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
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.
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):
Active HHV6 infection has been found superimposed on Legionnaire's
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
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
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):
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
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
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
to ms-index page
first uploaded 13th
Nov 2005; updated 21st August 2011