HHV-6 in MS

There is growing evidence that HHV-6A plays a role in MS, either directly or indirectly as an activator of viruses such as EBV or an endogenous retrovirus such as HERV-W.

• HHV-6A DNA has been found in cell-free specimens from MS patients but not from healthy controls. (Alvarez-Lafuente 2004, Chapenko 2004, Berti 2002, Soldan 1997)

• More HHV-6 DNA is found in MS patient serum during exacerbations than during relapses. (Alvarez-Lafuente 2004)

• More HHV-6 DNA is found in MS plaques than in non-affected white matter by immunohistochemistry and in-situ PCR. (Challoner 1995, Goodman 2003)

• Lymphoproliferative response to HHV-6A is greater in MS patients than in controls; 67% of MS patients have significant lmphocyte response to HHV-6 vs 32% of controls. (Soldan 2000)

• HHV-6 intrathecal antibodies (antibodies generated in the spinal fluid) have been 22% of MS patients but 0% of controls. (Derfuss 2005)

• IgM and IgG antibodies to HHV-6 early antigen (antibodies that are only found during active infection) are significantly greater in MS patients than in controls. (Patnaik 1995, Soldan 1997, Ablashi 2000)

• Claude Genain and investigators at UCSF induced MS-like lesions in marmoset monkeys by injecting them with HHV-6A. (International Conference on HHV-6 & 7, 2006)s

The idea that infectious agents may play a significant role in MS dates back at least 200 years.  Many characteristics of the disease suggest the possible involvement of pathogens, including its relapsing/remitting nature, geographic variations in distribution, and epidemics such as the reported outbreak in the Faroe Islands beginning in the 1940's. 

Reasons to suspect viruses as a cause of MS:

• All demyelinating disorders with known etiology have been caused by viruses
• Antiviral treatments such as beta interferon have been effective in MS
• MS symptoms wax and wane as do viral infections
• MS symptoms worsen with viral infections such as colds
• Herpes infections, like MS, flare in response to stress, heat and other infections
• Environmental factors are more important than inherited susceptibility
• Geographic outbreaks have been reported

Over the years a number of individual agents have been investigated for a role in MS.  Candidates for triggers of MS have included mycobacterium tuberculosis, measles, mumps, rubella, retroviruses herpes simplex and varicella zoster, adenovirus, coronavirus, and vaccinia virus as well as bacteria such as Borrelia burgdorferi.

Today, attention focuses primarily on  (HHV-6), Epstein Barr virus (EBV), Chlamydia pneumonia (Cpn) and human endogenous retroviruses (HERVs). Since these viruses and pathogens potentiate each other, it is possible that there are many infections involved in a chain reaction, with the end result being an autoimmune process that continues long after the initial infections have passed.

One of the obstacles preventing further study of HHV-6A in serum of MS patients is that current commercial assays are not sensitive enough to detect the virus in cases of low-grade chronic infection. (See Testing) The HHV-6 Foundation is working with scientists and commercial diagnostic companies to produce an assay based on the early antigen protein of HHV-6. In four studies in the late nineties (when this assay was briefly available) this assay showed dramatic differences between patients with MS and controls without MS.

Molecular mimicry involving HHV-6 has been proposed as one mechanism by which the autoimmune process could be triggered. One study showed that certain residues on the HHV-6 genome are identical to residues of myelin basic protein.  Importantly, both T-cells and antibody responses to this peptide sequences were found elevated in MS patients. Moreover, in vitro infection of glial precursor cells was found to impair cell replication and increase the expression of oligodendrocyte markers, suggesting that HHV-6 infection of the CNS may influence the neural repair mechanisms.

The leading theory of CMV- induced autoimmunity in transplant patients is that cell surface protein from CMV infected tissues is incorporated into the viral envelope of CMV inducing graft-host disease post transplant. Similarly, an argument could be made that myelin proteins from infected oligodendrocytes could become incorporated into the HHV-6A envelope as they enter and leave the cell, inducing CNS autoimmunity in MS and CFS patients. This is an area of current interest at the Viral Immunology Division at the NINDS at the NIH.

Recently, many studies have suggested HHV-6A as a factor in a subset of patients with both CFS and MS. Studies using assays that differentiate between active and latent virus have shown an exceptionally strong association between HHV-6A and both MS and CFS. We now know that due to the high level of latent virus found in controls, active infection should be measured by looking for HHV-6 DNA in cell free serum or plasma. This explains why there has been confusion about the association of HHV-6A with CFS in the past. The negative studies were done primarily with testing methods that did not differentiate latent from active virus. 

In MS, 88% of patients complain of moderate to severe fatigue. As in CFS, MS patients also suffer from impaired information processing speed, enlarged cerebral ventricular volumes, and altered glucose metabolism in the prefrontal cortex. Okada et al have reported an 11% reduction in prefrontal grey matter by morphometric analysis in CFS patients; a pattern also found in MS. HHV-6A DNA has been demonstrated in the cerebral spinal fluids, plaques and other neural cells in both conditions. This has led some scientists to speculate that the two disorders share a common etiology.

Antiviral therapies are already used successfully for both MS (inferferon, amantadine) and CFS (ampligen). Once active HHV-6A infections can be determined in CFS and MS patients through the use of more sensitive assays in commercial laboratories, these conditions may be treatable to some degree with antiviral and immune modulators. Such treatment has the potential to relieve fatigue and improve CNS function in patients with HHV-6A viremia.