Human herpesvirus 6 or HHV-6 was serendipitously discovered when enlarged balloon-like cells were discovered in AIDS patients with cancer. A ubiquitous virus, HHV-6 is established in virtually everyone past the age of two. HHV-6 infection during childhood is usually benign and goes unnoticed but fever and rash sometimes occur.
In extreme cases seizures, gait problems and learning difficulty may result. HHV-6 is now the focus of research involving immune suppression (organ transplantation), multiple sclerosis, cardiomyopathy, hepatitis, epilepsy, chronic fatigue syndrome, optic neuropathy, etc
HHV-6A and HHV-6B
HHV-6’s two variants, HHV-6A and HHV-6B, were uncovered in 1991 by Daram Ablashi and colleagues (Ablashi et al. 1991). Although genetically almost a match (88% similarity) they differ significantly in important areas including means of transmission, prevalence, the types of cells they infect and the types of illness they may cause. Most researchers still do not differentiate between the two.
HHV-6A has generated the most interest in multiple sclerosis and chronic fatigue syndrome (ME/CFS) but it is still unclear which variant plays the greatest role. HHV-6A is more prevalent in the cerebral spinal fluid of ME/CFS patients but HHV-6B could more prevalent in the difficult to reach brain tissues. HHV-6B is associated primarily with early childhood infections – and, in rare cases, meningitis, encephalitis and epilepsy.
Tests discriminating between the two invariably find that HHV-6B is the predominant strain in healthy people (Caserta et al. 2003). While HHV-6B is almost ubiquitous in children past two, HHV-6A is rarely detected in them. Its incidence in the general population is lower but unknown.
One reason for HHV-6B’s greater prevalence may be its means of transmission; while HHV-6B is easily transmitted via the saliva, HHV-6A has only intermittently been found in the saliva and its means of transmission is unclear (Ward 2000).
HHV-6 and Chronic Fatigue Syndrome (ME/CFS)
The Early Years: Flawed Methodology
HHV-6 was discovered not long after the Incline Village ME/CFS outbreak in the early 1980s and researchers leapt to assess its incidence in the ‘new disease’. In the last 20 years over twenty-five studies have examined HHV-6 prevalence in chronic fatigue syndrome (ME/CFS).
Research was sparked in the early 1990s by several studies showing increased antibody titers in CFS patients (Buchwald et al. 1992). Research into HHV-6 peaked in the early to mid 1990s with 18 studies examining the subject between 1989 and 1995.
The primitive technology at the time, however, confounded researchers’ efforts. Ablashi, a co-discoverer of HHV-6A, noted that most of the early studies used ‘extremely insensitive assays for HHV-6 antibodies’. Because many of the early studies were done on whole blood, a technique that picks up latent (i.e. benign) viruses, he characterized their results as ‘muddled’.
Wallace and Reeves extended their critique to later studies as well asserting they either relied on serological studies, were too small, lacked adequately matched controls or may have mischaracterized HHV-7 as HHV-6 (Wallace et al. 1999, Reeves et al. 2000).
Research declined since 1995 with eight studies in last 13 years. Three papers published around 2000 by established researchers with well characterized study groups that did not find increased HHV-6 prevalence in ME/CFS patients appeared to have dealt a body blow to the HHV-6/chronic fatigue syndrome scenario (Wallace et al. 1999, Reeves et al. 2000, Koelle et al. 2002). Only one study on HHV-6 prevalence has appeared in the last four years.
Flawed Methodology Redux?
Yet HHV-6 may be heading back to the top of the research agenda. The Wallace, Reeves and Koelle studies were criticized for searching for the virus in the wrong types of cells (PBMCs) and recent successful antiviral trials suggest the virus does play a prominent role in some ME/CFS patients’ illnesses.
The HHV-6 Foundation asserts that the presence of latent viruses in peripheral blood mononuclear cells (PBMCs) makes them an inappropriate medium to search for evidence of an active infection. They propose that the following commercial tests can be used, “albeit imperfectly,” to characterize active infections: PCR DNA tests on serum or plasma, IgM early antigen, IgG or IgM antibodies, primary cell culture and lymphocyte response.
The Foundation produced a chart indicating that when these tests are used they almost uniformly find significantly higher rates of active infection in ME/CFS patients vs. healthy controls. Their chart indicates that 47% of ME/CFS patients (360/760) harbor an active infection compared to 8% of healthy controls (44/530).
When the most sensitive early antigen tests are used the percentage of ME/CFS patients with active HHV-6 infection rose still higher (54% 57%, 77%) but remained low in healthy controls (8%, 12%, 16%).
Several reports have bolstered HHV-6’s case in ME/CFS. Ablashi et al. found that more CFS patients carried antibodies for an early IgM antigen (p41/38) in their serum than controls (57-16%). Culture studies found HHV-6 infection was present in about half of CFS patients (n=22) and that most of the HHV-6 found was variant A (70%) (Ablashi et al. 2000). No statistical analyses, however, were done.
Dr. Peterson reported he found active HHV-6A in the cerebral spinal fluid (CSF) of a subset of CFS patients (20%) who had central nervous system abnormalities (abnormal MRI, severe cognitive problems, headaches, paresthesias [burning, pricking, tickling, tingling sensations]).
Peterson also reported laboratory findings suggesting some chronic fatigue syndrome patients with active HHV-6 infections are at risk from lymphoma. In another recent study PCR evidence of active HHV-6 infection was found in 30% of CFS patients vs. 9% of controls (Nicholson et al. 2003).
A report from the 2006 HHV-6 Conference in Barcelona indicated that 22-25% of ME/CFS patients (n=75) tested positive for HHV-6 infection using rapid culture, antigenemia and nested PCR. Another report indicated found 40% of patients (n=17) had active HHV-6 and HHV-7 infections compared with 0% of the controls (n=30). Chapenko, however, did not find increased HHV-6 infection in ME/CFS patients (Chapenko 2006).
A successful antiviral trial focused on ME/CFS patients with high antibody levels to HHV-6 and Epstein-Barr virus (EBV), suggested HHV-6 and/or EBV reactivation can play a profound role in some ME/CFS patients’ illness (Kogelnik et al. 2005).
The Montoya and Lerner studies revived interest in this HHV-6 in ME/CFS. The Whittemore-Peterson Neuro-Immune Institute is reportedly focusing on it and after years of ignoring the pathogen question Dr. Hanna of the NIH recently stated a new interest in the subject. Enough interest has been aroused to get a special Satellite conference on Chronic Fatigue Syndrome added on to the 2008 International HHV-6 Conference.
At least four possibilities exist with regard to HHV-6 and chronic fatigue syndrome (ME/CFS):
- HHV-6 reactivation could cause at least some cases of ME/CFS
- HHV-6 could be an opportunistic pathogen which exacerbates ME/CFS
- HHV-6 reactivation could be present but not exacerbate ME/CFS
- HHV-6 reactivation may not occur in some ME/CFS patients
The most critical problem facing HHV-6 researchers now is devising a commercially available tests that accurately measures HHV-6A activity. Kristin Loomis, the executive director of the HHV-6 Foundation recently stated that their
“primary objective is to get a test on the market that will be a sensitive indicator of active infection.”
HHV-6 in ME/CFS appeared for a time to be dead subject. Will it emerge Lazarus-like to tell us something vital about this disease? Or will it raise its head only to sputter once again under the weight of contrary evidence? Only time will tell.
Two Struggling Fields
A successful clinical trial would have dramatic effects on both HHV-6A and ME/CFS research. Both fields are struggling for legitimacy and funding. Dr. Gallo’s comment on HHV-6’s plight extends to ME/CFS as well: “Statistics indicate that ME/CFS is an important disease to everyone except the research community.”
A successful Montoya study has the potential to kill two birds with one stone; by documenting the first successful treatment for ME/CFS it would enhance the disease’s legitimacy considerably and thus link HHV-6A with an emerging ‘important’ disease; i.e. chronic fatigue syndrome (ME/CFS). This is one reason both HHV-6 and ME/CFS researchers, advocates and patients await the trial’s results with such anticipation.