Human Herpesvirus 6 (HHV-6) and Chronic Fatigue Syndrome
Human Herpesvirus 6 (HHV-6) is one of eight known members of the human herpesvirus family. The virus, which was discovered in 1986 at the NCI, infects cells of the immune and central nervous system.

Serologic testing demonstrates that more than 95% of the worlds population is positive for antibodies to HHV-6, indication an immune response to infection by the virus. After initial infection, HHV-6 viral DNA remains latent within the cell nuclei in blood and other body tissue.

Two variants of HHV-6 are recognized: HHV-6A and HHV-6B. Primary infection with HHV-6B causes roseola in children and more than 95% of the population has antibodies to this variant. Primary infection with HHV-6A is believed to occur late childhood or adulthood and may occur without symptoms. The A strain is much more pathogenic and attacks the brain and immune system. The prevalence of HHV-6A infection is not known.

HHV6-A reactivation in adulthood can result in illness. Normally, reactivations are kept in check by the immune system and the virus resumes latency. Reactivation in adults has been associated with mononucleosis syndrome, autoimmune disorders, and nervous system diseases. HHV-6 has been specifically linked to MS, AIDS and CFS.

In individuals whose immune system has been compromised by disease (AIDS) or medical treatments (chemotherapy or immunosupressive drugs), a reactivation of HHV-6 can result in suppression of bone marrow function or inflammation and cause damage in tissues such as brain, liver, or lungs.

Recent studies have revealed active HHV-6 infections in single random blood samples taken from MS patients (54% positive) and CFS patients (39% positive). After testing a second sample from patients who were negative, 24% tested positive for active infection. Results showed that on average these samples were positive 50% of the time. This suggests that active infection of HHV-6 may be intermittent, with the viral load changing over time.

Normal healthy controls were negative for active HHV-6. This demonstrates that active HHV-6 infections are abnormal and not found in healthy people without disease associations.

Dr. Ablashi found that 70% of the HHV-6 isolates from patients were variant A, which is more neurotropic. He found that CFS patients exhibited HHV-6 DNA in the cerebrospinal fluid (CSF) and was able to infect cord blood cells with CSF from these patients. He concluded that HHV-6 may well account for the neurological manifestations in CFS patients.

In addition there is a wide spectrum of lymphoid, hematopoetic and autoimmune diseases which are associated with elevated titers of HHV-6, from which replicating virus has been isolated. Such diseases include atypical polyclonal lymphoproliferation, Hodgkin's disease, CFS and systemic lupus erythematosis.

Contrary to the findings of the CDC, HHV-6 can account for many of the clinical symptoms of CFS. The problem with the CDC testing, says Knox and Cartrigan, is that "it tested both patient and control groups using serum samples, lymphocytes and three PCR methods." These are not adequate means of detecting active HHV-6 infection.

The ability of HHV-6 to induce high level production of proinflammatory cytokines, combined with its frequent infection of the brain and spinal cord and its ability to infect and destroy all types of lymphocytes (including NK cells whose function is known to be impaired in CFS patients) can account for a range of clinical abnormalities that define CFS.

Whether or not these agents are causative, many studies have suggested that persistent viral activity plays a role in the perpetuation of symptoms. The good news is that the possibility exists that CFS may be effectively treated with currently available anti-viral medications. Longitudinal studies of antivirals are required to determine precisely what role HHV-6 infection plays in the pathogenesis of the disease.

Jill McLaughlin
Executive Director
National CFIDS Foundation, Inc.
Needham, MA 02492


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Chronic Fatigue Syndrome and Herpesviruses: the Fading Evidence.

Journal: Herpes 2000 May;7(2):46-50
Authors: Soto NE, Straus SE.
Affiliation: National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, USA.
NLM Citation: PMID: 11867001

Herpesviruses, in particular Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6), have, for the past two decades, come under considerable scrutiny as aetiological agents of chronic fatigue syndrome (CFS).

However, virological findings of herpesviruses in CFS have not been consistent between different studies, and the unusual patterns of serological responses to EBV, CMV and HHV-6 have not been specific for CFS, being observed also in asymptomatic individuals.

In addition, patients with symptomatology suggestive of CFS do not appear to have an increased frequency of these herpesviruses, as detected by culture or polymerase chain reaction, compared with controls, which argues against an ongoing active herpetic infection.

Studies have also shown that the presumable elevation of antibody titres to EBV, CMV or HHV-6 in CFS are not observed only with these viruses, but also with other organisms such as herpes simplex virus and measles.


H. Eastman, M. Roman, C. Owen, K. Olsen, K. Steininger, D. Peterson, S. Gupta, J. Whitman, and D. Ablashi

Over the years, many viral agents have been suspected in the etiology of CFS. Recently, HHV-6, a beta herpesvirus, has been reported to be involved in the pathogenesis of CFS. We investigated the active infection of HHV-6 in CFS patients using (1) short-term culture of peripheral blood mononuclear cells (PBMCs), (2) IgM and IgG antibody evaluation in the plasma, and (3) nested PCR on plasma, cerebral spinal fluid (CSF), and PBMCs. We also characterized the HHV-6 isolates obtained as being Variant A or B. Seven CFS patients showing active HHV-6 infection were treated with three different antiherpesvirus compounds (Foscarnet, Ganciclovir, Valciclovir) to see if control of HHV-6 infection would alter the clinical manifestations.

Specifically, we studied 24 CFS patients staged according to the severity of the disease. These patients came from Sierra Internal Medicine, Incline Village, NV, and the Medical Sciences Division, University of California at Irvine, Irvine, CA. The immunovirological assays used (i.e., IFA to detect HHV-6 antigen positive cells or to titer plasma for antibody) have previously been described (Ablashi et al., J Clin Virol 16:129, 2000). PBMCs from CFS patients were cultured (14 days) to detect HHV-6 infection using HHV-6 monoclonal antibodies. The modified nested PCR protocol used was based on the method described by Secchiero el al. (J Clin Microbiol 33:2124, 1997). HHV-6 specific primers against the major capsid protein were used. These primers generate a 258 bp fragment in the second stage PCR. DNA was isolated from PBMCs, plasma, and CSF samples using QIAgen columns.

1. HHV-6 infection was detected in 14/24 (58.3%) of the CFS patients by the methods described. HHV-6 infection was detected in the PBMCs in short-term culture as early as three days, using IFA and HHV-6 early (p41) and late (gpl 16) monoclonal antibodies. The number of infected PBMCs varied from patient to patient. 2. IgM antibody to HHV-6 detected by IFA ranged from 1:20 to >1:160, and the IgG titer ranged from 1:80 to 1:1280. The presence of HHV-6 IgM antibody correlated well with the presence of HHV-6 in the PBMCs in 85% of the samples studied. 3. Nested PCR detected HHV-6 DNA in 15% of the plasmas and 25% of the CSF from the CFS patients. 4. Approximately 70% of the HHV-6 isolates from CFS patients were Variant A. 5. Out of the seven patients treated with antiviral compounds, the patient treated with Foscarnet clinically improved, and no HHV-6 infection was detectable. Of the four patients treated with Ganciclovir, only one showed slight clinical improvement. However, HHV-6 infection could be detected in the PBMCs of this patient. Of the two patients treated with Valciclovir, one improved clinically with no HHV-6 infection detectable. The second patient remained HHV-6 negative without any clinical improvement.

1.) The data presented, although preliminary, show that the majority of CFS patients studied have HHV-6 infection.

2.) It was surprising to find CFS patients exhibiting HHV-6 DNA in the CSF or plasma as well as in HCBMCs infected with CSF from these patients. These data suggest the presence of cell-free infectious virus in the CSF. In CFS, it is possible that HHV-6 is invading the central nervous system and may participate in the neurological manifestations associated with this disease.

3.) Seventy percent of the HHV-6 isolates from CFS patients were classified as Variant A, which is more neuro-tropic.

4.) Potent antiviral agents, such as Foscarnet and Valciclovir, are useful in suppressing HHV-6, thereby resulting in improved patient condition. However, longitudinal studies of more patients with CFS using newer antiviral agents which are less toxic are required to determine what specific role HHV-6 infection plays in the pathogenesis of this disease. AACFS - 5th International Research Conference, at Seattle, Washington 2001

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