williams, M., Schooley, R., Robinson, C. and R. Glaser. 1988. Antibodies to Epstein-Barr virus specific DNase and DNA polymerase in the chronic fatigue syndrome. Arch. Intern. Med. 148, 1957-1960.

Lerner, AM, Beqaj SH, Deeter RG, Dworkin HJ, Zervos M, Chang CH, Fitzgerald JT, Goldstein J, O’Neill W. 2002a. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today (Barc). 38(8):549-61.

Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. 2002b. IgM serum antibodies to human cytomegalovirus nonstructural gene products p52 and CM2(UL44 and UL57) are uniquely present in a subset of patients with chronic fatigue syndrome. In Vivo. 2002 16 (3):153-9.

Lerner AM, Dworkin HJ, Sayyed T, Chang CH, Fitzgerald JT, Beqaj S, Deeter RG, Goldstein J, Gottipolu P, O’Neill W. 2004a. Prevalence of abnormal cardiac wall motion in the cardiomyopathy associated with incomplete multiplication of Epstein-Barr Virus and/or cytomegalovirus in patients with chronic fatigue syndrome.In Vivo. 18(4):417-24

Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT., 2004b. IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome. In Vivo. 2004 Mar-Apr;18(2):101-6.

Peckerman, A., LaManca, J., Dahl, K., Chemitiganti,R., Qureishi, B. and B. Natelson. Abnormal Impedance Cardiography predicts symptom severity in chronic fatigue syndrome. The American Journal of the Medical Sciences.326:55-60.

Natelson, B., Ye, N., Moul, D., Jenkins, F., Oren, D., Tapp, W., and Y. Cheng. 1994. High titers of anti Epstein-Barr virus DNA polymerase are found in patients with severe fatiguing illness. J. Med. Virol. 42, 42-46.

Padgett, D., Hotchkiss, A., Pyter, L., Nelson, R., Yang, E., Yeh, P., Litsky, M., Williams, M. and R. Glaser. 2004. Epstein-Barr Virus-encoded dUTPase modulates immune function and induces sickness behavior in mice.

Sutkowski, N., Chen, G., Calderon, G. and B. Huber. 2004. Epstein-Barr Virus latent membrane protein LMP-2A is sufficient for transactivation of the Human Endogenous Retrovirus HERV-K18 superantigen. Journal of Virology 78, 7852-7860. S., Whistler, T., Cameron, B., Hickie, , Reeves, W. and A. Lloyd. 2006. Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr Virus. BMC Infectious Diseases 6: 15.

White, P., Thomas, J. and A. Mess. 1998. Incidence, risk and prognosis for acute and chronic fatigue syndromes and psychological disorders after glandular fever. Br. J. Psychiatry 173, 475-4hein anin78.

White, P., Thomas, J., Kangro, H., Bruce-Jones, W., Arness, J., Crawford, D.,Grover, S. and A. Cleare. 2001. Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet 358, 1946-54.

2 comments

{ 1 comment… read it below or add one }

Gary J.Edgerton July 18, 2013 at 9:38 am

My question is; after experiencing a severe mononucleosis infection in the past, what effect on the human body do extremely high levels of EBNA and VCA IGG have? Is it possible for someone to feel ill simply due to the result of the stress and strain these high titers place on the immune system in general?

Becoming re-infected with the Epstein-Barr virus is extremely rare. However, more research is needed with regards to the effects of the possible long-term hyperactive immune responses to this disease. Rather than trying to simply make it fit under the wastebasket diagnosis of Chronic Fatigue Syndrome, folks like myself who have had mono in the past and still suffer from chronic low-grade fevers, on and off swollen glands and disabling fatigue are deserving of more thorough studies in this area.

Reply

Leave a Comment