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Amyotrophic Lateral Sclerosis. 2005; 6: 77–87
REVIEW ARTICLE
Sporadic amyotrophic lateral sclerosis: A hypothesis of persistent (nonlytic) enteroviral infection
JOHN RAVITS
Neurology Section, Virginia Mason Medical Center and Neurogenomics Laboratory, Benaroya Research Institute of Virginia
Mason, Seattle, USA
Abstract
Because of recently reported reverse transcriptase polymerase chain reaction evidence of enterovirus in sporadic
amyotrophic lateral sclerosis (SALS) and because of newly available anti-enteroviral drugs binding enteroviral capsids, it is
reasonable to re-formulate an enteroviral hypothesis of SALS using recent advances in molecular virology. Viral persistence
is non-lytic and non-cytopathic infection that evades host’s immune surveillance. Enteroviruses are known to cause
persistent as well as lytic infection both in vitro and in vivo. Both virion as well as host factors modulate between persistent
and lytic infection. Apoptosis, or programmed cell death, is a process of active non-necrotic cell death. It has complex
interplay with viruses and may be either promoted or opposed by them. Apoptosis is a major factor in motor neuron death in
SALS. Viral tropism is the process by which viruses select and propagate to target cells. It is controlled by capsid
conformation and surface receptors on host cells. Enteroviruses have a region on their capsids known as the canyon which
docks on such receptors. Docking induces conformational changes of the capsid and genome release. Poliovirus, tropic for
motor neurons, docks on the poliovirus receptor, about which much is known. The virus penetrates the motor system
focally after crossing either the blood-muscle or the blood-brain barriers. It propagates bidirectionally along axons and
synapses to contiguous motor neurons, upper as well as lower, which sequester infection and create avenues for spread over
long distances. If chronic and persistent rather than acute and lytic, such viruses trafficking in a finite system of non-dividing
cells and inducing apoptosis would cause cell death that summates linearly rather than exponentially. Taken together, these
explain signature clinical features of SALS — focal onset weakness, contiguous or regional spread of weakness, confinement
to upper and lower motor neurons, and linear rates of progression. The hypothesis predicts the following testable
investigations: 1) viral detection may be possible by applying amplification technology to optimally acquired nervous tissue
processed by laser microdissection; 2) genetic susceptibility factors such as cell surface receptor polymorphisms may
combine with sporadic exposure and chance penetration of the motor system in SALS; 3) a transgenic animal model might
be created by inserting such genetic factors into an animal host and inoculating intramuscularly rather than intracerebrally
biochemical fractions of SALS motor neurons at vulnerable periods in the developmental life cycle of the transgenic host;
and 4) continual long-term administration of anti-enteroviral agents called capsid-binding compounds which stabilize
capsids and prevent genome release might be efficacious.
Key words: Amyotrophic lateral sclerosis, enterovirus, persistent viral infection, apoptosis, poliovirus receptor, capsid binding
compounds
Introduction
‘‘We believe that a number of current diseases
affecting differentiated systems like the nervous…system yet of unknown etiology may
likely be caused by infectious agents like
viruses which have evolved to persist and
replicate in differentiated cells without causing
lysis of the cell they infect. With the availability
of highly sensitive molecular techniques to
identify limited amounts of materials, this
hypothesis can be adequately tested in the
coming decades. From the evidence that is
evolving, it is likely that the study of such
persistent viruses will dominate virology in the
twenty-first century.’’
J.C. de la Torre and M.B.A. Oldstone, 1996 (1)
A viral cause of sporadic amyotrophic lateral
sclerosis (SALS) has been hypothesized for decades
(reviewed in 2)(3–18). Enteroviruses (Figure 1)
have led the candidate viruses because of the tropism
of poliovirus, an enterovirus subtype, for motor
neurons (19–27). Retroviruses are also candidates
Correspondence: J. Ravits, Neurology Section, Virginia Mason Medical Center and Neurogenomics Laboratory, Benaroya Research Institute, PO Box 900,
1100 Ninth Avenue, Seattle, WA 98111, USA. E-mail: [email protected]
(Received 18 May 2004; accepted 11 November 2004)
ISSN 1466-0822 print/ISSN 1471-180X online # 2005 Taylor & Francis Group Ltd
DOI: 10.1080/14660820510027026
78
J. Ravits
Figure 1. Structure of the poliovirion. A complete capsid
structure of virulent poliovirus type 1 [PV1(M)] illustrated as a
water-accessible molecular surface. One of the 12 pentameric
subunits of the capsid and its five constituent triangular
pseudoprotomeric subunits are illustrated. The 5x and 3x labels
indicate the locations of the five-fold and the three-fold axes of
this pentamer. The two-fold axes occur at the intersection of the
three adjacent pentamers. The central pseudoprotomer illustrates
the subunit geometry of viral capsid proteins VP1, VP2, and
VP3(ii). The biologically relevant protomer (to viral assembly) is
pear-shaped and consists of VP1, VP2, and VP3(i). The internal
VP4 protein is not visible from the surface. The canyon’s north
wall (A), south wall (C), and bottom (B) are indicated. The major
poliovirus antigenic sites are labeled Ia, Ib, II, and III on an
adjacent pseudoprotomer. [Reproduced with permission from
Harber J, Bernhardt G, Lu H, et al: Canyon Rim Residues,
Including Antigenic Determinants, Modulate Serotype-Specific
Binding of Polioviruses to Mutants of the Poliovirus Receptor.
Virology 1995;214:559–70 (reference 20).]
(1,50–55). Host as well as viral factors are significant
since some viruses cause lytic infection in one cell
line and persistent infection in others. Time of
infection is also significant since infection causes
lytic infection at one time in the life of the host and
persistent infection at another. Viruses escape
immune surveillance to persist in host cells through
a
number
of
strategies
(1,51–53,56–58).
Enteroviruses can cause persistent as well as lytic
infections (reviewed in 59) (60,61). Polioviruses, in
particular, can cause persisting infection (25,62–77).
The central nervous system (CNS) is a unique
compartment for persisting infection (53,78–80): it
is relatively isolated from the immune system by the
blood-brain barrier, its neurons have relative
absence of major histocompatibility-complex molecules fundamental to invoking immunologic
response (81,82), its cells are static and cannot be
overgrown by replacements, and its extensive networks of axons and dendrites create avenues for
sequestering and spreading infection over long
distances. SALS is fundamentally a disease of the
CNS — all motor neurons reside inside the CNS
compartment and only axons of the lower motor
neurons extend outside it. SALS, traditionally
regarded as a disease in which inflammation and
immune response are absent, in fact has subtle
responses (reviewed in 83) (84–90).
Viral-associated apoptosis
because motor neuron syndromes are associated
with both HIV and HTLV1 retroviral subtypes (28–
38). Amplification technologies, polymerase chain
reaction (PCR) (39,40) and reverse transcriptase
polymerase chain reaction (RT-PCR) (41–43) have
reinvigorated the search. To date, three studies from
two laboratories have reported evidence of enterovirus in nervous systems of patients dying from
SALS using RT-PCR (44–46) and three studies
from three laboratories, two of them recent, have
reported negative results with this technique (47–
49). With the availability of highly effective antienteroviral therapy (i.e., [(oxazolylphenoxy)alkyl]isoxazole capsid-binding compounds), the hypothesis
remains significant.
Apoptosis, or programmed cell death, is a process of
active non-necrotic cell death. It has a complex
interplay with viruses and may be either promoted or
opposed by them (91–99). Very little is known about
this interplay; one example is the Sindbus virus that
induces an encephalitis and hind limb paralysis in
mice by apoptosis (100,101). Another example is the
poliovirus, which can either induce or oppose
apoptosis depending on viral properties and host
cell factors (102–106). One function of apoptosis is
regulation of embryonic development (107–109). In
embryonic development, 50% or more of motor
neurons are eliminated by apoptosis, underlining
motor neurons’ intrinsic apoptotic capability (110).
Based on biochemical (111–115), and morphologic
(114) evidence, apoptosis is now thought to be a
major factor in cell death in SALS (reviewed in 116
and 117). The interplay of viruses and apoptosis in
the nervous system has been speculated but never
proven to be important in neural degeneration
(96,109,118–120).
Viral persistence (non-lytic infection) and the
privilege of the CNS
Cell surface receptors, viral tropism, and viral
sequestration
Viral persistence is non-lytic and non-cytopathic
infection that evades host’s immune surveillance
Viral tropism is the process by which viruses select
and propagate to targets cells (reviewed historically
Persistent enteroviral infection in ALS
in 121). It is controlled by capsid conformation
and receptors on the cell’s surface. Models are the
pircornaviruses (122–124), especially polioviruses,
tropic for motor neurons (reviewed in 125)
(19,22,23,126). Key to poliovirus’s tropism is the
poliovirus receptor (PVR) (127–133). PVR is a cellsurface sialylated glycoprotein belonging to the
immunoglobulin superfamily and has three extracellular immunoglobulin-like domains, a transmembrane domain and a cytoplasmic tail. Its gene maps
to chromosome 19q 13.1–13.2. The cellular function of PVR is unknown. It is found only in primate
cell lines. A transgenic mouse model expressing
human PVR has susceptibility to poliovirus infection
when it otherwise has none. This has allowed
significant evaluation of PVR’s molecular biology
(134). PVR underlies both viral selection and
infection— PVR protruding from the cell surface
fits into a depression on the surface of the virion
capsid known as the canyon, a depression located
just below the five-fold axis of symmetry on the
north face of the icosahedal structure (Figure 2).
This induces conformational changes in the capsid
leading to destabilization, uncoating and RNA
release (132,133,135–138). Since PVR is distributed
in cell lines not infected by the virus, other factors
are important in its tropism for and sequestration in
the motor system (139–145).
Focal access and contiguous viral propagation
One of the best-understood and most relevant
models of viral propagation is again the poliovirus
(reviewed in 125) (146–148). Extensive clinical
(149–157) and experimental (146,149,150,157–
162) observations indicate poliovirus penetrates the
motor system either from the periphery or from the
CNS. From the periphery, it establishes a focal nidus
in muscle by first crossing the blood-muscle barrier
and then travels retrograde along motor neurons to
invade the motor system (163). From the CNS, it
first crosses the blood-brain barrier then invades the
motor system. Once inside motor neurons, poliovirus propagation is trans-neuronal to contiguous
motor neurons, either horizontal between neighboring neurons or trans-synaptic between upper and
lower motor neurons. Both axonal and transsynaptic transmissions are bidirectional: antegrade
or retrograde along axons and orthodromic or
antidromic across synapses. Axonal transmission is
probably through fast transport systems (161).
Motor neurons create avenues for spreading over
long distances infection already sequestered by
its unique tropism. Thus, poliovirus infection
begins focally and spreads contiguously to
infect the entire motor system, upper as well
as lower motor neurons, a feature known from
early pathologic studies of acute lytic polio (21–
23,149).
79
Figure 2. Locations of human PVR (hPVR) binding mutations on
the poliovirus capsid and a virus-receptor model. (a) Stereo view
showing details of the five-fold depression, referred to as the
canyon. The axes of icosahedral symmetry are labeled around a
single representative of the 60 triangular pseudoprotomeric facets.
The view is seen along the icosahedral two-fold axes of symmetry
looking down upon the canyon area. Residues exchanged in the
antigenic hybrids (NAgI and NAgII) are represented in magenta
color, while the amino acid substitutions resulting from sitedirected mutagenesis are colored in cyan. The sphingosine
molecule occupying the hydrophobic pocket of the viral capsid
protein VP1 protein is shown in yellow. (b) Stereo view of the
same area as that shown in (a) except that the view is
perpendicular to the axes of the icosahedral five- and two-fold
symmetry. (c) A poliovirus receptor modeled after the CD4
molecule is docked into the canyon. Orientation is the same as
that in (b). Domain 1, an immunoglobulin V-like domain (gold)
enters the canyon. The smaller domain 2, an immunoglobulin Clike domain, is colored green and sits above the surface of the
virion. It is possible that domain 1 contacts residues of the north
wall (nearest NAgI) and south wall (the NAgII face) simultaneously based on spatial considerations alone. Also, binding of the
receptor to the canyon rim regions does not necessarily involve
contacts of the receptor to the bottom of the canyon. [Reproduced
with permission from Harber J, Bernhardt G, Lu H, et al. Canyon
Rim Residues, Including Antigenic Determinants, Modulate
Serotype-Specific Binding of Polioviruses to Mutants of the
Poliovirus Receptor. Virology 1995;214:559–70 (reference 20).]
Viral etio-pathogenesis of SALS
Cardinal clinical features of SALS are focal onset,
regional or contiguous spread, confinement to upper
and lower motor neurons, relatively linear progression for each patient, but highly variable among
different patients. These are readily explained by
persistent viral infection. Persistent infection is nonlytic and non-cytopathic. Viral properties, host
susceptibility factors and time of exposure may all
80
J. Ravits
be important factors in its establishment. Tropism
for motor neurons, controlled by viral capsid conformation and host cell-surface receptors, ensures
infection selects motor neurons and stays sequestered. Infection may gain access either after penetrating the blood-muscle barrier or the blood-brain
barrier. Once inside, it spreads contiguously. Horizontal propagation includes crossing the midline at
spinal and brainstem levels because of relative
proximity of anterior horns and brainstem nuclei.
Vertical or trans-synaptic propagation causes a jump
between lower and upper motor neurons, the latter
leading to propagation over long distances. Because
infection is persistent and propagation through the
motor system is successive, progression is linear
rather than accelerating. Because of variation of
biologic factors such as viral load, viral virulence and
host cell factors, progression rates are highly variable
among different host patients. As infection propagates, it switches on apoptosis, a capability well
established in motor neurons and known to have
complex interplay with viruses. Since motor neurons
are limited in number and non-dividing, cell death
summates. This is manifested clinically as progressive muscle weakness that begins focally, spreads
regionally, and progresses linearly. Thus, SALS is
reminiscent of the description the Icelandic veterinarian Bjorn Sigurdsson employed of Visna-Maedi
disease in sheep, the original ‘slow virus’ and one
of the first descriptions of what was later found to
be a retroviral disease: ‘acute disease in slow
motion’! (164).
Implications for therapy
Capsid-binding compounds
The capsid binding compounds [(oxazolylphenoxy)alkyl]isoxazoles, have been designed for treatment
of enteroviral and picornavirus infections (165–172).
These compounds bind in the hydrophobic pocket
situated at the base of the canyon site on the north
face of the virion icosahedral capsid where cellular
receptors interact. This binding raises the floor of
the canyon and alters the virion’s ability to attach
and bind to receptors, thus inhibiting disassembly
and RNA release (Figure 3). Since these drugs act
on the virion’s capsid and not its RNA genome, they
block viral propagation – once virus has released
RNA and infected a cell, capsid-binding drugs
would have little effect. Therefore, for them to be
effective in SALS, assuming the viral pathogenesis, a
constant level of drug would have to be present in
the body over months or years and it would be
controlling rather than curative treatment. Since the
hydrophobic pocket has unique topology not found
in other classes of proteins, the compounds are viral
specific and have minimal host toxicity (166). One of
these compounds, VP 63843 (PleconarilH), is well
tolerated, well absorbed after oral administration,
Figure 3. Diagrammatic view of picornavirus with enlargement of one icosahedral asymmetric unit showing the outline of the canyon and
the entrance to the antiviral-binding pocket. The protomeric assembly unit (which differs from the geometric definition of the asymmetric
unit) is shown in heavy outline on the icosahedron. [Reproduced with permission from Oliveira MA, Rossmann MG, et al. The structure of
human rhinovirus 16. Structure1993;1:51–68 (reference 170).]
Semi-nested in 2
centers
has few side-effects, little toxicity, and crosses readily
into the central nervous system and into gray matter
(173,174). Anecdotal evidence of benefit in one
SALS patient has been reported (175).
Other therapeutic strategies
Other specific anti-picornavirus therapy includes
inhibitors of 3C protease and recombinant soluble
intercellular adhesion molecules (reviewed in 176).
Interferons are potent mediators resisting enteroviruses (165). Cells exposed to enteroviruses
increase production of interferon through an intracellular cascade and this increases resistance to
infection. Alpha interferon, a potent inhibitor of
enteroviral infection, may be even more effective
when combined with capsid-binding compounds
(177). Therapeutic strategies to alter apoptosis pathways are in early stages of development (reviewed in
178) (179–182). Strategies combining antiviral and
anti-apoptotic with current anti-neuroexcitatory
therapies may be effective. Vaccination is now
conceivable to prevent chronic viral infections (183).
1
1
Nested, in situ
RT-PCR
Semi-nested for
echovirus 7
Nested
1
1 or 2
Nested
1–4 (usu. 1 or 2)
Positive 8/10 (72%) SALS & 1/2
(50%) FALS, Negative 0/6 (0%) controls
Negative 0/28 (0%) SALS
Negative 0/6 (0%) controls
Positive 15/17 (88%) SALS
Negative 1/29 (3%) controls
Negative for echo 7 0/20 (0%) SALS
spinal cords and 0/10 (0%) cortex
Positive 3/5 (60%) SALS
Positive 2/14 (14%) controls
Negative 24/24 (100%) ALS
Negative 17/17 (100%) controls
Positive 5/5 (100%) positive controls
Nested
1
Spinal cord
Archived tissue
Archived tissue
Uncertain
Uncertain
Retrospective
Retrospective
Prospective
Prospective
(2 Centers)
Frozen
Archived tissue
Retrospective
Frozen
Spinal cord and
cortex
Spinal cord
Spinal cord, brain
stem, and cortex
Spinal cord
Archived tissue
Retrospective
Woodall, 1994
(ref44)
Swanson, 1994
(ref47)
Berger, 2000
(ref45)
Walker, 2001
(ref48)
Giraud, 2001
(ref46)
Nix, 2004
(ref49)
Collection method
Formalin-fixed, paraffin
embedded
Formalin-fixed, paraffin
embedded (one frozen)
Formalin-fixed, paraffin
embedded
Frozen
Spinal cord
RT-PCR Method
81
Predictions
Prospective or
retrospective
Study
Table I. Summary of RT-PCR studies and methodologies.
Fixative
Neuraxis Level
Sample sites
Results
Persistent enteroviral infection in ALS
The hypothesis predicts the following: 1) viral
presence either may be detectable only using highly
sensitive techniques on optimally procured and
processed nervous system tissue. Laser microdissection is a new technology that allows isolation of cells
and thus overcomes problems of sampling; 2) host
genomic factors such as cell surface receptors or host
immune factors may be important susceptibility
factors that permit establishment of persistent
infection; 3) disease may depend on the chance
concurrence of these genetic susceptibility factors,
sporadic infection, motor system penetration provided through the blood-muscle barrier breakdown
(from exercise, trauma or other factors), and
possibly vulnerable times in the host’s development;
4) an animal model might be created by inserting
genetic susceptibility factors such as cell surface
receptors into a transgenic animal and inoculating with extract from frozen motor neurons –
intramuscular inoculation may allow better entry to
the motor system than intracerebral inoculation;
controlling times of exposure may be important;
5) continual long-term administration of capsidbinding compounds such as VP 63843 (PleconarilH)
that readily penetrate the CNS may be efficacious.
Recent investigations of persisting enteroviral
detection
Signal-to-noise ratio of persisting enteroviral infection in motor neurons would be infinitesimal due to
low viral copy, small virion size, small viral genome
(7.4 kB), high host nucleic acid noise level from
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J. Ravits
within the motor neuron, and high host nucleic acid
noise level from the surrounding tissue. RT-PCR is
able to amplify signal billion-fold or more and
enteroviral RT-PCR has extremely high sensitivity
and specificity (42,184–187). RT-PCR detection of
low-copy persisting viral genome is more complex
than lytic infection (188,189). Six RT-PCR studies
searching enteroviruses have been completed: three
studies from two laboratories are positive (44–46)
and three studies from three laboratories are negative
(47–49). The methodological issues and results are
summarized in Table I. Problems for most of these
studies variously include: 1) retrospective testing of
archived specimens; 2) collection, fixation and
storage not specifically designed for nucleic acid
preservation and PCR technology; 3) random,
limited and non-selective tissue sampling; 4) testing
tissue homogenates with little or no information
about the neuropathologic status of motor neuron
degeneration in the tested tissue (190); 5) different
RT-PCR methods including simple, nested and seminested amplification, different primers and different
sensitivities (190); and 6) lack of internal controls
such as housekeeping genes or validation studies with
positive controls for establishing sensitivities (190).
Interestingly, the best-designed studies have been
negative (48,49), but they have been performed on
frozen tissue, and the more problematically designed
studies have tended to be positive, but they have been
performed on formalin-fixed tissue. Thus, the possiblity remains that formalin fixation may better
preserve viral signal or better deliver it to RT-PCR
than freezing. RT-PCR can be performed on formalin-fixed, paraffin-embedded archived tissue (191–
197) and recent protocols for spinal cord samples
have been published (198). Sample size may also be
important and paradoxically less tissue may be more
likely to reveal persisting virus than larger samples,
possibly because of increased noise and inhibitor
factors (199–201). Clearly, the most significant limit
to detection of enterovirus in ALS is the severe
reduction of the targets of investigation, motor
neurons, due to elimination by the disease and the
marked variation of regional topography of pathology
along the neuraxis. Use of laser-based tissue microdissection that is able to isolate, collect, and
standardize specific cells such as motor neurons will
resolve these methodologic problems (202,203).
Note
*
The ratio of diameters of enterovirus (30 nm) to motor
neurons (30–120 mm) is 1 to 1000–4000 and the corresponding ratio of volumes is ,1 to 109.
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