Historically, multiple sclerosis (MS) has been
associated with many different viruses, including several members of the
Herpesviridae family. However, no human or animal virus has been
identified as a true “cause” of MS; rather, the epidemiologic and
diagnostic data suggest that viral infection may be a cofactor affecting
the pathogenesis of MS. Human herpesvirus-6 (HHV-6) is a ubiquitous
herpesvirus associated with a common childhood illness, roseola, and this
virus is one of those most recently associated with MS. During the past
decade, a number of investigations have examined anti–HHV-6-specific
antibody responses, HHV-6 viral DNA, or HHV-6 presence in central nervous
system (CNS) tissue in both MS patients and controls. There is a growing
body of evidence associating HHV-6 infection of the CNS with MS in at
least a subpopulation of patients, although the specific factors that
define the vulnerable subpopulation(s) of MS patients have not been
elucidated. This evidence is provocative but not definitive, and it does
not distinguish between HHV-6 as a causal agent in MS versus HHV-6 as a
cofactor. Although more clinically based data are needed, the controversy
surrounding HHV-6 and MS has again focused attention on the role of viral
infection in the clinical and pathologic course of MS.
Suggested citation: Is There a Role for Human Herpesvirus-6 in the
Course of Multiple Sclerosis?. Delgado S, McCarthy M. Int J MS Care
[Serial on-line]. March 2002;4(1).
Multiple sclerosis (MS) is a chronic, demyelinating disorder in which
the immune system attacks the white matter of the central nervous system
(CNS). Mechanisms involved in the causes of this disease are complex and
multifactorial.1 Evidence based on animal disease models, such
as that derived from Theiler’s murine encephalomyelitis virus infection,
supports the theory that infectious agents, including human viruses, may
play an important role in the pathogenesis of MS in genetically
Historically, MS has been associated with many different viruses,
including several members of the Herpesviridae family.5
However, no human or animal virus has been identified as a true
“cause” of MS; rather, the epidemiologic and diagnostic data suggest
that viral infection may be a cofactor affecting the pathogenesis of MS.6
Among human viruses, herpesviruses have certain features that are
potentially relevant to the pathogenesis of MS.6 Herpesviruses
typically cause primary infection in childhood and then follow a lifelong
course of latent and recurrent infection, which can persist in the CNS.
Several herpesviruses can induce demyelination as well. Human
herpesvirus-6 (HHV-6) is a ubiquitous herpesvirus associated with a common
childhood illness, roseola (Table 1). This virus is one of those most
recently associated with MS.7,8 The controversy surrounding
HHV-6 and MS has again focused attention on the role of viral infection in
the clinical and pathologic course of MS.
A viral infection can cause tissue damage within the CNS by different
mechanisms. First, a virus may have a direct cytopathic effect on the cell
it infects. In this instance, viral replication and the production of
progeny virus can destroy the cell’s specialized function(s). An example
of this is the CNS demyelination seen in progressive multifocal
leukoencephalopathy, a demyelinating disorder in which a polyomavirus (JC)
infects astrocytes and oligodendrocytes. Because oligodendrocytes are the
principal cells responsible for myelin production in the CNS, their
destruction by the JC virus results in loss of myelin. Second, viral
infection can act to “trigger” MS attacks by stimulating antiviral
immune responses that may not be properly regulated. Increased risk of
clinical MS exacerbations following viral infection has been described for
upper respiratory tract infections.9,10 Viruses may act to
trigger a local immune response to viral proteins juxtaposed to normal
myelin antigens in viral-infected brain or spinal cord, causing secondary
inflammation and demyelination.11 Alternatively, viral
infection may trigger an autoimmune reaction by “molecular mimicry,”
whereby a virus can express antigens with structural homology to normal
myelin antigen and thus elicit a mistaken autoimmune attack.12
In this instance, a viral infection can stimulate antigen-specific clones
of T cells, which, after being activated, could enter the CNS and
stimulate immune attack on normal “self” antigens expressed within
myelinated tissues, again causing damage to myelin. Some authors have
suggested that the pathogenesis of demyelination in MS may be
heterogeneous within different plaques and among different MS patients.13
This concept raises the possibility that different causal agents could be
associated with MS lesions, and thus both viral and autoimmune mechanisms
could be involved in selected subpopulations of patients.14
Overview of Human Herpesvirus-6.
variants: HHV-6A, HHV-6B
cells: astrocytes, oligodendrocytes
of cell destruction
cell death (apoptosis)
of inflammatory cytokines (eg, TNF-a)
= tumor necrosis factor alpha
HHV-6 was first isolated in 1986 from lymphocytes of patients with
lymphoproliferative disorders.15 It is a member of the b-herpesvirus
subgroup, closely related to cytomegalovirus (CMV) and human herpesvirus-7
(HHV-7).16 The viral genome is arranged as a linear segment of
double-stranded DNA.17 HHV-6 can be separated into two strain
variants, HHV-6A and HHV-6B, according to DNA restriction analysis, in
vitro cellular tropism, and antigenic differences detected by monoclonal
antibodies.18,19 These two HHV-6 variants share a genomic
homology of about 94% to 96%.20 Variant HHV-6A is considered
more neurotropic than is HHV-6B in that HHV-6A is more frequently
identified in cerebrospinal fluid (CSF) than HHV-6B is. However, HHV-6B
predominates as the persistent variant in peripheral blood mononuclear
cells from both children and adults.21 The two variants may
have distinct immunologic properties; HHV-6A can infect individuals with
prior exposure to HHV-6B. Thus, immunity to HHV-6B does not necessarily
prevent infection by HHV-6A.
HHV-6 grows most productively in CD4-expressing T-lymphocytes.22
Efficient HHV-6 replication in primary lymphocyte culture in the
laboratory setting requires activation of T-lymphocytes with a mitogen
such as phytohemagglutinin and interleukin 2 to stimulate cell
proliferation.15,23,24 HHV-6 also infects other immune system
cells such as CD8-expressing T-lymphocytes, natural killer cells, and
macrophages.25,26 The cell surface receptor molecule for HHV-6
has been reported to be CD46.27 CD46 is a glycoprotein present
on the surface of all nucleated cells. It protects against spontaneous
complement activation on autologous cells. Cermelli and Jacobson recently
postulated that virus-induced down-regulation or inactivation of CD46 in
genetically predisposed individuals could secondarily allow complement
activation, which may lead to myelin damage and increased immune activity
against myelin antigens.5
HHV-6 infection can induce apoptosis of CD4-expressing T-lymphocytes in
vitro and in vivo.28,29 HHV-6–mediated apoptosis may be
caused by cytokines, inflammatory molecules secreted by virus-infected
immune cells.30 This could explain the reported susceptibility
to apoptosis of uninfected CD4-expressing T-lymphocytes in human HHV-6
infection in vivo.29 The induction of apoptosis in
CD4-expressing cells in vivo could cause a dysregulation of the immune
system and have important significance in the course of autoimmune
disorders such as MS.
HHV-6 also has demonstrated neurotropism, that is, the capacity to grow
in the cell types that are found in the brain and spinal cord, including
embryonic glia, glioblastoma, and neuroblastoma cell lines, and human
fetal astrocytes.25,31-33 HHV-6 infection in human fetal
astrocytes can activate the HIV-1 major gene promoter34;
therefore, HHV-6 may act as a cofactor in AIDS-related neurologic
disorders and play a similar role in the pathogenesis of MS in association
with other viruses. HHV-6 can also infect cultured adult oligodendroglia
and microglia,35 which establishes an experimental basis for
predicting that HHV-6 can infect oligodendrocytes surrounding MS plaques.
HHV-6 has also been reported to infect human endothelial cells in vitro.36
Infection of cerebral vascular endothelial cells could give rise to a
chronic inflammation of blood vessels (vasculitis) induced by HHV-6, which
may be a mechanism of CNS complications of HHV-6 infection.37
HHV-6 vasculitis would lead to breakdown of the blood-brain barrier and to
increased passage of potentially autoreactive immune system cells into the
CNS. Therefore, antigens expressed within myelin would be more accessible
to immunologic attack.
Infection of the CNS
Epidemiologic studies indicate that more than 90% of all individuals
are exposed to HHV-6 during early childhood, probably before age 2.38,39
The presence of HHV-6 DNA in the CSF has been reported in children with
repeated febrile seizures after primary infection40 and in the
CSF of seven of 10 children with exanthem subitum.41 HHV-6 DNA
has been detected by polymerase chain reaction (PCR) technique in 43% to
85% of specimens of normal human brain tissue.42-44 Studies
have shown an association of HHV-6 with meningitis or encephalitis45,46
and with increased intrathecal production of anti–HHV-6 early
antigen immunoglobulin M (IgM), a possible indicator of viral reactivation
in patients with meningitis or encephalitis.47 Knox and
colleagues directly demonstrated by immunohistochemistry the presence of
HHV-6–infected astrocytes, oligodendrocytes, and neurons in autopsy
brain tissue from an HIV-infected child with fulminant encephalitis.48
These findings suggest that HHV-6 can infect the CNS directly and remain
in a latent state in normal or immune-suppressed individuals. Thus, the
CNS could be a reservoir of latent or chronic HHV-6 infection, and
reactivation could occur locally.40
There is additional neuropathologic evidence linking HHV-6 infection
with demyelination in the CNS. Yanagihara et al described HHV-6–infected
neurons and astrocytes in areas of white matter demyelination found in an
adult bone marrow transplant patient with encephalitis.49 HHV-6
viral particles were demonstrated within oligodendrocytes in multifocal
demyelinating white matter lesions of a patient with fulminant
encephalomyelitis.50 HHV-6–infected cells have been found in
association with areas of active demyelination in postmortem tissues from
a patient with subacute demyelinating leukoencephalitis who was previously
diagnosed as having MS.51 In a case report, HHV-6 antigens were
demonstrated in astrocytes from a patient with chronic myelopathy and
progressive spastic paraparesis associated with demyelination, axonal
loss, chronic inflammation, and gliosis.52
and MS: Are They Linked?
Several considerations make HHV-6 a strong candidate to play a role in
the course of MS, either as a causal agent or as a cofactor. HHV-6 is a
ubiquitous, as well as lymphotropic and neurotropic, virus. It can cause
common primary infection in early childhood, and it may remain latent in
CNS tissue until optimal conditions permit its reactivation and
replication. HHV-6 may induce secretion of inflammatory cytokines such as
tumor necrosis factor alpha (TNF-a), which could promote immune-mediated
demyelination in MS.53,54 As previously described, there is
also neuropathologic evidence of an association of HHV-6 with active
demyelinating lesions within the CNS.
During the past decade, a number of studies have suggested an
association between HHV-6 and MS. These investigations have examined
anti–HHV-6-specific antibody responses, HHV-6 viral DNA, or HHV-6
presence in CNS tissue. In 1993, Sola et al reported significantly higher
titers of serum anti–HHV-6 antibodies in MS patients compared to normal
controls.55 In 1997, Soldan et al documented increased serum
IgM response to HHV-6 early antigen (p41/38) in relapsing-remitting MS
patients compared with chronic progressive MS patients or patients with
other neurologic or autoimmune diseases or normal controls.56
These researchers also detected HHV-6 DNA in the serum of 15 out of 50 MS
patients but in none of 47 non-MS cases studied by PCR. Ablashi et al also
found increased serum IgM and IgG responses to HHV-6 early antigen p41/38
in MS patients compared with patients with other neurologic diseases and
normal controls.57 However, in more recent studies, comparison
of serum HHV-6 antibody between MS patients and normal controls showed no
Studies examining HHV-6 DNA have yielded conflicting results. HHV-6 DNA
has been detected in the CSF of MS patients but in none of the controls in
two reports.57,59 Other studies have failed to find significant
differences in HHV-6 DNA between MS and control groups60 or
failed to detect serum or CSF HHV-6 DNA in MS patients.61,62
Fillet et al examined a group of newly diagnosed MS patients (before
treatment), but they did not find differences in either the serum or CSF
HHV-6 DNA between these MS patients and patients with other neurologic
diseases or normal individuals.63 In a recent analysis of HHV-6
viral DNA transcription, Rotola et al concluded that HHV-6 and HHV-7 gene
sequences are similarly prevalent in peripheral blood mononuclear cells of
MS patients and controls.64 However, these viral gene sequences
were maintained in a “non-transcriptional state,” typical of latency.
Using immunohistochemical techniques, Challoner et al found expression
of HHV-6 antigens in the nuclei of oligodendrocytes associated with
demyelinated plaques in brain sections from MS patients but not from
controls.43 Knox et al also described HHV-6–infected cells in
90% of CNS tissue sections showing active demyelination, ie, sections
associated with inflammatory cells that were obtained from patients with
definite MS.65 This compared with 13% of tissue sections
without active disease, suggesting that HHV-6 infection is prevalent in
areas of active demyelination. Using PCR to study postmortem brain samples
of MS patients, Sanders et al reported a higher frequency of gene
sequences from multiple herpesviruses, including HHV-6, herpes simplex
virus (HSV), and varicella zoster virus (VZV), in active demyelinated
plaques compared with inactive plaques.44 However, the
researchers did not find statistically significant differences between MS
cases and controls. Thus HHV-6 can associate with other viruses, such as
HSV and VZV, that can cause persistent or latent infection of nervous
tissues and reactivate in demyelinating plaques. This association may have
significance for the pathologic course of MS. HHV-6 could function as a
cofactor to facilitate concurrent chronic replication of these other
viruses within neural cells. Thus, HHV-6 would indirectly support or
promote viral-induced mechanisms of neurologic damage.
Conflicting results among these studies of HHV-6 in MS patients may be
due to multiple causes, such as variation in technical protocols,
detection of different variants of HHV-6 with different antigenic
reactivity, and differences among MS subpopulations studied.5
Active HHV-6 viral infection in some MS patients may fluctuate over time
during disease progression,56 causing inconsistency in viral
detection. One recent study found an increased prevalence of HHV-6A in
patients with MS,66 and earlier studies reported an increased
association of MS with HHV-6B.43,57,67 It remains to be
determined if both HHV-6 strain variants could be involved in the
development and course of MS in different subpopulations of patients,
which possibly could be distinguished by clinical, immune, or genetic
parameters. Given the marked heterogeneity of MS lesions and possible
involvement of different pathogenic mechanisms (recently reviewed by
Noseworthy et al68), HHV-6 could be a more or less significant
factor in specific, genetically susceptible subpopulations of patients.
It is not possible at this time to conclude that HHV-6 “causes” MS.
There is a growing body of evidence associating HHV-6 infection of the CNS
with MS in at least a subpopulation of patients, although the specific
factors that define the vulnerable subpopulation(s) of MS patients have
not been elucidated. This evidence is provocative but not definitive, and
it does not distinguish between HHV-6 as a causal agent in MS versus HHV-6
as a cofactor. The pathogenesis and course of HHV-6 infection have
interesting parallels to that of MS, and the viral cycles of latency and
reactivation could contribute to clinical remissions and exacerbations in
susceptible MS patients. Whether HHV-6 is the causal agent of the initial
MS “attack,” a local inflammatory reaction in the CNS could stimulate
HHV-6 replication in oligodendrocytes by recruiting immunologically
activated, CD4-expressing T-lymphocytes that secrete inflammatory
molecules. Viral replication in these oligodendrocytes and T-lymphocytes
could cause further inflammation and both immune and viral-associated
demyelination. This could translate clinically into more severe relapses
and higher risk for progressive or permanent disability.
Given the provocative but inconclusive evidence for the role of HHV-6
in the course of MS, more clinically based data are needed. Do HHV-6
latency and reactivation parallel clinical remissions and exacerbations in
HHV-6–infected MS patients? Should MS patients at risk for HHV-6
reactivation receive anti-viral medication during MS exacerbations or even
during remissions? A useful approach to these questions would be a
longitudinal clinical and virologic study of HHV-6 gene expression and
specific antibody responses in MS patients to determine whether these
markers of HHV-6 infection correlate over time with MS-related clinical
and MRI imaging findings. Subpopulations of MS patients with evidence of
HHV-6 infection could then participate in clinical trials of effective
anti–HHV-6 drugs. A placebo-controlled, double-blind trial of the anti-herpesvirus
agent acyclovir in 60 MS patients has already been reported.69
Acyclovir tended to reduce the frequency of MS exacerbations and
significantly reduced titers of anti-HSV IgG antibodies in treated
patients. However, acyclovir is not the optimal anti-viral agent to use
against HHV-6. It is commonly used to treat HSV and VZV infections
associated with fever blisters or shingles. Ganciclovir and foscarnet,
used in the treatment of CMV infection, are more potent anti-viral drugs
against beta-herpesviruses such as CMV and HHV-6.6 In addition to specific
anti-herpesvirus drugs, the beta-interferons are known to have broad
anti-viral effects,6 so these MS medications may have some
adjunctive effects on HHV-6 infection. There may also be synergy or
cooperativity between interferons and specific anti-herpesvirus drugs,6
and this possibility could be studied specifically with respect to HHV-6
in MS patients taking interferons. Ultimately, well-controlled clinical
trials regarding this issue are the best means to establish whether MS
patients could benefit from anti-viral medications and to establish
effective doses of these agents and proper protocols for using them as
either therapeutic or prophylactic agents.
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