Special Theme – Association of Herpesviruses with Chronic Disease
Herpesviruses and Multiple Sclerosis
Anthony Simmons, Department of Pediatrics and Sealy Center for Vaccine Development, University of Texas
Medical Branch, Galveston, TX, USA.
THE LITERATURE IMPLICATING HERPESVIRUSES IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS (MS) IS
REVIEWED, WITH PARTICULAR EMPHASIS ON THE POSSIBLE ASSOCIATION BETWEEN MS AND HUMAN
KEY WORDS characteristic changes in the cerebrospinal fluid (CSF).
❚ MULTIPLE SCLEROSIS ❚ PATHOGENESIS No specific treatment was available until recently,
when beta interferon and glatiramer acetate were both
❚ AETIOLOGICAL COFACTORS ❚ HERPESVIRUSES ❚ HERPES SIMPLEX
shown to reduce the number of potentially damaging
VIRUS TYPES 1 AND 2 (HSV-1 AND -2) ❚ VARICELLA ZOSTER VIRUS relapses by approximately one-third. While there have
❚ EPSTEIN-BARR VIRUS (EBV) ❚ CYTOMEGALOVIRUS (CMV) ❚ HUMAN been many suppositions about the mechanisms of
HERPESVIRUS 6, 7 AND 8 (HHV-6, -7 AND -8) action of these compounds, the exact reasons for their
activity remain unknown.
SUMMARY Herpes Simplex Viruses Types 1 and 2
Evidence suggests that multiple sclerosis (MS) is caused by host
genetic factors in association with one or more environmental agents. It has been decades since it was first suggested that the
The clinical and pathological features of MS implicate viral epidemiology of herpes simplex virus (HSV) infections
infections as either cofactors in its aetiology or triggers of relapses, is consistent with their involvement in MS (Table 1).1
although no specific environmental factors have been identified. In For instance, the age at which HSV-2 infections are
particular, several herpesviruses have attracted interest because first detected, as well as the age of peak incidence, are
their ability to cause latent infections that periodically reactivate has similar to those for MS. If age-specific HSV-1 immunity
some familiarity with the relapsing–remitting course of MS. Further, data from various places are compared, an inverse
most human herpesviruses can be readily found within the central relationship of immunity levels with latitude is
nervous system and several are known to be capable of inducing apparent, and it has been suggested that this might be
demyelination, both in humans and in experimentally infected related to the effects of ultraviolet irradiation on HSV-1
animals. This brief review takes a systematic look at reported activation and transmission rates.2 In an attempt to
associations between herpesviruses and MS and suggests some unite these observations, it has been suggested that MS
criteria that must be met in further studies. One of the greatest is triggered by infection with HSV-2 in persons lacking
challenges in confirming or refuting a role for herpesviruses in immunity to HSV-1. Prior HSV-1 immunity, if related
chronic diseases is their ubiquitous nature. It is stated from the to subsequent risk of MS, would be protective. This
outset that the associations described here remain controversial. hypothesis appears to be consistent with the
generalizations concerning effects of migration on
subsequent rates of MS, and with certain other features
of MS epidemiology.2
Multiple Sclerosis: Background Recent studies showing early neuronal damage in
Information MS patients have caused a resurgence of interest in a
possible role for the neurotropic alpha-herpesviruses,
MULTIPLE SCLEROSIS (MS) PRIMARILY affects young particularly HSV-1 and -2.3 HSV-1 DNA has been
adults, particularly women. In its commonest form, MS found in some cases of acute MS but not in stable MS or
is characterized clinically by a relapsing and remitting healthy controls. In one study, HSV-1 mRNA and DNA was
course with each remission contributing progressive detected in peripheral blood mononuclear cells of a
deterioration in clinical condition associated with the significant number of acute MS patients but not in control
disease. No symptoms or signs are pathognomonic and subjects. These data indicate that HSV-1 reactivates in
diagnosis depends on a combination of characteristic patients during clinical episodes and, therefore, HSV-1
clinical and radiological features together with remains a candidate for a trigger of MS relapses.4
Table 1: Summary of evidence supporting potential roles for herpesviruses in multiple sclerosis
Geographical Virus or viral
Relapsing– distribution Circumstantial nucleic acid in Plaque-associated Viruses known
remitting consistent serological blood or brain viral antigen or to be
epidemiology with MS support during acute MS DNA sequences neurotropic
HSV1 VZV EBV9,10,13 HSV HHV-623,24 HSV-1 and -2
EBV11 MDV37 HHV-6 HHV-625,26 VZV
MS, multiple sclerosis; HSV, herpes simplex virus; VZV, varicella zoster virus; EBV, Epstein-Barr virus; HHV, human
herpesvirus; MDV, Marek’s disease virus.
60 Herpesviruses and MS • HERPES 8:3 2001
Varicella Zoster Virus patients but not control subjects. The focal point of
interest, however, is a report by Challoner et al.23 in
The association between varicella zoster virus (VZV) which HHV-6 DNA sequences were detected, using
and MS is limited largely to clinical experience and representational differential analysis, in the brains of
epidemiological surveys. Both MS and varicella are patients with MS. Following this lead, HHV-6 antigen
most prevalent in temperate zones and rare in expression was detected in MS brains and shown to be
countries close to the equator. Migration studies associated specifically with MS plaques. Subsequently,
suggest that exposure to an unidentified environmental plaque-associated DNA sequences have been described
agent prior to the age of 14 years is associated with an by others24 and a plethora of reports have surfaced
increased risk of MS.5 The prevalence of VZV infection describing looser associations between MS and HHV-6.
and MS are both lower in Hutterites, who educate their Some correlate active systemic infection with MS. For
children at home, than in their non-Hutterite instance, using a rapid culture assay, Knox et al.25 found
neighbours.6 An early serological study found the that blood samples from 22 of 41 patients with definite
geometric mean titre of antibodies to VZV to be MS were found to contain active HHV-6 infections,
significantly higher among 59 MS cases than among compared with 0 of 61 normal controls (P<0.0001).
patients with other diseases and normal individuals.7 While there was no significant difference between
In an uncontrolled study, based on improvement of HHV-6 viraemia-positive and HHV-6 viraemia-negative
symptoms and pathology after repeated exposure to patients with respect to type of disease (relapsing–
high antigen (myelin basic protein) doses in an remitting or progressive), patients with active HHV-6
experimental model of MS, administration of VZV viraemia were significantly younger and experienced a
vaccine to MS patients caused apparent benefits, as shorter duration of disease than in HHV-6 viraemia-
assessed both clinically and by magnetic resonance negative patients.
imaging.8 Berti et al.26 recently confirmed a previous
observation that HHV-6 DNA is present in the serum of
Epstein-Barr Virus MS patients but not in normal individuals. In addition,
it was suggested that HHV-6 viraemia may be
A considerable amount of work describing associations correlated with clinical activity. Taus et al.27 analysed a
between Epstein-Barr virus (EBV) and MS has been small number of patients for HHV-6 DNA in CSF
published over the past 2 decades. All patients with MS samples and peripheral blood mononuclear cells; and
have been reported to be EBV seropositive9,10 and antibody titres in serum and CSF. Viral DNA was not
cumulative circumstantial evidence points weakly to a detected in CSF or blood and antibody titres were
post-pubertal primary EBV infection as a potential comparable between MS and controls. Curiously, this
unidentified aetiological event in the induction of MS study reported that 30.4% of MS patients were
disease. Perhaps more convincing is an association seronegative to HHV-6, which is far below the normal
between EBV reactivation and disease activity in MS prevalence in adults.
patients suggesting that EBV might trigger an underlying Human herpesvirus 6 has two variants, A and B, and
disease process.11 A cluster of eight cases of MS in the phylogenetic stability of each suggests that they
Denmark was correlated significantly with the presence should be regarded as distinct but closely related viruses.
of a single subtype of EBV, although the genotyping in There are conflicting reports in the literature regarding
this study was limited.12 A report of elevated EBV whether variant A28–30 or B23,31,32 is primarily associated
antibody titres during the clinical course of a case of MS with MS, which might be explained in part by the
presenting in infancy raises an interesting but still different methodologies used to make the association and
speculative aetiological possibility for MS.13 by the divergence of the monoclonal antibody epitope
Several groups have reported retrovirus particles or commonly used to identify the viral variants.33
reverse transcriptase activity in lymphocyte cell
cultures from MS patients, generally in association with Human Herpesvirus 7
EBV.14–18 Perron et al.19 recently described endogenous
retroviral elements integrated into human chromosomal Very little investigation of a possible association
regions previously implicated in susceptibility to MS. between human herpesvirus 7 (HHV-7) and MS has been
As a consequence, a complex multi-step aetiology of carried out. Four publications make specific reference to
MS was proposed, involving triggering of specific HHV-7. The virus has been found to be equally
genetic elements by EBV or other infectious agents. prevalent in a latent form in peripheral blood
mononuclear cells of MS patients and healthy
Cytomegalovirus controls.34 Soldan et al.30 measured the
lymphoproliferative response to HHV-7-infected cell
There are no reports demonstrating a convincing link lysate and found no significant difference between
between MS and cytomegalovirus (CMV). Sanders et patients and controls. In the same study that found no
al.20 used a polymerase chain reaction approach to association between MS and HHV-6, Taus et al.27 also
compare active with inactive plaques from patients reported no relationship between MS and HHV-7.
with MS. CMV sequences were detected in 9–22% of Neither HHV-7 nor HHV-6A antibodies were found in
specimens, irrespective of source. Previous research CSF in the previously mentioned study that detected
also failed to find significant differences in terms of immunoglobulin M antibodies to HHV-6B.31
CMV seroprevalance between patients with stable MS
and control patients.21 Human Herpesvirus 8
Human Herpesvirus 6 As is the case for HHV-6, it has been claimed that
human herpesvirus 8 (HHV-8) is strongly neurotropic.35
Human herpesvirus 6 (HHV-6), a recently discovered No evidence has been found to support a specific
beta-herpesvirus, is known to cause sporadic cases of association between this virus and MS, however.
encephalitis22 and HHV-6 DNA has been found in
post-mortem brain samples from MS brains.20 It is, Birds and Marek’s Disease Virus
therefore, a neurotropic virus and arguably a commensal
of the brain. There are now many reports describing There have been several reports claiming that birds are
associations between HHV-6 and MS. Most are based on very likely to be involved as vectors of the exogenous
either: detection of HHV-6 antibodies in serum or CSF; causative agent of MS.36–39 In particular, after intensive
or amplification of HHV-6 DNA from sera or CSF of MS investigation, wild birds were strongly implicated as
Herpesviruses and MS • HERPES 8:3 2001 61
vectors responsible for a cluster of MS cases in Key Future Investigation
West (FL, USA). Marek’s disease virus (MDV), a gamma
herpesvirus with known neurotropic capacity, emerged Continued research into the pathogenesis of MS is
as the most likely pathogen. The discovery that certain assured and an association with viral infections in the
EBV and MDV antigens cross react raises the possibility primary pathogenesis or catalysts for demyelinating
that prior EBV infection could protect against episodes must always be borne in mind when
potentially harmful effects of exposure to MDV, which, formulating hypotheses or interpreting results. For a
in part, could explain the complex epidemiology of MS. specific herpesvirus to be considered a candidate, it
would obviously be important that all patients have
Herpesviruses in the Treatment of MS evidence of past or recent infection, by either
serological or lymphoproliferation tests. While an
Replication-defective HSV is a candidate for delivery of autoimmune process could be triggered at a site distant
exogenous genes into the nervous system. The possibility from MS plaques, direct and ongoing involvement in
of using such HSV strains for introducing anti- the process of demyelination means that the virus or
inflammatory cytokines (e.g. interleukin 4) into areas of viral antigens should be localized to plaques and viral
demyelination has been explored, with some success, in DNA should be detectable in the brain. Positive
experimental autoimmune encephalomyelitis (EAE) of findings should be confirmed in a variety of geographic
mice.40,41 The concept of introducing genes encoding regions and the initial observation should preferably be
neuroprotective agents into the central nervous system is made by a laboratory that has had no prior experience
in its infancy and seems guaranteed to receive further with working with the agent involved. To date, only
attention. In addition, CMV has been used to deliver one virus, HHV-6, comes close to satisfying these
DNA encoding myelin proteolytic protein (PLP) into criteria and antiviral trials will be needed to clarify
mice prior to sensitization for EAE, which is a popular any connection.
model for studying pathogenetic mechanisms of Perhaps significantly, beta interferon, a
demyelination. EAE was exacerbated following neuroprotective drug currently used in the
sensitization early after receiving the naked CMV–PLP management of MS, has antiviral activity against
DNA construct, whereas late sensitization ameliorated it, HHV-6. Age of infection is known to have a profound
a result that has important implications for future influence on the symptoms and tissue tropism
attempts to modulate immune responses using this associated with several viral infections. Consequently,
approach. Tsunoda et al.42 also reported exacerbation of an issue that merits investigation is the possibility that
EAE by a plasmid comprising CMV sequences. late acquisition of one of the ubiquitous pathogens
discussed here, presumably between early childhood
Is There a Rationale for Antiviral and adolescence, is responsible for triggering the
autoimmune process underlying MS. Finally, the
Treatment? possibility that MDV or other avian pathogens could be
involved should not be regarded as a flight of fancy
The results of a randomized, double-blind, placebo- and these potential associations merit further
controlled study of aciclovir led Lycke et al.43 to investigation.
conclude that aciclovir-susceptible viruses might
trigger MS exacerbations. Further studies are justified
using valaciclovir with the caveat that several
questions need to be resolved before embarking on
such a course. First, at what stage of MS is antiviral
therapy likely to be most efficacious? Several reports
suggest that early treatment might have a better chance Address for correspondence:
of a positive result. Secondly, what virus should be Dr Anthony Simmons, Department of Pediatrics and
targeted? Clearly, any study should include HHV-6 as a Sealy Center for Vaccine Development, University of
major target. Finally, a point that is related to the Texas Medical Branch, Galveston, TX 77555-0739,
preceding question, what dosage should be used? USA.
Taking into account the wide range of sensitivities to
aciclovir of different HHV-6 isolates, the largest dose E-mail: firstname.lastname@example.org
that can be tolerated safely should be used. The
current recommendation is that a 2 g dose of oral Received for publication: 1 June 2001
valaciclovir administered every 6 h should be Accepted for publication: 8 August 2001
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Herpesviruses and MS • HERPES 8:3 2001
Herpes in 2002
Two new developments to look out for in Herpes: Independent Submissions
• Part-themed rather than fully themed issues; In 2002, we will be actively encouraging independent
• Independent submissions. submissions. So, if you have any ideas for articles we will be
pleased to hear from you. All unsolicited submissions will
Part-themed Issues undergo the same rigorous peer review as commissioned
Means we can retain the Journal's reference value on selected articles.
topics, while ensuring each issue has something of interest to
most readers. It also gives flexibility for late change to the See page 83 for full notes for authors or visit the Journal’s
non-themed content. section on the IHMF website at: www.ihmf.org/journal
Next year’s themes are planned to include:
• Prevention of transmission of genital and neonatal herpes; Tell us your thoughts on these developments or any other
• Serological screening for HSV infection; aspect of the Journal by contacting us at:
• Transmission of herpesviruses by blood transfusion, Fax: +44 (0) 1903 234862; E-mail: email@example.com
solid-organ transplantation and stem-cell transplantation.