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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 82 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). 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