Human Herpes Virus 6, Epstein-Barr Virus
and Endogenous Retroviruses: an input into Multiple Sclerosis?

A Brief Note

Human Herpes Virus 6 (HHV6), discovered in 1986, is a very common virus of early childhood, establishing itself in most children around the age of two and often causing a fever lasting for about three days. This age is too early in a person's life to fit the epidemiological data for the acquisition of a primary pathogen in MS, although rare late primary infection, which might result in chronic active disease, cannot be completely ruled out. The virus is neurotropic, but primary infection seldom causes serious disease. It ordinarily remains largely dormant in the CNS: occasionally it briefly reactivates without symptoms.

Several studies have found elevated indicators of HHV6 in persons with MS. Challoner and co-workers found HHV6 DNA to be very common in the adult human brain; using immunohistochemical methods they found viral protein expression within the nuclei of of oligodendrocytes adjacent to MS lesions.
[Challoner PB, Smith KT, Parker JD et al., Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7440-4.] On the face of it this seems like strong evidence of a primary causal connection. But is it? Let us look at at a parallel situation. Active ongoing infection with HHV6 is generally universal in persons with end-stage AIDS. [Corbellino M, et al. Disseminated human herpesvirus 6 infection in AIDS. Lancet 1993; 342:1242; Knox KK, Carrigan DR. Disseminated active HHV-6 infections in patients with AIDS. Lancet. 1994 Mar 5; 343(8897): 577-8.] The latter workers, using immunohistochemistry, found that in biopsied lymph nodes from AIDS patients the densities of HHV6 infections were significantly (p<0.016) higher in areas undergoing active HIV destruction than in areas free of destructive changes. [ last viewed 13th Nov 2005.] An increased HHV6 load has been found in the lesions of AIDS-associated Progressive Multifocal Leukoencephalopathy, suggesting a cascade of pathogens (HIV, JC polyoma virus and HHV6.) [Blumberg BM, Mock DJ, Powers JM, et al., The HHV6 paradox: ubiquitous commensal or insidious pathogen? A two-step in situ PCR approach. J Clin Virol. 2000 May; 16(3): 159-78.]

Active HHV6 infection has been found superimposed on Legionnaire's Disease.
[Russler SK, Tapper MA, Knox KK et al., Pneumonitis associated with coinfection by human herpesvirus 6 and Legionella sp. in an immunocompetent adult. Am J Pathol. 1991; 138(6): 1405-11.] 2 of 3 patients with viral encephalitis, in whom both HHV6 and Herpes Simplex Virus (HSV) were isolated, died, a much higher proportion than in encephalitis due to HSV alone, where 1 of 19 died. [Tang YW, Espy MJ, Persing DH, Smith TF. Molecular evidence and clinical significance of herpesvirus coinfection in the central nervous system. J Clin Microbiol. 1997 Nov;35(11):2869-72.]

It seems that HHV6 is what might be termed a 'henchman'. That is, an organism widely present in human tissues and which is roused from a state of inactivity to cause gross pathology in areas that are already compromised by a primary intracellular pathogen. (It will be noted that Legionella pneumotropica is a strongly intracellular bacterium.) One might hypothesize that HHV6 may act as a 'henchman' in chronic infections with Chl pneumoniae, which is of course also an intracellular pathogen. One might further speculate that eradication of the chlamydial infection, support of mitochondrial fatigue and restoration of normal immune function might return HHV6 to a state of dormancy.

Epstein-Barr Virus (EBV) is another possible henchman. Usually acquired in childhood, late adolescence, or early adulthood, this common herpesvirus causes infectious mononucleosis and then establishes life-long latency in B lymphocytes; reactivations occur sporadically, with shedding of the virus in the saliva. Antibodies to EBV nuclear antigen-1 slowly rise after infection in the blood, and remain elevated for life. Antibodies to EBVNA-1 are found in oligoclonal bands in the CSF of patients with MS
(Rand KH, Houck H et al., Epstein-Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis. J Neurol Sci. 2000 Feb 1;173(1):32-9.) and CD8+ T cell responses to latent EBV proteins are higher in MS patients than in controls. (Sabine Cepok, Dun Zhou et al., Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest. 2005 May 2; 115(5): 1352–1360)

Endogenous retroviruses have been suggested as participants in the progression of MS. These ancient sequences of virus DNA are replicas of those inserted into the genome by an accident of infection during germ-cell formation.

Might HERVs play a role in the development of MS? It seems possible. Activation of the HERVs HERV-H/RGH, HERV-W and ERV-9 was described when specific cell types (mainly B cells) from MS patients were cultivated in vitro. Viral RNA from these HERVs has been detected by reverse-transcriptase PCR methods in sera/plasma and brain tissues from MS patients, although not exclusively from these patients
[reviewed by Clausen J. Endogenous retroviruses and MS: using ERVs as disease markers. Int MS J. 2003 Apr;10(1):22-8.] Is their activation a cytokine-mediated epiphenomenon, or does it have a pathogenic input into the disease? The many-phased natural history of MS suggests the re-awakening of inherent viruses. Clausen comments: 'preliminary evidence suggests that specific ERVs may act as auto-, super- or neoantigens with the potential to enhance inflammatory responses or induce autoimmune reactions.'

Again, might these inner aliens return to a state of dormancy when the primary cause of cytokine disturbance is removed? It seems likely: we have been living with these beings, their genome trapped within ours, for untold time.

Return to ms-index page



first uploaded 13th Nov 2005; updated 21st August 2011