- Open Access
Epidemics to eradication: the modern history of poliomyelitis
Virology Journal volume 4, Article number: 70 (2007)
Poliomyelitis has afflicted humankind since antiquity, and for nearly a century now, we have known the causative agent, poliovirus. This pathogen is an enterovirus that in recent history has been the source of a great deal of human suffering. Although comparatively small, its genome is packed with sufficient information to make it a formidable pathogen. In the last 20 years the Global Polio Eradication Initiative has proven successful in greatly diminishing the number of cases worldwide but has encountered obstacles in its path which have made halting the transmission of wild polioviruses a practical impossibility. As we begin to realize that a change in strategy may be crucial in achieving success in this venture, it is imperative that we critically evaluate what is known about the molecular biology of this pathogen and the intricacies of its interaction with its host so that in future attempts we may better equipped to more effectively combat this important human pathogen.
The word poliomyelitis, the medical term used to describe the effect of poliovirus (PV) on the spinal cord, is derived from the Greek words for gray (polio) and marrow (myelon). The first known clinical description of poliomyelitis is attributed to Michael Underwood, a British physician, who in 1789 reported observing an illness which appeared to target primarily children and left those afflicted with residual debility of the lower extremities. In subsequent years, additional cases of poliomyelitis would be reported. Initial outbreaks in Europe were documented in the early 19th century and outbreaks in the United States were first reported in 1843. However, it was not until the early 20th century that the number of paralytic poliomyelitis cases reached epidemic proportions.
In 1938, in efforts to support care for patients with poliomyelitis as well as fund research to combat the illness, the National Foundation for Infantile Paralysis (now the March of Dimes) was established. The number of paralytic cases in the United States, estimated to have been in excess of 21,000, peaked in 1952. Fortunately, on April 12, 1955, the March of Dimes declared that the Salk polio vaccine was both safe and effective. Then, in 1963, the development of a second vaccine, the Sabin polio vaccine, was announced. With the introduction of effective vaccines, the incidence of poliomyelitis rapidly declined. Indeed, in the United States, the last case of poliomyelitis due to infection with wild type (wt) virus was reported in 1979. Less than a decade later, in 1988, the World Health Organization (WHO) launched a global campaign to eradicate PV.
Since initial descriptions of poliomyelitis were first documented to the present time, innumerable milestones have been reached in understanding the molecular biology of PV and the pathogenesis of poliomyelitis. Such advances have certainly led to the more effective management of poliomyelitis. Nonetheless, many questions remain unanswered. One such question pertains to the determinants of neuropathogenesis, specifically regions of the virus genome important for aspects of virus replication in the cells which it targets.
In this review, the current state of our understanding of the molecular biology and pathogenesis of poliovirus, as it relates to current eradication efforts, is explored.
PV was discovered to be the causative agent of poliomyelitis in 1909 by Karl Landsteiner and Erwin Popper, two Austrian physicians . Owing to the expression of three unique sets of four different neutralization antigenic determinants on the poliovirion surface referred to as N-Ag1, 2, 3A, and 3B [110, 155], the virus occurs in three serotypes, termed types 1, 2, and 3, where the names Mahoney, Lansing, and Leon designate a strain of each serotype, respectively [21, 98, 125, 137]. The polioviruses are classified as members of the Picornaviridae, a large family of small RNA viruses, consisting of nine genera: Enterovirus, Rhinovirus, Cardiovirus, Aphthovirus, Hepatovirus, Parechovirus, Erbovirus, Kobuvirus, and Teschovirus (Table 1). The Enterovirus genus, to which the polioviruses belong, can be further subdivided into eight clusters (i.e., Poliovirus, Human enterovirus A, Human enterovirus B, Human enterovirus C, Human enterovirus D, Simian enterovirus A, Bovine enterovirus, and Porcine enterovirus B) (Table 2), which include predominantly human pathogens exhibiting marked variation in the disease syndromes they produce.
Admittedly, the initial classification of human enteroviruses was based on the clinical manifestations observed in human infections as well as on the pathogenesis in intracranially- and subcutaneously-inoculated experimental suckling mice. The four categories into which human enteroviruses were subdivided were: (1) polioviruses, which caused flaccid paralysis (poliomyelitis) in humans but not in suckling mice lacking CD155; (2) coxsackie A viruses (CAV), which were linked to human central nervous system (CNS) pathology and skeletal muscle inflammation (myositis) as well as acute flaccid paralysis in suckling mice; (3) coxsackie B viruses (CBV), associated with ailments of the human cardiac and central nervous systems, and necrosis of the fat pads between the shoulders, focal lesions in skeletal muscle, brain, and spinal cord, as well as spastic paralysis in the suckling mouse experimental model; and (4) echoviruses, which were not originally associated with human disease nor with paralysis in mice [41, 121, 201]. With groundbreaking advances in molecular biology, a modified classification stratagem has evolved. Under the new scheme, human enteroviruses are subdivided into five species: Poliovirus and Human enterovirus A, B, C, and D. The three PV serotypes (i.e., PV1, 2, and 3) constitute the species Poliovirus, and 11 coxsackie A virus serotypes (i.e., CAV1, 11, 13, 15, 17, 18, 19, 20, 21, 22, and 24) constitute the Human enterovirus C (HEV-C)  (Table 2). But recently, the Executive Committee of the International Committee on Taxonomy of Viruses (ICTV) has endorsed a proposal, which awaits ratification by the ICTV membership, to move the polioviruses into the Human enterovirus C species. On the basis of genome sequences, the C-cluster human enteroviruses bearing the greatest degree of relatedness to the polioviruses are CAV11, CAV17, and CAV20 . Indeed, genetically, these three C-cluster coxsackie A viruses differ notably from the polioviruses only in the structural (P1) capsid region .
The poliovirus genome
The genome of the polioviruses as well as that of members of the Human enterovirus C cluster is approximately 7400 nucleotides (nt) in length (PV, 7441 nt) and composed of single-stranded RNA consisting of three distinct regions: a relatively long 5'NTR (PV, 742 nt) that is covalently linked to the virus-encoded 22-amino acid long VPg protein [110, 196]; a single open reading frame (ORF) encoding the viral polyprotein; and a comparatively short 3'NTR followed by a virus-encoded poly(A) tract of variable length (PV, 60 adenine residues) [47, 97, 163, 182, 202] (Fig. 1A).
The 5'NTR is predicted to harbor a significant degree of complex secondary structure [1, 158, 179] (Fig. 2). Computer analysis has predicted six domains (domains I-VI) within the 5'NTR, many of which have been validated by genetic and biochemical analyses  as well as visualized by electron microscopy . In this region of the genome, eight cryptic AUG triplets have been identified which precede the initiation codon at nt 743. This segment of the genome can be further subdivided into: (i) the 5'-terminal cloverleaf, an indispensable cis-acting element in viral RNA replication [3, 113, 144, 147] as well as in regulating the initiation of translation; and (ii) the IRES , which mediates cap-independent translation of the viral mRNA by facilitating initiation of translation independent of a capping group and even a free 5' end [36, 90, 91, 147, 149, 150].
In contrast to the 5'NTR, comparatively less is known about the 3'NTR. Nonetheless, this region is known to be poly-adenylated and predicted to exhibit conserved secondary structures consisting of two hairpins [89, 160]. Moreover, evidence indicates that it has a functional role in RNA replication [31, 32, 50, 89, 108, 123, 157, 159, 160]. Specifically, it has been shown that while deletion of the 3'NTR has only minimal effects on the ability of PV to propagate in HeLa cells, the ability of the virus to propagate in cells of neuronal origin is markedly reduced both in vitro and in vivo .
The 250-kDa polyprotein encoded by the single ORF can be further subdivided into regions denoted P1, P2, and P3, encoding the structural and nonstructural proteins. Following translation of pUp-terminated mRNA [81, 134], proteolytic cleavage of the unstable "polyprotein" by virus-encoded proteinases, 2Apro and 3C/3CDpro in cis and in trans  (Fig. 1B), gives rise to proteins with functions in viral proliferation. Processing of the polyprotein is thought to proceed in accordance to a pathway established by protein folding resulting in masking of certain cleavage sites and by amino acid sequences adjoining the scissile bond  The first cleavage of the genomic polyprotein at a tyrosine-glycine dipeptide is catalyzed by the 2A proteinase and results in release of a 97-kDa polyprotein consisting of the P1 structural segment of the genome . Subsequent cleavages of the P1 precursor into stable end products VP0, VP3, and VP1 is mediated by the 3CD proteinase . Cleavage of VPO into capsid proteins VP4 and VP2 occurs during maturation of the virion and is mediated by an unknown mechanism that has been hypothesized to be viral proteinase independent . The cleavage of P2 and P3 precursors into stable end products [2Apro, 2B, 2BC, 2C, 3A, 3AB, 3B (VPg), 3C/3CDpro, and 3Dpol] at glutamine-glycine dipeptides is catalyzed by the 3Cpro/3CDpro .
The cellular life cycle of poliovirus
The life cycle of PV occurs within the confines of the cytoplasm of infected cells (Fig. 3). It is initiated by attachment of the poliovirion to the N-terminal V-type immunoglobulin-like domain of its cell surface receptor, the human PV receptor (hPVR) or CD155 [99, 122, 175]. Release of the virus RNA into the cell cytoplasm (uncoating) is thought to occur by destabilization of the virus capsid secondary to CD155-mediated release of the myristoylated capsid protein VP4 and of the putative N-terminal amphipathic helix of VP1 from deep within the virion [reviewed in ]. Subsequently, the myristoylated VP4 and VP1 amphiphatic helix are thought to insert into the cell membrane , thereby leading to the creation of pores in the cell membrane through which the virus RNA may enter the cytoplasm. Alternatively, since the virus can be found on endosomes [101, 102, 139], others believe the virus is taken up by receptor-mediated endocytosis. However, both classic endocytotic pathways (clathrin-coated pits or caveoli) as the means of uptake have been excluded [45, 84]. Additionally, if entry of the virus involves endosomes, acidification of this compartment is not necessary for release of the virus RNA into the cytoplasm . Thus the exact mechanism by which the virus releases its RNA genome into the cytoplasm of infected cells remains to be elucidated.
Nonetheless, once in the cytoplasm of infected cells, an unknown cellular phosphodiesterase is believed to cleave the 5'NTR-linked viral protein VPg. This process is followed by initiation of translation of the RNA genome by host cell ribosomes . Concurrently, shut off of cap-dependent host cell translation occurs by 2Apro-mediated cleavage of the eukaryotic translation initiation factor 4G (eIF4G), an element of the cap recognizing complex eIF4F [100, 181, 193]. Interestingly, a byproduct of eIF4G cleavage binds viral RNA and promotes IRES-dependent translation of the viral polyprotein . Moreover, inhibition of host cell transcription occurs via inactivation of transcription factor TFIIIC  and cleavage of the TATA box binding protein (TBP) by 3Cpro .
With the synthesis of virus proteins, replication of the RNA begins. Initially, for the first three hours following infection of a permissive host cell, the kinetics of RNA replication is exponential. This is followed by a linear phase for one and a half hours, which ultimately enters a period of rapid decay in the rate of synthesis . The process of RNA replication takes place in the cytoplasm on host cell endoplasmic reticulum-derived rosette-like membranous structures, the formation of which is induced by viral proteins 2C and 2BC [14, 38, 188]. Subsequently, a hydrophobic domain in 3AB anchors this protein in the membranes, and the affinity of 3AB for 3Dpol and 3CDpro recruits the replication complex to this new sub-cellular compartment. Within the confines of this micro-environment in the host cell cytoplasm, replication of the virus RNA genome follows a complex pathway involving the formation of intermediates – a replicative form, consisting of double stranded RNA, and a replicative intermediate, composed of a negative-strand partially hybridized to multiple nascent positive-strands [reviewed in ]. Briefly, viral RNA replication starts with uridylylated VPg (VPg-pU-pU)-primed synthesis of complementary negative-strand RNA molecules via the transcription of poly(A) by the RNA dependent RNA polymerase 3Dpol. The negative-strand RNA molecules then serve as templates for the synthesis of positive-strand RNA molecules . Newly synthesized positive-strand RNA molecules can serve as mRNA templates for continued translation of viral proteins or targeted as virus RNA molecules to be encapsidated in progeny poliovirions by covalent linkage of VPg to their 5' ends .
Encapsidation of VPg-linked positive-strand RNA molecules, a process which constitutes the final steps in the cellular life cycle of PV, appears to be linked to RNA synthesis  at the interface of membranous structures in the cytoplasm of infected cells . To start, 3CDpro cleaves the P1 precursor polypeptide, thereby giving rise to proteins VP0, VP1, and VP3, which assemble to form a protomer . Five protomers then aggregate thereby generating a pentamer , of which twelve ultimately assemble to constitute the procapsid . The VPg-linked positive-strand virus RNA may be encapsidated either by condensation of pentamers about the viral RNA [65, 154] or by incorporation of the virus RNA into procapsids . Cleavage of VPO into VP2 and VP4, possibly via an autocatalytic mechanism , finalizes virus assembly by stabilizing the capsid and thereby converting the provirion into a mature, infectious virus particle . The mature virus capsid is an icosahedron composed of sixty copies each of VP1-VP4, and exhibiting five-, three-, and two-fold axes of symmetry. The outer surface of mature virus capsid is formed by capsid proteins VP1-3, while VP4 is found internally .
The last step in completion of the cellular life cycle, which under experimental conditions in vitro lasts approximately seven to eight hours, is release of mature, infectious poliovirions through lysis of the infected cell. Upon release, on the order of 1% of poliovirions will in turn initiate effective infections of permissive host cells .
The poliovirus 5' Non-Translated Region (5'NTR)
Given the genetic austerity exhibited by RNA viruses, including the picornaviruses, it is surprising that they contain relatively long 5'NTRs (10% of the genome for polioviruses). These long segments of RNA, however, are packed with information displaying unique features. An important feature of the PV genomic RNA, a mRNA, that distinguishes it from most cellular mRNAs, is the absence of a 7-methyl guanosine (m7G) cap structure, which in cellular mRNAs interacts with the eIF4F cap-binding complex early in translation initiation of cellular proteins. In picornaviruses, the initiation of translation depends upon the internal ribosomal entry site (IRES), a novel cis-acting genetic element which functions as a docking site for host cell ribosomes [90, 150]. Evidence for IRES-mediated, cap-independent translation of the picornavirus RNA genome emerged from experiments utilizing dicistronic RNAs harboring the IRES of encephalomyocarditis virus (EMCV)  or PV . Jang and colleagues demonstrated that nucleotides 260–484 in the 5'NTR of EMCV were necessary for the efficient in vitro translation of artificial mono- and dicistronic mRNAs in nuclease-treated HeLa cell extracts and in rabbit reticulocyte lysates (RLLs) . Similarly, Pelletier and Sonenberg showed that under conditions which inhibited host cell translation (in PV-infected cells), translation of the second cistron, harboring the bacterial chloramphenicol acetyltransferase (CAT) gene, mediated by the PV 5'NTR was unaffected while translation of the first cistron containing the herpes simplex virus-1 (HSV-1) thymidine kinase (TK) gene did not occur . Since their discovery, IRES elements have been found in the genomes of other viruses [reviewed in ], including all picornaviruses (e.g., foot and mouth disease virus, FMDV ; hepatitis C virus, HCV ; and simian immunodeficiency virus, SIV ). IRES elements have also been discovered in cellular mRNAs of numerous organisms, including those encoding: human amyloid β A4 precursor protein ; fly transcription repressor hairless ; rat growth factor receptor ; and yeast transcriptional activator TFIID  [reviewed in ].
On the basis of sequence homology and comparisons of predicted structure models, the IRES elements of most picornaviruses have been classified as either type 1, exemplified by entero- and rhinoviruses, or type 2, typified by cardio- and apthoviruses [reviewed in ]. The two classes of IRES elements exhibit functional differences in their ability to initiate translation in cell-free translation systems such as RRLs and HeLa cell-free extracts. Type 2 IRES elements, exemplified by the EMCV IRES, initiate translation efficiently in RLLs. In contrast, type 1 IRES elements, exemplified by the PV IRES, show a deficiency in their ability to initiate translation in RLLs which is rescued by the addition of cytoplasmic extract from HeLa cells [30, 46]. The difference in the ability of the type 2 IRES to initiate translation under these conditions underscores differences in host factors encountered by this class of IRES in the two systems. This in turn is suggestive of variation in the efficiency of IRES-mediated translation depending on the infected host cell, and consequently on the ability of the virus to produce pathologic changes.
In addition to the IRES domain, the 5' and 3' boundaries of which have been defined at about nt 134 and nt 556, respectively, by deletion analysis in vitro [86, 103, 133], the PV 5'NTR harbors signals important for replication of the virus RNA genome. The 5'-terminal 88 nt of the 5'NTR form a characteristic clover leaf structure, which has been shown to be an indispensable cis-acting element in viral RNA replication [3, 144]. Additionally, the 5'NTR contains two spacer regions. One lies between the cloverleaf and the IRES (nt 89–123) and the other maps to the region between the 3' end of IRES and the initiation codon of the polyprotein (nt 640–742). The former is a sequence without a formally ascribed function. The latter has been demonstrated to be conserved in length (100–104 nt) albeit not in sequence. In line with this observation, emerging evidence indicates that the length of this spacer is important for optimal viral protein synthesis as when short open reading frames are introduced between the IRES and the initiation codon viral protein synthesis in vitro and, in some instances, neurovirulence are diminished . Furthermore, when this spacer region between the IRES and the initiation codon is deleted, PV exhibits an att phenotype . The function of this spacer, which is absent in the closely related rhinovirus 5'NTRs, remains a mystery. As emerging data from the Wimmer group  [Toyoda H, Franco D, Paul A, Wimmer E, submitted] [De Jesus N, Jiang P, Cello J, Wimmer E, unpublished] indicates, the short spacer between the cloverleaf and the IRES is loaded with genetic information essential for properties characteristic of PV.
Interaction of trans-acting factors with the poliovirus 5'NTR
IRES-mediated translation of picornavirus RNAs involves interactions with canonical, standard eukaryotic translation initiation factors (e.g., eIF2A) as well as non-canonical, cellular trans-acting factors that play different roles in cellular metabolism (discussed below). Experimental techniques employed to identify host cell factors that interact with the PV 5'NTR include: RNA electrophoretic mobility shift assay, UV-mediated crosslinking of proteins to RNA, and biochemical fractionation in junction with supplementation assay. Indeed, while their abundance in cells targeted by PV remains to be characterized, a number of cellular proteins have been found to interact with the PV 5'NTR. These include: eIF2A ; eIF4G ; autoantigen La ; poly(rC) binding proteins 1 and 2 (PCBP1 and PCBP2) [59, 144]; pyrimidine tract-binding protein (pPTB) [79, 80, 152]; p97/upstream of N-ras (UNR) ; p48/50, p38/39, and p35/36 [52, 62, 75, 130]; p60 ; and nucleo-cytoplasmic SR protein 20 (Srp20) .
As mentioned above, the only eukaryotic translation initiation factors that have been demonstrated to interact with the PV 5'NTR are eIF2A and eIF4G. Specifically, eIF2A complexes with nt 97–182 of the PV 5'NTR , and deletion of a 40 amino acid region of eIF4G (642–681) substantially diminishes PV translation initiation presumably by interference with the ribosome scanning process that propels PV IRES-driven translation .
Among the numerous cellular proteins hypothesized to be involved in translation of the viral RNA and which have been subjected to functional analyses are the following: PCBP1, PCBP2, La, pPTB, p97/UNR [reviewed in ], and Srp20 . PCBP1 and PCBP2 are cellular proteins each harboring three K homology (KH) RNA-binding domains. Initially termed p38, PCBP was found to interact with stem-loop IV of the PV IRES. Subsequently, PCBP was found to have affinity for stem-loop I of the 5'NTR (the cloverleaf) [59, 144]. Disruption of the interaction between PCBP and stem-loop IV in vitro by mutations in stem-loop IV, depletion of PCBP from HeLa cell-free extracts, and injection of anti-PCBP antibodies into Xenopus laevis oocytes resulted in reduced translation of the viral RNA [17–19, 59]. Analogously, evidence suggests that the interaction between PCBP and the cloverleaf (specifically stem-loop B) is also necessary for efficient translation of the virus RNA [60, 178]. Stem-loop D of the cloverleaf RNA binds the viral protein 3CD (and, very poorly, 3Cpro). The cloverleaf, PCBP, and 3CD for a ternary complex that is essential for initiation of plus-strand RNA synthesis [3, 4, 48, 168]. It has been hypothesized to be involved in a switch mechanism governing use of the viral RNA as either a template for translation or replication. Binding of 3CD to a complex formed by the cloverleaf RNA and PCBP inhibits translation in a cell-free extract and is hypothesized to promote replication, thereby providing a mechanism to ensure an adequate balance between these two processes. Incompatibility of the cloverleaf RNA with the viral 3CD, as in the context of chimeras, would be expected to result in decreased virus viability. Indeed, while it has been shown that a virus containing the 5'NTR of CB3 (nt 1–625) and remaining parts of the genome from PV1(M) was viable , a virus containing the 5'NTR of human rhinovirus 14 (HRV14) and the remainder parts of the genome from PV3, exhibited a lethal phenotype, because the PV 3CD was unable to interact effectively with the HRV14 stem-loop D . In the latter, the virus was rescued by insertion of two nucleotides into stem-loop D (CUAC60GG61) of the HRV14 cloverleaf .
The nuclear protein La is an autoantigen targeted by antibodies produced by patients with autoimmune disorders such as systemic lupus erythematous and Sjogren's syndrome. Normally, it functions in termination of RNA polymerase III transcription [68, 69]. First characterized as HeLa cell protein p52, La is found in HeLa cell-free extracts but not in RLLs. Supplementation of RLLs with La has been demonstrated to stimulate translation of PV RNA .
The nuclear protein polypyrimidine tract-binding protein (PTB), also known as hnRNP 1, which plays a role in alternative splicing of the cellular pre-mRNA [61, 66, 143], associates with three sites within the PV 5'NTR (nt 70–286, nt 443–539, and nt 630–730) as determined by UV-crosslinking . An attenuating mutation, C472U, reduced the affinity of the PV 5'NTR to pPTB in neuroblastoma cells (SH-SY5Y) without disrupting this interaction in HeLa cells . nPTB, a neuronal-cell specific homologue of PTB, was later described to bind less efficiently to the PV IRES in the presence of the C472U attenuating mutation .
The cytoplasmic RNA-binding protein UNR was originally identified as p97 in HeLa cells and lacking in RLLs. Studies in which endogenous expression of the unr gene was disrupted by homologous recombination, transient expression of UNR effectively reestablished efficient translation by human rhinovirus and PV IRESs .
Lastly, Srp20 is a member of the SR family of splicing regulators. Recently, it has been found to interact with PBCP2 , a cellular RNA-binding protein that (as discussed above) binds to sequences within the PV IRES and is necessary for translation of the viral RNA. Bedard and colleagues  have shown that PV translation is inhibited by depletion of Srp20 in HeLa cell extracts and diminished by down-regulation of Srp20 protein levels by RNA interference in vivo. Whether Srp20 interacts directly with IRES sequences was not determined.
PV tropism is limited to humans and non-human primates. In its natural host, PV transmits via the fecal-oral route. To date, the specific sites and cell types in which the virus initially replicates following entry into the host remain enigmatic. Nevertheless, the ability to isolate virus from the lymphatic tissues of the gastrointestinal tract, including the tonsils, Peyer's patches of the ileum, and mesenteric lymph nodes [24, 25, 106, 173, 174], as well as the feces [106, 174], prior to the onset of illness suggests susceptible cells in these tissues may be sites of primary replication. Following initial replication of the virus in susceptible cells of the pharynx and gastrointestinal tract, in the majority of infected individuals a minor, transient viremia, but no neurologic complications, will develop. As the infection progresses, the virus will spread further to other sites of the reticuloendothelial system. Consequently, the great majority of PV infections, nearly 95%, including almost all infections in which a minor viremia develops, are 'innaparent' or asymptomatic. In 4–8% of infected individuals that develop primary viremia, a secondary, major viremia often associated with a 'minor, non-specific illness' will ensue. Also known as abortive poliomyelitis, the clinical manifestations of this 'minor, non-specific illness' include many signs and symptoms generally associated with other viral illnesses: (a) an upper respiratory infection, characterized by sore throat and fever; (b) a gastrointestinal illness, presenting with nausea, vomiting, abdominal discomfort, and constipation or (infrequently) diarrhea; and/or (c) an illness mimicking influenza, marked by headache, myalgia, and generalized malaise [24, 106, 174]. In turn, a minute segment of infected individuals that experience major viremia will progress to develop signs and symptoms indicating PV invasion of the CNS, as characterized by non-paralytic aseptic meningitis or paralytic poliomyelitis. Non-paralytic aseptic meningitis occurs in 1–2% of PV infections and is associated with rigidity of the neck, back, and lower limbs as well as an augmented number of leukocytes (10–200 cell/mm3) and slightly above-normal protein levels (40–50 mg/dL) in the cerebrospinal fluid (CSF) . Paralytic poliomyelitis occurs in 0.1–1% of all PV infections, depending on the offending serotype . Based on the specific manifestation, paralytic poliomyelitis without apparent affect in sensation or cognition is classified as either: (i) spinal poliomyelitis, characterized by acute flaccid paralysis secondary to selective destruction of spinal motor neurons and subsequent dennervation of the associated skeletal musculature; (ii) bulbar poliomyelitis, presenting with paralysis of respiratory muscles following attack of neurons in the brain stem that control breathing; and (iii) bulbospinal poliomyelitis, exhibiting effects on both the brain stem and spinal cord [26, 35]. Among cases of paralytic poliomyelitis, it is estimated that fatalities result in 2–5% of children and 15–30% of adults, numbers which are drastically increased in cases featuring bulbar paralysis .
Isolation of PV from the CSF is diagnostic but seldom achieved . Additionally, the precise mechanism(s) of PV invasion of the CNS is not well understood. Three hypotheses for mechanisms utilized by the virus to gain entry into the CNS have been proposed: (1) the virus invades the CNS by retrograde axonal transport [71, 138, 139]; (2) the virus crosses the blood-brain barrier (BBB), presumably independent of the presence of the cellular receptor for PV, CD155 ; and (3) the virus is imported into the CNS by infected macrophages – the Trojan horse mechanism [51, 57]. In support of the theory of CNS invasion due to permeation of the BBB, Yang and colleagues found that PV accumulated in the CNS of CD155 transgenic (tg) mice at a constant rate that was markedly higher than the accumulation rate for albumin, which is not believed to cross the BBB . Earlier, Blinzinger et al., had interpreted their own finding of PV particles in endothelial cells forming part of the BBB to indicate that the virus breached the CNS through its vasculature . Following this line of thought, evidence for entry of PV into the CNS via infected macrophages is largely circumstantial, emerging from observations that PV replicates in macrophages expressing CD155 [51, 57] and that macrophages infected with Visna virus  and human immunodeficiency virus (HIV)  traverse the BBB.
However, experimental evidence from studies in non-human primates [22, 23] and CD155 tg mice [62, 138, 165] supports the hypothesis of CNS invasion mediated by retrograde axonal transport along peripheral nerves. The observations that paralysis of the injected limb can be prevented by transection of the nerve linking the site of injection to the spinal cord, and that skeletal muscle injury concurrent with PV infection predisposes to paralysis initially localizing to the afflicted limb (as observed in phenomena denoted provocation poliomyelitis and iatrogenic poliomyelitis) [71, 131], strongly suggest a neural pathway for PV entry into the CNS. Specially strong evidence supporting a neural pathway of CNS invasion emerged from a study published by Ohka et al., in which the authors reported recovery of intact 160S virion particles in the sciatic nerve of CD155 tg mice transected at various intervals following intramuscular inoculation with PV, an observation suggesting a role for fast retrograde axonal transport driving poliovirions along peripheral nerves to the spinal cord, where the cell bodies of motor neurons targeted by the virus reside . This observation supported early reports of the presence of PV in axons during experimental poliomyelitis [20, 55].
Prior to the 20th century, virtually all children were infected with PV while still protected by maternal antibodies. In the 1900s, following the industrial revolution of the late 18th and early 19th centuries, improved sanitation practices led to an increase in the age at which children first encountered the virus, such that at exposure children were no longer protected by maternal antibodies . Consequently, epidemics of poliomyelitis surfaced .
In the mid-20th century, in efforts to combat the ever growing epidemics of poliomyelitis ravaging the United States, research focused on the design of vaccines as a means of halting transmission. The first vaccine to be produced was the inactivated (or "killed") PV vaccine (IPV) by Jonas Salk on April 12, 1955. In producing IPV, all three PV serotypes were (and continue to be) grown in vitro in African green monkey kidney (Vero) cells and inactivated by formaldehyde. IPV was shown to effectively immunize and protect against poliomyelitis .
A second vaccine which was demonstrated to be both safe and effective was the oral (or "live") PV vaccine (OPV) developed by Albert Sabin in 1963. In truth, testing of the vaccine began in 1957 under the auspices of the WHO, but it was not until 1961 that the United States Public Health Service endorsed OPV, then only produced in the monovalent form. Trivalent OPV (or simply "OPV" as will be referred to henceforth) became available in 1963 and, owing to its unique ability to produce unmatched gastrointestinal immunity, thereby preventing infection with wt virus, soon became the preferred PV vaccine in the United States and many other countries. OPV is composed of att strains of all three PV serotypes, grown in vitro in Vero cells, in a 10:1:3 ratio of types 1:2:3, respectively .
The att strains comprising OPV were generated by serial passage of wt strains at high multiplicity of infection (MOI) in a series of hosts ranging from cells derived from a variety of sources including monkey testis, kidney, and skin to live monkeys , accompanied by selection of variants following experimental bottlenecking events such as single-plaque cloning and limiting dilution. The desirable characteristics of selected variants were: (i) ability to replicate effectively in the gastrointestinal tract; (ii) defectiveness in the ability to invade or replicate within the CNS; and (iii) genetic stability so as to withstand the pressures of replication within the human host without reversion to a neurovirulent phenotype. These qualities were those present in variants which came to be the Sabin vaccine strains.
Years later, comparison of the nucleotide sequences of the att Sabin strains and their neurovirulent parental strains revealed a series of mutations, some of which were subsequently found to be responsible for the att phenotypes of the Sabin strains. PV type 1 (Sabin) [PV1(S)] harbored 7 nucleotide substitutions localizing to the 5'NTR, 21 amino acid alterations within the polyprotein, and 2 nucleotide substitutions within the 3'NTR . PV type 3 (Sabin) [PV3(S)] contained 2 nucleotide substitutions in the 5'NTR, 4 amino acid changes within the polyprotein, and a single nucleotide deletion within the 3'NTR . Lastly, PV type 2 (Sabin) [PV2(S)] exhibited a single nucleotide substitution within the 5'NTR as well as one amino acid change within the polyprotein [115, 147, 164]. Subsequent sequence analysis of revertants with regained neurovirulence indicated that mutations mapping to the 5'NTR specified the att phenotype of the three Sabin strains. Attenuating point mutations within the 5'NTR of the Sabin vaccine strains (nt 480, 481, and 472 in serotypes 1, 2, and 3, respectively) localize to the IRES (domain V) (Fig. 2) and their presence has been linked to deficiencies in viral replication in the CNS and in neuroblastoma cells [106, 107] as well as reductions in translation of the viral mRNAs as compared to wt sequences [184–186].
Moreover, all Sabin strains exhibit ts phenotypes, which map to the 5'NTR mutation (for all 3 types) [94, 114, 118], to the capsid precursor (for all 3 types) [27, 107, 114, 142], as well as to the 3Dpol coding sequence (for type 1) [27, 39, 118, 146, 187, 191]. The ts phenotype is thought to be the most important trait of the vaccines to confer attenuation.
Poliovirus eradication and evolution
Thanks in part to the effectiveness and ease of administration of OPV as well as to the efforts of public health officials in the United States, the transmission of wt PV was halted by 1979, less than 20 years since introduction of OPV . Indeed, OPV was the weapon of choice in the fight against vaccine-preventable poliomyelitis of the Pan American Health Organization (PAHO) under the leadership of Ciro de Quadros, M.D., M.P.H. By transforming vaccines and immunization against PV into a top priority of governments, vaccine producers, and public health experts, de Quadros was able to institute teams to further his cause at the Ministry of Health in nearly every country in the Americas. In 1985, PAHO announced its goal to eradicate wt PV in the Western Hemisphere by 1990. The target date was met. The last case of wt PV-induced paralytic poliomyelitis was documented in Peru in 1991. Three years later, in 1994, the International Commission for the Certification of Poliomyelitis Eradication announced that transmission of wt PV in the Americas had been discontinued.
Decades prior, while the United States was actively attempting to halt transmission of wt PV by vaccination with OPV, the WHO was trying to finalize the eradication of another highly infectious agent – smallpox. By 1967, programs to eradicate smallpox had proven successful in many regions of the globe, including Western Europe, North America, and Japan. In 1967, in line with recommendations made by a WHO Expert Committee on Smallpox 3 years earlier to vaccinate the entire world's population as a means of furthering efforts to eradicate the variola virus, the WHO introduced the Intensified Smallpox Eradication Program. The mass vaccination strategy employed to eradicate an agent, estimated to have caused 10–15 million cases of smallpox as early as 1967, eventually paid off. The last recorded case of smallpox occurred in Somalia in 1979. In 1980, the 33rd World Health Assembly announced the first successful eradication of a major human disease – smallpox .
In 1988, the WHO envisioned the eradication of yet another agent causing major human disease (i.e., PV) by launching a global campaign to eradicate wt PV by the year 2000. Of the two available polio vaccines, the Sabin OPV was chosen to further the planned eradication efforts. Two characteristics of OPV propelled it for selection by the WHO as the instrument of choice in the Global Polio Eradication Initiative: (1) its effectiveness in producing gastrointestinal immunity; and (2) the fact that no special instrumentation (i.e., needles) was required for its administration.
Undoubtedly, the use of OPV in mass vaccinations has resulted in dramatic reductions in the number of cases of poliomyelitis due to infections with wt PV from an estimated 350,000 in over 125 endemic countries in 1988 to just 1,874 in 2006. But perhaps counter-intuitively, the use of OPV now poses enormous challenges to this endeavor. A major flaw of OPV is that it is genetically unstable, a characteristic that makes it particularly susceptible to evolve into circulating vaccine-derived polioviruses (cVDPV), exhibiting wt PV-like properties, including neurovirulence. The Centers for Disease Control (CDC) estimates that in the United States, while OPV was being used, one case of vaccine-associated paralytic poliomyelitis (VAPP) emerged for every 2 to 3 million doses of OPV administered, which accounted for 8 to 10 cases of VAPP in this country per year. In fact, in the United States, the vast majority (95%) of cases of paralytic poliomyelitis documented between 1980 and 1999 resulted from cVDPV-induced VAPP . In 1996, in order to reduce the incidence of VAPP among vaccine recipients, the United States Advisory Committee on Immunization Practices (ACIP) recommended the increased use of IPV by replacing the first two vaccine doses of the immunization schedule with IPV as opposed to OPV. While the risk of VAPP was reduced among vaccine recipients, the equivalent reduction in risk did not translate for non-immune contacts of vaccine recipients. With this in mind, in 1999, the ACIP recommended that starting in the year 2000 use of OPV be discontinued and that IPV be used exclusively in the United States.
Specifically, genetic changes that would endow OPV with wt PV phenotypes, transforming att vaccine strains into cVDPV with the ability to cause VAPP among vaccine recipients and/or their close contacts, could take the form of reversions of known attenuating mutations and recombination, whether inter- or hetero-typic . Certainly, as discussed above, comparisons of the nucleotide sequences of wt PV strains with revertants of the att Sabin OPV strains were key in identifying the determinants of attenuation. But perhaps just as important in the genesis of cVDPV is the possibility of recombination. Admittedly, recombination among human enteroviruses has been hypothesized to be a common occurrence in nature.
In fact, recombination between RNA viruses, a process originally considered highly unlikely, was shown first with polioviruses . Later, Agol and his colleagues provided evidence that recombination can also occur between different serotypes of PV [170, 189]. Significantly, the 3 Sabin vaccine strains have been shown to undergo rampant intertypic recombination in vaccine recipients [17, 33, 37, 42, 63, 64, 93, 105, 111, 117, 148]. Finally, recombination between polioviruses was shown to occur in a cell-free HeLa cell extract .
It has been speculated that recombination may serve as a mechanism to augment the potential of viruses to adapt and evolve. The evolution of OPV into highly diverged cVDPV, via recombination between PV and other closely related enteroviruses, in inadequately immunized populations is a very real concern [8, 95, 112, 171, 177]. For the most part, recombinants between the Sabin vaccine strains and other human enteroviruses exhibit crossover points within the non-structural region of the genome, such that the PV 5'NTR and structural P1 regions are retained. Consequently, of particular concern are recombinations that results in viruses which have lost the att phenotype of the parental vaccine strains and gained phenotypic characteristics that would make them indistinguishable from wt PV, thereby acquiring the ability to cause poliomyelitis.
Recently, in the current climate of attempting to eradicate PV, the possibility of genetic exchanges between the Sabin OPV strains and closely related viruses has come into the limelight. Indeed the propensity of OPV strains to recombine in recipients of the vaccine has been documented in numerous outbreaks of VAPP secondary to the unchecked circulation of cVDPV in poorly immunized communities [8, 95, 112, 171, 177]. Moreover, the possibility exists that, as previously hypothesized [[72, 166]; Jiang P, Faase JAJ, Toyoda H, Paul A, Gorbalenya AE, Wimmer E, unpublished], in a world free of PV and anti-PV antibodies as envisioned by the WHO, viruses closely related to the polioviruses such as the C-cluster coxsackie A viruses (e.g., CAV20) may fill the niche left vacant by the polioviruses. Could C-cluster coxsackie A viruses evolve to utilize CD155 as a cellular receptor, thereby completely altering the disease syndromes with which they would be associated? If only the structural region of C-cluster coxsackie A viruses evolved to recognize the PV cellular receptor while maintaining the rest of the genome unchanged, would such a virus replicate in the same cell types and to the same levels as wt PV or would the C-cluster coxsackie A virus-specific genome segments impose cell-internal restrictions on viral replication? If simply the presence of C-cluster coxsackie A virus-derived genome segments results in restricted viral replication, which particular genome segments are accountable for such phenotypic differences? Moreover, would attenuating mutations in the PV genome translate into attenuating mutations in viruses that result from the recombination of PV with a closely-related yet non-neurovirulent C-cluster coxsackievirus? These are precisely some of the questions currently under investigation in the Wimmer laboratory.
The biochemical synthesis of poliovirus
Despite the undeniable success of the Global Polio Eradication Initiate in the nineteen years since its introduction, characteristics inherent to OPV, logistical obstacles in ensuring 100% vaccination, as well as the realization that de novo synthesis of viruses is a possibility, have brought into question the feasibility of the control of poliomyelitis by means of the total eradication of wt PV. Current recommendations by the WHO include the cessation of OPV vaccination 3 years following the last reported case of poliomyelitis due to infection with wt PV. In time, cessation of vaccination would inevitably result in lost of herd immunity, which in turn generates an ever increasing pool of susceptible individuals to the same agent against which immunization was originally targeted and to one similar that is evolving to replace it. In such discussions, an important consideration remains: can a virus that can be synthesized ever truly be considered eradicated?
Evidence for the ability to chemically synthesize a virus (i.e., PV) first emerged from a study published by Eckard Wimmer's group in 2002 , which described the de novo biochemical synthesis of infectious PV by utilizing as instruction only the published nucleotide sequence of the genome. The initial step in the scheme to synthesize PV1(M) consisted of generating a complete complementary DNA (cDNA) copy of the virus genome bearing a phage T7 RNA polymerase promoter at the 5' end. This endeavor was accomplished by a laborious process in which: (i) overlapping segments of 400 to 600 base pairs (bp) were synthesized by piecing together purified oligonucleotides (approximately 69 nt in length) of plus and minus polarity with overlapping complementary sequences at the ends, followed by ligation of the segments into a plasmid vector; (ii) cloned segments were sequenced to pinpoint segments with correct sequences and those containing only a small number of mutations that could be corrected either by sub-cloning or by site-directed mutagenesis; (iii) cloned segments were sequentially joined to generate three large DNA fragments 3026, 1895, and 2682 bp in length; and (iv) combining the three DNA fragments to produce the full-length sPV1(M) cDNA. To ensure the wt sequence of PV1(M) could be distinguished from that of sPV1(M), in generating the sPV1(M) cDNA, 27 nucleotide substitutions were engineered as markers in the sPV1(M) cDNA. Next, the T7 promoter-containing sPV1(M) cDNA was transcribed in vitro with T7 RNA polymerase to yield highly infectious virus RNA, which was equivalent in length to virion RNA. The presence of all genetic markers engineered into the sPV1(M) cDNA was established by restriction enzyme digest analysis of products of reverse transcriptase-polymerase chain reaction (RT-PCR) in which virus RNA isolated from sPV1(M)-infected HeLa cells was used as template. De novo synthesis of PV from transcript RNA derived from sPV1(M) cDNA in a cell-free extract of uninfected HeLa cells, as previously described for wt PV1(M) , was confirmed with the yield of end products of proteolytic processing of the virus polyprotein as well as the production of infectious virus. Comparison of virus-specific proteins generated by incubation of sPV1(M) cDNA-derived transcript RNA with an S3 cytoplasmic extract of HeLa cells with the corresponding proteins derived from wt PV1(M) cDNA-derived transcript RNA validated the products of in vitro translation as PV-specific proteins. The production of infectious virus by incubation of sPV1(M) cDNA-derived transcript RNA with an S3 cytoplasmic extract of HeLa cells was ascertained by analysis of plaque formation on HeLa cell monolayers on which aliquots of the transcript RNA-containing cytoplasmic extract had been incubated. The ability of CD155-specific monoclonal antibody (mAb) D171 to block infection of HeLa cells by sPV1(M) was verified by the observation that incubation of HeLa cells with mAb D171 prior to addition of sPV1(M) entirely voided the virus' plaque forming ability. Lastly, to characterize the disease-inducing potential of sPV1(M), the neurovirulence phenotype of this virus was examined in CD155 tg mice. Following intracerebral (i.c.) inoculation with sPV1(M), adult CD155 tg mice often developed neurological signs characteristic of poliomyelitis, including flaccid paralysis and even death. The inoculum required to produce paralysis and/or death in half the mice inoculated (PLD50) was markedly increased over that required to produce the same signs of disease with wt PV1(M). The degree of attenuation of sPV1(M) compared to the parental PV1(M) was rather unanticipated. All nucleotide substitutions engineered into the sPV1(M) ORF, with the exception of XmaI and StuI restriction sites generated in the 5'NTR and 2B regions, produced silent mutations. But the changes in the 2B coding region had previously been demonstrated not to influence virus replication in vitro [126, 198]. Hence, when the findings were first published, the authors attributed the att phenotype of sPV1(M) in CD155 tg mice to the silent mutations and then unidentified mechanisms .
In a subsequent study , the authors set forth to determine what aspect of the sPV1(M) genome was responsible for the phenotypic changes observed in comparisons with wt PV1(M). In collaboration with others the author of this review showed that a single nucleotide substitution (A103G) mapping to the spacer region between the cloverleaf and the IRES within the 5'NTR determines the att phenotype of sPV1(M).
In our quest to determine what alterations in the genotype of sPV1(M) resulted in the observed neurophenotypic changes, two strategies were employed: (1) exchange of genomic segments between sPV1(M) and wt PV1(M) followed by analysis of neurovirulence in vivo; and (2) sequence analysis of viruses recovered from the spinal cords ofsPV1(M)-inoculated CD155 tg mice that had succumbed to infection in concert with comparison of these sequences with that of sPV1(M) virus that constituted the inoculum. In all instances, we identified a change at one locus in the sequences of recovered viruses. Analyses of the in vitro phenotypes in tissue culture as well as the in vivo phenotypes in CD155 tg mice of a series of PV variants revealed the critical nucleotide in determining two important characteristics of sPV1(M): (i) an att neurophenotype in adult CD155 tg mice; and (ii) a ts phenotype in neuronal cells of human origin.
Considering that the nucleotide we identified as an important determinant of the replicative phenotypes of PV in vivo as well as in vitro (A103) is highly conserved among polioviruses and human C-cluster coxsackie A viruses and that, in evolution, conservation often equates with functional importance, we have continued our analysis of this locus to studying the effect of mutating this nucleotide (A103G) in CAV20 – one of three human C-cluster enteroviruses exhibiting the highest degree of sequence homology to the polioviruses [De Jesus N, Jiang P, Cello J, Wimmer E, unpublished].
Whether accidentally or not, over centuries poliovirus has evolved to specifically target alpha motor neurons in the spinal cord of its human host, thereby causing acute flaccid paralysis, the characteristic sign of paralytic poliomyelitis. Fortunately, since its inception in 1988, the WHO's Global Polio Eradication Initiative, along with great economic and intellectual efforts, has served to greatly reduce the number of documented cases of poliomyelitis worldwide. Nonetheless, the ultimate goal of halting poliovirus transmission as a means of eradicating poliomyelitis has proven rather elusive. In light of this realization and considering the possibility that a virus that can be synthesized may never truly be considered eradicated, it is imperative that new strategies to combat poliovirus be considered, whether these be in the form of the development of new vaccines and/or anti-viral drugs. In this endeavor it is important that aspects of the pathogenesis of this virus, such as interactions with host factors that play roles in replication and/or translation of the viral genome be identified, as well as sites of primary replication and the mechanism(s) of CNS invasion be more clearly elucidated. For it is only by understanding the intricacies of the life cycle of this pathogen within the human host that we will be able to more effectively develop new treatment modalities.
Agol VI: The 5'-untranslated region of picornaviral genomes. Adv Virus Res. 1991, 40: 103-180.
Agol VI: Vaccine-derived polioviruses. Biologicals. 2006, 34: 103-108. 10.1016/j.biologicals.2006.02.007.
Andino R, Rieckhof GE, Baltimore D: A functional ribonucleoprotein complex forms around the 5' end of poliovirus RNA. Cell. 1990, 63: 369-380. 10.1016/0092-8674(90)90170-J.
Andino R, Rieckhof GE, Achacoso PL, Baltimore D: Poliovirus RNA synthesis utilizes an RNP complex formed around the 5'-end of viral RNA. EMBO J. 1993, 12: 3587-3598.
Andino R, Boddeker N, Silvera D, Gamarnik AV: Intracellular determinants of picornavirus replication. Trends Microbiol. 7: 76-82. 10.1016/S0966-842X(98)01446-2.
Ansardi DC, Porter DC, Anderson MJ, Morrow CD: Poliovirus assembly and encapsidation of genomic RNA. Adv Virus Res. 1996, 46: 1-68. 10.1016/S0168-1702(96)01371-8.
Arita M, Shimizu H, Miyamura T: Characterization of in vitro and in vivo phenotypes of poliovirus type 1 mutants with reduced viral protein synthesis activity. J Gen Virol. 2004, 85: 1933-1944. 10.1099/vir.0.19768-0.
Arita M, Zhu SL, Yoshida H, Yoneyama T, Miyamura T, Shimizu H: A Sabin 3-derived poliovirus recombinant contained a sequence homologous with indigenous human enterovirus species C in the viral polymerase coding region. J Virol. 2005, 79: 12650-12657. 10.1128/JVI.79.20.12650-12657.2005.
Baird SD, Turcotte M, Korneluk RG, Holcik M: Searching for IRES. RNA. 2006, 12: 1755-1785. 10.1261/rna.157806.
Beales LP, Holzenburg A, Rowlands DJ: Viral internal ribosome entry site structures segregate into two distinct morphologies. J Virol. 2003, 77: 6574-6579. 10.1128/JVI.77.11.6574-6579.2003.
Bedard KM, Daijogo S, Semler BL: A nucleo-cytoplasmic SR protein functions in viral IRES-mediated translation initiation. EMBO J. 2007, 26: 459-467. 10.1038/sj.emboj.7601494.
Bergelson JM, Chan M, Solomon KR, St John NF, Lin H, Finberg RW: Decay-accelerating factor (CD55), a glycosylphosphatidylinositol-anchored complement regulatory protein, is a receptor for several echoviruses. Proc Natl Acad Sci USA. 1994, 91: 6245-6248. 10.1073/pnas.91.13.6245.
Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW: Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science. 1997, 275: 1320-1323. 10.1126/science.275.5304.1320.
Bienz K, Egger D, Troxler M, Pasamontes L: Structural organization of poliovirus RNA replication is mediated by viral proteins of the P2 genomic region. J Virol. 1990, 64: 1156-1163.
Blinzinger K, Simon J, Magrath D, Boulger L: Poliovirus crystals within the endoplasmic reticulum of endothelial and mononuclear cells in the monkey spinal cord. Science. 1969, 163: 1336-1337. 10.1126/science.163.3873.1336.
Blomqvist S, Bruu AL, Stenvik M, Hovi T: Characterization of a recombinant type 3/type 2 poliovirus isolated from a healthy vaccinee and containing a chimeric capsid protein VP1. J Gen Virol. 2003, 84: 573-580. 10.1099/vir.0.18708-0.
Blyn LB, Chen R, Semler BL, Ehrenfeld E: Host cell proteins binding to domain IV of the 5' noncoding region of poliovirus RNA. J Virol. 1995, 69: 4381-4389.
Blyn LB, Swiderek KM, Richards O, Stahl DC, Semler BL, Ehrenfeld E: Poly(rC) binding protein 2 binds to stem-loop IV of the poliovirus RNA 5' noncoding region: identification by automated liquid chromatography tandem mass spectrometry. Proc Natl Acad Sci USA. 1996, 93: 11115-11120. 10.1073/pnas.93.20.11115.
Blyn LB, Towner JS, Semler BL, Ehrenfeld E: Requirement of poly(rC) binding protein 2 for translation of poliovirus RNA. J Virol. 1997, 71: 6243-6246.
Bodian D, Howe HA: An experimental study of the role of neurons in the dissemination of poliomyelitis virus in the nervous system. Brain. 1940, 63: 135-166. 10.1093/brain/63.2.135.
Bodian D, Morgan IM, Howe HA: Differentiation of types of poliomyelitis viruses. Am J Hyg. 1949, 49: 234-245.
Bodian D: Emerging concept of poliomyelitis infection. Science. 1955, 122: 105-108. 10.1126/science.122.3159.105.
Bodian D: Viremia, invasiveness and the influence of injections. Ann N Y Acad Sci. 1955, 61: 877-882. 10.1111/j.1749-6632.1955.tb42545.x.
Bodian D: Poliovirus in chimpanzee tissues after virus feeding. Am J Hyg. 1956, 64: 181-197.
Bodian D, Horstmann DM: Polioviruses. Viral and Rickettsial Infections of Man. Edited by: Horsfall F, Tamm I. 1965, Philadelphia, PA: Lippincott, 430-473. 4
Bodian D: Poliomyelitis. Pathology of the Nervous System. Edited by: Minckler J. 1972, New York, NY: McGraw-Hill, 3: 2323-2344.
Bouchard MJ, Lam DH, Racaniello VR: Determinants of attenuation and temperature sensitivity in the type 1 poliovirus Sabin vaccine. J Virol. 1995, 69: 4972-4978.
Boussadia O, Niepmann M, Creancier L, Prats AC, Dautry F, Jacquemin-Sablon H: Unr is required in vivo for efficient initiation of translation from the internal ribosome entry sites of both rhinovirus and poliovirus. J Virol. 2003, 77: 3353-3359. 10.1128/JVI.77.6.3353-3359.2003.
Brown BA, Ehrenfeld E: Translation of poliovirus RNA in vitro: changes in cleavage pattern and initiation sites by ribosomal salt wash. Virology. 1979, 97: 396-405. 10.1016/0042-6822(79)90350-7.
Brown B, Oberste MS, Maher K, Pallansch MA: Complete genomic sequencing shows that polioviruses and members of human enterovirus species C are closely related in the noncapsid coding region. J Virol. 2003, 77: 8973-8984. 10.1128/JVI.77.16.8973-8984.2003.
Brown DM, Kauder SE, Cornell CT, Jang GM, Racaniello VR, Semler BL: Cell-dependent role for the poliovirus 3' noncoding region in positive-strand RNA synthesis. J Virol. 2004, 78: 1344-1351. 10.1128/JVI.78.3.1344-1351.2004.
Brown DM, Cornell CT, Tran GP, Nguyen JH, Semler BL: An authentic 3' noncoding region is necessary for efficient poliovirus replication. J Virol. 2005, 79: 11962-11973. 10.1128/JVI.79.18.11962-11973.2005.
Cammack N, Phillips A, Dunn G, Patel V, Minor PD: Intertypic genomic rearrangements of poliovirus strains in vaccinees. Virology. 1988, 167: 507-514.
Cello J, Paul AV, Wimmer E: Chemical synthesis of poliovirus cDNA: generation of infectious virus in the absence of natural template. Science. 2002, 297: 1016-1018. 10.1126/science.1072266.
Centers for Disease Control and Prevention: Epidemiology and Prevention of Vaccine-Preventable Diseases. Edited by: Atkinson W, Hamborsky J, McIntyre L, Wolfe S. 2006, Washington, D.C.: Public Health Foundation, 9
Chen CY, Sarnow P: Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science. 1995, 268: 415-417. 10.1126/science.7536344.
Cherkasova EA, Yakovenko ML, Rezapkin GV, Korotkova EA, Ivanova OE, Eremeeva TP, Krasnoproshina LI, Romanenkova NI, Rozaeva NR, Sirota L, Agol VI, Chumakov KM: Spread of vaccine-derived poliovirus from a paralytic case in an immunodeficient child: an insight into the natural evolution of oral polio vaccine. J Virol. 79: 1062-1070. 10.1128/JVI.79.2.1062-1070.2005.
Cho MW, Teterina N, Egger D, Bienz K, Ehrenfeld E: Membrane rearrangement and vesicle induction by recombinant poliovirus 2C and 2BC in human cells. Virology. 1994, 202: 129-145. 10.1006/viro.1994.1329.
Christodoulou C, Colbere-Garapin F, Macadam A, Taffs LF, Marsden S, Minor P, Horaud F: Mapping of mutations associated with neurovirulence in monkeys infected with Sabin 1 poliovirus revertants selected at high temperature. J Virol. 1990, 64: 4922-4929.
Clark ME, Hammerle T, Wimmer E, Dasgupta A: Poliovirus proteinase 3C converts an active form of transcription factor IIIC to an inactive form: a mechanism for inhibition of host cell polymerase III transcription by poliovirus. EMBO J. 1991, 10: 2941-2947.
Committee on Enteroviruses: The Enteroviruses; Committee on the Enteroviruses, National Foundation for Infantile Paralysis. Am J Public Health. 1957, 47 (12): 1556-1566.
Cuervo NS, Guillot S, Romanenkova N, Combiescu M, Aubert-Combiescu A, Seghier M, Caro V, Crainic R, Delpeyroux F: Genomic features of intertypic recombinant sabin poliovirus strains excreted by primary vaccinees. J Virol. 2001, 75: 5740-5751. 10.1128/JVI.75.13.5740-5751.2001.
De Jesus N, Franco D, Paul A, Wimmer E, Cello J: Mutation of a single conserved nucleotide between the cloverleaf and internal ribosome entry site attenuates poliovirus neurovirulence. J Virol. 2005, 79: 14235-14243. 10.1128/JVI.79.22.14235-14243.2005.
Del Angel RM, Papavassiliou AG, Fernandez-Tomas C, Silverstein SJ, Racaniello VR: Cell proteins bind to multiple sites within the 5' untranslated region of poliovirus RNA. Proc Natl Acad Sci USA. 1989, 86: 8299-8303. 10.1073/pnas.86.21.8299.
DeTulleo L, Kirchhausen T: The clathrin endocytic pathway in viral infection. EMBO J. 1998, 17: 4585-4593. 10.1093/emboj/17.16.4585.
Dorner AJ, Semler BL, Jackson RJ, Hanecak R, Duprey E, Wimmer E: In vitro translation of poliovirus RNA: utilization of internal initiation sites in reticulocyte lysate. J Virol. 1984, 50: 507-514.
Dorsch-Hasler K, Yogo Y, Wimmer E: Replication of picornaviruses. I. Evidence from in vitro RNA synthesis that poly(A) of the poliovirus genome is genetically coded. J Virol. 1975, 16: 1512-1517.
Du Z, Yu J, Ulyanov NB, Andino R, James TL: Solution structure of a consensus stem loop D RNA domain that plays important roles in regulating translation and replication in enteroviruses and rhinoviruses. Biochemistry. 2004, 43: 11959-11972. 10.1021/bi048973p.
Duggal R, Cuconati A, Gromeier M, Wimmer E: Genetic recombination of poliovirus in a cell-free system. Proc Natl Acad Sci USA. 1997, 94: 13786-13791. 10.1073/pnas.94.25.13786.
Duque H, Palmenberg AC: Phenotypic characterization of three phylogenetically conserved stem-loop motifs in the mengovirus 3' untranslated region. J Virol. 2001, 75: 3111-3120. 10.1128/JVI.75.7.3111-3120.2001.
Eberle KE, Nguyen VT, Freistadt MS: Low levels of poliovirus replication in primary human monocytes: possible interactions with lymphocytes. Arch Virol. 1995, 140: 2135-2150. 10.1007/BF01323236.
Ehrenfeld E, Gebhard JG: Interaction of cellular proteins with the poliovirus 5' noncoding region. Arch Virol. 1994, 269-277. Suppl 9
Ehrenfeld E, Semler BL: Anatomy of the poliovirus internal ribosome entry site. Curr Top Microbiol Immunol. 1995, 203: 65-83.
Eilbott DJ, Peress N, Burger H, LaNeve D, Orenstein J, Gendelman HE, Seidman R, Weiser B: Human immunodeficiency virus type 1 in spinal cords of acquired immunodeficiency syndrome patients with myelopathy: expression and replication in macrophages. Proc Natl Acad Sci USA. 1989, 86: 3337-3341. 10.1073/pnas.86.9.3337.
Fairbrother RW, Hurst EW: The pathogenesis of and propagation of the virus in experimental poliomyelitis. J Pathol Bacteriol. 1930, 33: 17-45. 10.1002/path.1700330103.
Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID: Chapter 1: The clinical features of smallpox. Smallpox and its eradication. 1988, Geneva, Switzerland: World Health Organization, 1-68.
Freistadt MS, Fleit HB, Wimmer E: Poliovirus receptor on human blood cells: a possible extraneural site of poliovirus replication. Virology. 1993, 195: 798-803. 10.1006/viro.1993.1433.
Fricks CE, Hogle JM: Cell-induced conformational change in poliovirus: externalization of the amino terminus of VP1 is responsible for liposome binding. J Virol. 1990, 64: 1934-1945.
Gamarnik AV, Andino R: Two functional complexes formed by KH domain containing proteins with the 5' noncoding region of poliovirus RNA. RNA. 1997, 3: 882-892.
Gamarnik AV, Andino R: Switch from translation to RNA replication in a positive-stranded RNA virus. Genes Dev. 1998, 12: 2293-2304.
Garcia-Blanco MA, Anderson GJ, Beggs J, Sharp PA: A mammalian protein of 220 kDa binds pre-mRNAs in the spliceosome: a potential homologue of the yeast PRP8 protein. Proc Natl Acad Sci USA. 1990, 87: 3082-3086. 10.1073/pnas.87.8.3082.
Gebhard JR, Ehrenfeld E: Specific interactions of HeLa cell proteins with proposed translation domains of the poliovirus 5' noncoding region. J Virol. 1992, 66: 3101-3109.
Georgescu MM, Delpeyroux F, Tardy-Panit M, Balanant J, Combiescu M, Combiescu AA, Guillot S, Crainic R: High diversity of poliovirus strains isolated from the central nervous system from patients with vaccine associated paralytic poliomyelitis. J Virol. 1994, 68: 8089-8101.
Georgopoulou A, Markoulatos P: Sabin type 2 polioviruses with intertypic vaccine/vaccine recombinant genomes. Eur J Clin Microbiol Infect Dis. 2001, 20: 792-799. 10.1007/s100960100610.
Ghendon Y, Yakobson E, Mikhejeva A: Study of some stages of poliovirus morphogenesis in MiO cells. J Virol. 1972, 10: 261-266.
Gil A, Sharp PA, Jamison SF, Garcia-Blanco MA: Characterization of cDNAs encoding the polypyrimidine tract-binding protein. Genes Dev. 1991, 5: 1224-1236. 10.1101/gad.5.7.1224.
Giraud S, Greco A, Brink M, Diaz JJ, Delafontaine P: Translation initiation of the insulin-like growth factor I receptor mRNA is mediated by an internal ribosome entry site. J Biol Chem. 2001, 276: 5668-5675. 10.1074/jbc.M005928200.
Gottlieb E, Steitz JA: The RNA binding protein La influences both the accuracy and the efficiency of RNA polymerase III transcription in vitro. EMBO J. 1989, 8: 841-850.
Gottlieb E, Steitz JA: Function of the mammalian La protein: evidence for its action in transcription termination by RNA polymerase III. EMBO J. 1989, 8: 851-861.
Gromeier M, Wetz K: Kinetics of poliovirus uncoating in HeLa cells in a nonacidic environment. J Virol. 1990, 64: 3590-3597.
Gromeier M, Wimmer E: Mechanism of injury-provoked poliomyelitis. J Virol. 1998, 72: 5056-5060.
Gromeier M, Bossert B, Arita M, Nomoto A, Wimmer E: Dual stem loops within the poliovirus internal ribosomal entry site control neurovirulence. J Virol. 1999, 73: 958-964.
Guest S, Pilipenko E, Sharma K, Chumakov K, Roos RP: Molecular mechanisms of attenuation of the Sabin strain of poliovirus type 3. J Virol. 2004, 78: 11097-11107. 10.1128/JVI.78.20.11097-11107.2004.
Gutierrez AL, Denova-Ocampo M, Racaniello VR, del Angel RM: Attenuating mutations in the poliovirus 5' untranslated region alter its interaction with polypyrimidine tract-binding protein. J Virol. 1997, 71: 3826-3833.
Haller AA, Semler BL: Stem-loop structure synergy in binding cellular proteins to the 5' noncoding region of poliovirus RNA. Virology. 1995, 206: 923-934. 10.1006/viro.1995.1015.
Hanecak R, Semler BL, Anderson CW, Wimmer E: Proteolytic processing of poliovirus polypeptides: antibodies to polypeptide P3-7c inhibit cleavage at glutamine-glycine pairs. Proc Natl Acad Sci USA. 1982, 79: 3973-3977. 10.1073/pnas.79.13.3973.
Harber JJ, Bradley J, Anderson CW, Wimmer E: Catalysis of poliovirus VP0 maturation cleavage is not mediated by serine 10 of VP2. J Virol. 1991, 65: 326-334.
Harris KS, Reddigari SR, Nicklin MJ, Hammerle T, Wimmer E: Purification and characterization of poliovirus polypeptide 3CD, a proteinase and a precursor for RNA polymerase. J Virol. 1992, 66: 7481-7489.
Hellen CU, Witherell GW, Schmid M, Shin SH, Pestova TV, Gil A, Wimmer E: A cytoplasmic 57-kDa protein that is required for translation of picornavirus RNA by internal ribosomal entry is identical to the nuclear pyrimidine tract-binding protein. Proc Natl Acad Sci USA. 1993, 90: 7642-7646. 10.1073/pnas.90.16.7642.
Hellen CU, Pestova TV, Litterst M, Wimmer E: The cellular polypeptide p57 (pyrimidine tract-binding protein) binds to multiple sites in the poliovirus 5' nontranslated region. J Virol. 1994, 68: 941-950.
Hewlett MJ, Rose JK, Baltimore D: 5'-terminal structure of polio virus polyribosomal RNA is pUp. Proc Natl Acad Sci USA. 1976, 73: 327-330. 10.1073/pnas.73.2.327.
Hirst GK: Genetic recombination with Newcastle disease virus, polioviruses, and influenza. Cold Spring Harb Symp Quant Biol. 1962, 27: 303-309.
Hogle JM, Chow M, Filman DJ: Three-dimensional structure of poliovirus at 2.9 A resolution. Science. 1985, 229: 1358-1365. 10.1126/science.2994218.
Hogle JM: Poliovirus cell entry: common structural themes in viral cell entry pathways. Annu Rev Microbiol. 2002, 56: 677-702. 10.1146/annurev.micro.56.012302.160757.
Holland JJ, Kiehn ED: Specific cleavage of viral proteins as steps in the synthesis and maturation of enteroviruses. Proc Natl Acad Sci USA. 1968, 60: 1015-1022. 10.1073/pnas.60.3.1015.
Iizuka N, Kohara M, Hagino-Yamagishi K, Abe S, Komatsu T, Tago K, Arita M, Nomoto A: Construction of less neurovirulent polioviruses by introducing deletions into the 5' noncoding sequence of the genome. J Virol. 1989, 63: 5354-5363.
Iizuka N, Najita L, Franzusoff A, Sarnow P: Cap-dependent and cap-independent translation by internal initiation of mRNAs in cell extracts prepared from Saccharomyces cerevisiae. Mol Cell Biol. 1994, 14: 7322-7330.
Jacobson MF, Baltimore D: Morphogenesis of poliovirus. I. Association of the viral RNA with coat protein. J Mol Biol. 1968, 33: 369-378. 10.1016/0022-2836(68)90195-2.
Jacobson SJ, Konings DA, Sarnow P: Biochemical and genetic evidence for a pseudoknot structure at the 3' terminus of the poliovirus RNA genome and its role in viral RNA amplification. J Virol. 1993, 67: 2961-2971.
Jang SK, Krausslich HG, Nicklin MJ, Duke GM, Palmenberg AC, Wimmer E: A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J Virol. 1988, 62: 2636-2643.
Jang SK, Davies MV, Kaufman RJ, Wimmer E: Initiation of protein synthesis by internal entry of ribosomes into the 5' nontranslated region of encephalomyocarditis virus RNA in vivo. J Virol. 1989, 63: 1651-1660.
Johnson VH, Semler BL: Defined recombinants of poliovirus and coxsackievirus: sequence-specific deletions and functional substitutions in the 5'-noncoding regions of viral RNAs. Virology. 1988, 162: 47-57. 10.1016/0042-6822(88)90393-5.
Karakasiliotis I, Markoulatos P, Katsorchis T: Site analysis of recombinant and mutant poliovirus isolates of Sabin origin from patients and from vaccinees. Mol Cell Probes. 2004, 18: 103-109. 10.1016/j.mcp.2003.09.009.
Kawamura N, Kohara M, Abe S, Komatsu T, Tago K, Arita M, Nomoto A: Determinants in the 5' noncoding region of poliovirus Sabin 1 RNA that influence the attenuation phenotype. J Virol. 1989, 63: 1302-1309.
Kew OM, Sutter RW, de Gourville EM, Dowdle WR, Pallansch MA: Vaccine-derived polioviruses and the endgame strategy for global polio eradication. Annu Rev Microbiol. 2005, 59: 587-635. 10.1146/annurev.micro.58.030603.123625.
King AMQ, Brown F, Christian P, Hovi T, Hyypiä T, Knowles NJ, Lemon SM, Minor PD, Palmenberg AC, Skern T, Stanway G: Family Picornaviridae. Virus Taxonomy: Classification and Nomenclature of Viruses. Seventh Report of the International Committee on Taxonomy of Viruses. Edited by: van Regenmortel MHV, Fauquet CM, Bishop DHL, Carstens EB, Estes MK, Lemon SM, McGeoch DJ, Maniloff J, Mayo MA, Pringle CR, Wickner RB. 2000, San Diego, CA: Academic Press, 657-683.
Kitamura N, Semler BL, Rothberg PG, Larsen GR, Adler CJ, Dorner AJ, Emini EA, Hanecak R, Lee JJ, van der Werf S, Anderson CW, Wimmer E: Primary structure, gene organization and polypeptide expression of poliovirus RNA. Nature. 1981, 291: 547-553. 10.1038/291547a0.
Koch F, Koch G: Morphological alterations of the host cell as an essential basis for poliovirus replication. The Molecular Biology of Poliovirus. Edited by: Koch F, Koch G. 1985, New York: Springer-Verlag/Wien, 226-266.
Koike S, Ise I, Nomoto A: Functional domains of the poliovirus receptor. Proc Natl Acad Sci USA. 1991, 88: 4104-4108. 10.1073/pnas.88.10.4104.
Krausslich HG, Nicklin MJ, Toyoda H, Etchison D, Wimmer E: Poliovirus proteinase 2A induces cleavage of eucaryotic initiation factor 4F polypeptide p220. J Virol. 1987, 61: 2711-2718.
Kronenberger P, Schober D, Prchla E, Blaas D, Fuchs R: Use of free-flow electrophoresis for the analysis of cellular uptake of picornaviruses. Electrophoresis. 1997, 18: 2531-2536. 10.1002/elps.1150181407.
Kronenberger P, Schober D, Prchla E, Ofori-Anyinam O, Vrijsen R, Rombaut B, Blaas D, Fuchs R, Boeye A: Uptake of poliovirus into the endosomal system of HeLa cells. Arch Virol. 1998, 143: 1417-1424. 10.1007/s007050050385.
Kuge S, Nomoto A: Construction of viable deletion and insertion mutants of the Sabin strain of type 1 poliovirus: function of the 5' noncoding sequence in viral replication. J Virol. 1987, 61: 1478-1487.
Kuhn R, Luz N, Beck E: Functional analysis of the internal translation initiation site of foot-and-mouth disease virus. J Virol. 1990, 64: 4625-4631.
Kutitova OK, Lipskaia GIu, Maslova SV, Agol VI: [Isolation of recombinant vaccine strains of poliovirus from patients with poliomyelitis.]. Mol Gen Mikrobiol Virusol. 1989, 11: 14-20.
La Monica N, Meriam C, Racaniello VR: Mapping of sequences required for mouse neurovirulence of poliovirus type 2 Lansing. J Virol. 1986, 57: 515-525.
La Monica N, Almond JW, Racaniello VR: A mouse model for poliovirus neurovirulence identifies mutations that attenuate the virus for humans. J Virol. 1987, 61: 2917-2920.
La Monica N, Racaniello VR: Differences in replication of attenuated and neurovirulent polioviruses in human neuroblastoma cell line SH-SY5Y. J Virol. 1989, 63: 2357-2360.
Landsteiner K, Popper E: Übertragung der Poliomyelitis acuta auf Affen. Zeitschr. Immunitätsforsch. 1909, Orig. 2: 377-390.
Lee YF, Nomoto A, Detjen BM, Wimmer E: A protein covalently linked to poliovirus genome RNA. Proc Natl Acad Sci USA. 1977, 74: 59-63. 10.1073/pnas.74.1.59.
Lipskaya GY, Muzychenko AR, Kutitova OK, Maslova SV, Equestre M, Drozdov SG, Bercoff RP, Agol VI: Frequent isolation of intertypic poliovirus recombinants with serotype 2 specificity from vaccine associated polio cases. J Med Virol. 1991, 35: 290-296. 10.1002/jmv.1890350415.
Liu HM, Zheng DP, Zhang LB, Oberste MS, Kew OM, Pallansch MA: Serial recombination during circulation of type 1 wild-vaccine recombinant polioviruses in China. J Virol. 2003, 77: 10994-11005. 10.1128/JVI.77.20.10994-11005.2003.
Lyons T, Murray KE, Roberts AW, Barton DJ: Poliovirus 5'-terminal cloverleaf RNA is required in cis for VPg uridylylation and the initiation of negative-strand RNA synthesis. J Virol. 2001, 75: 10696-10708. 10.1128/JVI.75.22.10696-10708.2001.
Macadam AJ, Arnold C, Howlett J, John A, Marsden S, Taffs F, Reeve P, Hamada N, Wareham K, Almond J, Cammack N, Minor PD: Reversion of the attenuated and temperature-sensitive phenotypes of the Sabin type 3 strain of polio virus in vaccinees. Virology. 1989, 172: 408-414. 10.1016/0042-6822(89)90183-9.
Macadam AJ, Pollard SR, Ferguson G, Skuce R, Wood D, Almond JW, Minor PD: Genetic basis of attenuation of the Sabin type 2 vaccine strain of poliovirus in primates. Virology. 1993, 192: 18-26. 10.1006/viro.1993.1003.
Maier D, Nagel AC, Preiss A: Two isoforms of the Notch antagonist Hairless are produced by differential translation initiation. Proc Natl Acad Sci USA. 2002, 99: 15480-15485. 10.1073/pnas.242596699.
Martin J, Samoilovich E, Dunn G, Lackenby A, Feldman E, Heath A, Svirchevskaya E, Cooper G, Yermalovich M, Minor PD: Isolation of an intertypic poliovirus capsid recombinant from a child with vaccine associated paralytic poliomyelitis. J Virol. 2002, 76: 10921-10928. 10.1128/JVI.76.21.10921-10928.2002.
McGoldrick A, Macadam AJ, Dunn G, Rowe A, Burlison J, Minor PD, Meredith J, Evans DJ, Almond JW: Role of mutations G-480 and C-6203 in the attenuation phenotype of Sabin type 1 poliovirus. J Virol. 1995, 69: 7601-7605.
Meerovitch K, Pelletier J, Sonenberg N: A cellular protein that binds to the 5'-noncoding region of poliovirus RNA: implications for internal translation initiation. Genes Dev. 1989, 3: 1026-1034. 10.1101/gad.3.7.1026.
Meerovitch K, Svitkin YV, Lee HS, Lejbkowicz F, Kenan DJ, Chan EK, Agol VI, Keene JD, Sonenberg N: La autoantigen enhances and corrects aberrant translation of poliovirus RNA in reticulocyte lysate. J Virol. 1993, 67: 3798-3807.
Melnick JL: Current status of poliovirus infections. Clin Microbiol Rev. 1996, 9: 293-300.
Mendelsohn CL, Wimmer E, Racaniello VR: Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell. 1989, 56: 855-865. 10.1016/0092-8674(89)90690-9.
Meredith JM, Rohll JB, Almond JW, Evans DJ: Similar interactions of the poliovirus and rhinovirus 3D polymerases with the 3' untranslated region of rhinovirus 14. J Virol. 1999, 73: 9952-9958.
Milstien JB, Walker JR, Eron LJ: Correlation of virus polypeptide structure with attenuation of poliovirus type 1. J Virol. 1977, 23: 811-815.
Minor PD: Antigenic structure of picornaviruses. Curr Top Microbiol Immunol. 1990, 161: 121-154.
Mirzayan C, Wimmer E: Genetic analysis of an NTP-binding motif in poliovirus polypeptide 2C. Virology. 1992, 189: 547-555. 10.1016/0042-6822(92)90578-D.
Molla A, Paul AV, Wimmer E: Cell-free, de novo synthesis of poliovirus. Science. 1991, 254: 1647-1651. 10.1126/science.1661029.
Molla A, Jang SK, Paul AV, Reuer Q, Wimmer E: Cardioviral internal ribosomal entry site is functional in a genetically engineered dicistronic poliovirus. Nature. 1992, 356: 255-257. 10.1038/356255a0.
Moss EG, O'Neill RE, Racaniello VR: Mapping of attenuating sequences of an avirulent poliovirus type 2 strain. J Virol. 1989, 63: 1884-1890.
Najita L, Sarnow P: Oxidation-reduction sensitive interaction of a cellular 50-kDa protein with an RNA hairpin in the 5' noncoding region of the poliovirus genome. Proc Natl Acad Sci USA. 1990, 87: 5846-5850. 10.1073/pnas.87.15.5846.
Nathanson N, Langmuir A: The Cutter incident. Poliomyelitis following formaldehyde-inactivated poliovirus vaccination in the United States during the spring of 1955. Am J Hyg. 1963, 78: 16-81.
Nathanson N, Martin JR: The epidemiology of poliomyelitis: enigmas surrounding its appearance, epidemicity, and disappearance. Am J Epidemiol. 1982, 110 (6): 672-692.
Nicholson R, Pelletier J, Le SY, Sonenberg N: Structural and functional analysis of the ribosome landing pad of poliovirus type 2: in vivo translation studies. J Virol. 1991, 65: 5886-5894.
Nomoto A, Lee YF, Wimmer E: The 5' end of poliovirus mRNA is not capped with m7G(5')ppp(5')Np. Proc Natl Acad Sci USA. 1976, 73: 375-380. 10.1073/pnas.73.2.375.
Nomoto A, Kitamura N, Golini F, Wimmer E: The 5'-terminal structures of poliovirion RNA and poliovirus mRNA differ only in the genome linked protein VPg. Proc Natl Acad Sci USA. 1977, 74: 5345-5349. 10.1073/pnas.74.12.5345.
Nomoto A, Omata T, Toyoda H, Kuge S, Horie H, Kataoka Y, Genba Y, Nakano Y, Imura N: Complete nucleotide sequence of the attenuated poliovirus Sabin 1 strain genome. Proc Natl Acad Sci USA. 1982, 79: 5793-5797. 10.1073/pnas.79.19.5793.
Nomoto A, Wimmer E: Genetic studies of the antigenicity and the attenuation phenotype of poliovirus. Molecular Basis of Virus Disease. Edited by: Russell WC, Almond JW. 1987, Cambridge, U.K.: Cambridge Univ. Press, 107-134.
Ohka S, Yang WX, Terada E, Iwasaki K, Nomoto A: Retrograde transport of intact poliovirus through the axon via the fast transport system. Virology. 1998, 250: 67-75. 10.1006/viro.1998.9360.
Ohka S, Matsuda N, Tohyama K, Oda T, Morikawa M, Kuge S, Nomoto A: Receptor (CD155)-dependent endocytosis of poliovirus and retrograde axonal transport of the endosome. J Virol. 2004, 78: 7186-7198. 10.1128/JVI.78.13.7186-7198.2004.
Ohlmann T, Rau M, Pain VM, Morley SJ: The C-terminal domain of eukaryotic protein synthesis initiation factor (eIF) 4G is sufficient to support cap-independent translation in the absence of eIF4E. EMBO J. 1996, 15: 1371-1382.
Ohlmann T, Lopez-Lastra M, Darlix JL: An internal ribosome entry segment promotes translation of the simian immunodeficiency virus genomic RNA. J Biol Chem. 2000, 275: 11899-11906. 10.1074/jbc.275.16.11899.
Omata T, Kohara M, Kuge S, Komatsu T, Abe S, Semler BL, Kameda A, Itoh H, Arita M, Wimmer E, Nomoto A: Genetic analysis of the attenuation phenotype of poliovirus type 1. J Virol. 1986, 58: 348-358.
Patton JG, Mayer SA, Tempst P, Nadal-Ginard B: Characterization and molecular cloning of polypyrimidine tract-binding protein: a component of a complex necessary for pre-mRNA splicing. Genes Dev. 1991, 5: 1237-1251. 10.1101/gad.5.7.1237.
Parsley TB, Towner JS, Blyn LB, Ehrenfeld E, Semler BL: Poly (rC) binding protein 2 forms a ternary complex with the 5'-terminal sequences of poliovirus RNA and the viral 3CD proteinase. RNA. 1997, 3: 1124-1134.
Paul AV, van Boom JH, Filippov D, Wimmer E: Protein-primed RNA synthesis by purified poliovirus RNA polymerase. Nature. 1998, 393: 280-284. 10.1038/30529.
Paul AV, Mugavero J, Yin J, Hobson S, Schultz S, van Boom JH, Wimmer E: Studies on the attenuation phenotype of polio vaccines: poliovirus RNA polymerase derived from Sabin type 1 sequence is temperature sensitive in the uridylylation of VPg. Virology. 2000, 272: 72-84. 10.1006/viro.2000.0354.
Paul AV: Possible unifying mechanism of picornavirus genome replication. Molecular Biology of Picornaviruses. Edited by: Semler BL, Wimmer E. 2002, Washington, D.C.:ASM Press, 227-246.
Paximadi E, Karakasiliotis I, Mamuris Z, Stathopoulos C, Krikelis V, Markoulatos P: Genomic analysis of recombinant sabin clinical isolates. Virus Genes. 2006, 32: 203-210. 10.1007/s11262-005-6877-1.
Pelletier J, Kaplan G, Racaniello VR, Sonenberg N: Cap-independent translation of poliovirus mRNA is conferred by sequence elements within the 5' noncoding region. Mol Cell Biol. 1988, 8: 1103-1112.
Pelletier J, Sonenberg N: Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature. 1988, 334: 320-325. 10.1038/334320a0.
Peluso R, Haase A, Stowring L, Edwards M, Ventura P: A Trojan Horse mechanism for the spread of visna virus in monocytes. Virology. 1985, 147: 231-236. 10.1016/0042-6822(85)90246-6.
Pestova TV, Hellen CU, Wimmer E: Translation of poliovirus RNA: role of an essential cis-acting oligopyrimidine element within the 5' nontranslated region and involvement of a cellular 57-kilodalton protein. J Virol. 1991, 65: 6194-6204.
Pfister T, Pasamontes L, Troxler M, Egger D, Bienz K: Immunocytochemical localization of capsid-related particles in subcellular fractions of poliovirus-infected cells. Virology. 1992, 188: 676-684. 10.1016/0042-6822(92)90522-Q.
Pfister T, Egger D, Bienz K: Poliovirus subviral particles associated with progeny RNA in the replication complex. J Gen Virol. 1995, 76: 63-71.
Pfister T, Mirzayan C, Wimmer E: Polioviruses: molecular biology. Encyclopedia of Virology. Edited by: Granoff AW. 1999, London, UK: Academic Press Ltd, 2: 1330-1348.
Phillips BA, Fennel R: Polypeptide composition of poliovirions, naturally occurring empty capsids, and 14S precursor particles. J Virol. 1973, 12: 291-299.
Pierangeli A, Bucci M, Pagnotti P, Degener AM, Perez Bercoff R: Mutational analysis of the 3'-terminal extra-cistronic region of poliovirus RNA: secondary structure is not the only requirement for minus strand RNA replication. FEBS Lett. 1995, 374: 327-332. 10.1016/0014-5793(95)01127-Z.
Pilipenko EV, Blinov VM, Romanova LI, Sinyakov AN, Maslova SV, Agol VI: Conserved structural domains in the 5'-untranslated region of picornaviral genomes: an analysis of the segment controlling translation and neurovirulence. Virology. 1989, 168: 201-209. 10.1016/0042-6822(89)90259-6.
Pilipenko EV, Gmyl AP, Maslova SV, Svitkin YV, Sinyakov AN, Agol VI: Prokaryotic-like cis elements in the cap-independent internal initiation of translation on picornavirus RNA. Cell. 1992, 68: 119-131. 10.1016/0092-8674(92)90211-T.
Pilipenko EV, Poperechny KV, Maslova SV, Melchers WJ, Slot HJ, Agol VI: Cis-element, oriR, involved in the initiation of (-) strand poliovirus RNA: a quasi-globular multi-domain RNA structure maintained by tertiary ('kissing') interactions. EMBO J. 1996, 15: 5428-5436.
Prevot D, Decimo D, Herbreteau CH, Roux F, Garin J, Darlix JL, Ohlmann T: Characterization of a novel RNA-binding region of eIF4GI critical for ribosomal scanning. EMBO J. 2003, 22: 1909-1921. 10.1093/emboj/cdg175.
Qin X, Sarnow P: Preferential translation of internal ribosome entry site-containing mRNAs during the mitotic cycle in mammalian cells. J Biol Chem. 2004, 279: 13721-13728. 10.1074/jbc.M312854200.
Racaniello VR, Baltimore D: Cloned poliovirus complementary DNA is infectious in mammalian cells. Science. 1981, 214: 916-919. 10.1126/science.6272391.
Ren RB, Moss EG, Racaniello VR: Identification of two determinants that attenuate vaccine-related type 2 poliovirus. J Virol. 1991, 65: 1377-1382.
Ren R, Racaniello VR: Poliovirus spreads from muscle to the central nervous system by neural pathways. J Infect Dis. 1992, 166: 747-752.
Rieder E, Gorbalenya AE, Xiao C, He Y, Baker TS, Kuhn RJ, Rossmann MG, Wimmer E: Will the polio niche remain vacant?. Dev Biol (Basel). 2001, 105: 111-122. 10.1159/000046547.
Rieder E, Xiang W, Paul A, Wimmer E: Analysis of the cloverleaf element in a human rhinovirus type 14/poliovirus chimera: correlation of subdomain D structure, ternary protein complex formation and virus replication. J Gen Virol. 2003, 84: 2203-2216. 10.1099/vir.0.19013-0.
Rohll JB, Percy N, Ley R, Evans DJ, Almond JW, Barclay WS: The 5'-untranslated regions of picornavirus RNAs contain independent functional domains essential for RNA replication and translation. J Virol. 1994, 68: 4384-4391.
Roivainen M, Piirainen L, Hovi T, Virtanen I, Riikonen T, Heino J, Hyypia T: Entry of coxsackievirus A9 into host cells: specific interactions with alpha v beta 3 integrin, the vitronectin receptor. Virology. 1994, 203: 357-365. 10.1006/viro.1994.1494.
Romanova LI, Tolskaya EA, Kolesnikova MS, Agol VI: Biochemical evidence for intertypic genetic recombination of polioviruses. FEBS Lett. 1980, 118: 109-112. 10.1016/0014-5793(80)81229-4.
Rousset D, Rakoto-Andrianarivelo M, Razafindratsimandresy R, Randriamanalina B, Guillot S, Balanant J, Mauclere P, Delpeyroux F: Recombinant vaccine-derived poliovirus in Madagascar. Emerg Infect Dis. 2003, 9: 885-887.
Rueckert RR: Picornaviridae and their replication. Virology. Edited by: Fields BN, Knipe DM. 1990, New York, NY: Raven Press, 507-548.
Sabin AB, Ward R: The Natural History of Poliomyelitis. I. Distribution of Virus in Nervous and Non-nervous Tissues. J Exp Med. 1941, 73: 771-793. 10.1084/jem.73.6.771.
Sabin AB: The significance of viruses recovered from the intestinal tracts of healthy infants and children. Ann N Y Acad Sci. 1956, 66: 226-230. 10.1111/j.1749-6632.1956.tb40126.x.
Selinka HC, Zibert A, Wimmer E: Poliovirus can enter and infect mammalian cells by way of an intercellular adhesion molecule 1 pathway. Proc Natl Acad Sci USA. 1991, 88: 3598-3602. 10.1073/pnas.88.9.3598.
Shafren DR, Dorahy DJ, Ingham RA, Burns GF, Barry RD: Coxsackievirus A21 binds to decay-accelerating factor but requires intercellular adhesion molecule 1 for cell entry. J Virol. 1997, 71: 4736-4743.
Shimizu H, Thorley B, Paladin FJ, Brussen KA, Stambos V, Yuen L, Utama A, Tano Y, Arita M, Yoshida H, Yoneyama T, Benegas A, Roesel S, Pallansch M, Kew O, Miyamura T: Circulation of type 1 vaccine derived poliovirus in the Philippines in 2001. J Virol. 2004, 78: 13512-13521. 10.1128/JVI.78.24.13512-13521.2004.
Simoes EA, Sarnow P: An RNA hairpin at the extreme 5' end of the poliovirus RNA genome modulates viral translation in human cells. J Virol. 1991, 65: 913-921.
Skinner MA, Racaniello VR, Dunn G, Cooper J, Minor PD, Almond JW: New model for the secondary structure of the 5' non-coding RNA of poliovirus is supported by biochemical and genetic data that also show that RNA secondary structure is important in neurovirulence. J Mol Biol. 1989, 207: 379-392. 10.1016/0022-2836(89)90261-1.
Slobodskaya OR, Gmyl AP, Maslova SV, Tolskaya EA, Viktorova EG, Agol VI: Poliovirus neurovirulence correlates with the presence of a cryptic AUG upstream of the initiator codon. Virology. 1996, 221: 141-150. 10.1006/viro.1996.0360.
Sonenberg N: Regulation of translation by poliovirus. Adv Virus Res. 1987, 33: 175-204.
Spector DH, Baltimore D: Requirement of 3'-terminal poly(adenylicacid) for the infectivity of poliovirus RNA. Proc Natl Acad Sci USA. 1974, 71: 2983-2987. 10.1073/pnas.71.8.2983.
Stanway G, Hughes PJ, Mountford RC, Reeve P, Minor PD, Schild GC, Almond JW: Comparison of the complete nucleotide sequences of the genomes of the neurovirulent poliovirus P3/Leon/37 and its attenuated Sabin vaccine derivative P3/Leon 12a1b. Proc Natl Acad Sci USA. 1984, 81: 1539-1543. 10.1073/pnas.81.5.1539.
Svitkin YV, Maslova SV, Agol VI: The genomes of attenuated and virulent poliovirus strains differ in their in vitro translation efficiencies. Virology. 1985, 147: 243-252. 10.1016/0042-6822(85)90127-8.
Svitkin YV, Pestova TV, Maslova SV, Agol VI: Point mutations modify the response of poliovirus RNA to a translation initiation factor: a comparison of neurovirulent and attenuated strains. Virology. 1988, 166: 394-404. 10.1016/0042-6822(88)90510-7.
Svitkin YV, Cammack N, Minor PD, Almond JW: Translation deficiency of the Sabin type 3 poliovirus genome: association with an attenuating mutation C472----U. Virology. 1990, 175: 103-109. 10.1016/0042-6822(90)90190-3.
Tardy-Panit M, Blondel B, Martin A, Tekaia F, Horaud F, Delpeyroux F: A mutation in the RNA polymerase of poliovirus Type 1 contributes to attenuation in mice. J Virol. 1993, 67: 4630-4638.
Teterina NL, Gorbalenya AE, Egger D, Bienz K, Ehrenfeld E: Poliovirus 2C protein determinants of membrane binding and rearrangements in mammalian cells. J Virol. 1997, 71: 8962-8972.
Tolskaya EA, Romanova LA, Kolesnikova MS, Agol VI: Intertypic recombination in poliovirus: genetic and biochemical studies. Virology. 1983, 124: 121-132. 10.1016/0042-6822(83)90295-7.
Toyoda H, Nicklin MJ, Murray MG, Anderson CW, Dunn JJ, Studier FW, Wimmer E: A second virus-encoded proteinase involved in proteolytic processing of poliovirus polyprotein. Cell. 1986, 45: 761-770. 10.1016/0092-8674(86)90790-7.
Toyoda H, Yang CF, Takeda N, Nomoto A, Wimmer E: Analysis of RNA synthesis of type 1 poliovirus by using an in vitro molecular genetic approach. J Virol. 1987, 61: 2816-2822.
Tsukiyama-Kohara K, Iizuka N, Kohara M, Nomoto A: Internal ribosome entry site within hepatitis C virus RNA. J Virol. 1992, 66: 1476-1483.
Ventoso I, MacMillan SE, Hershey JW, Carrasco L: Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-4F complex. FEBS Lett. 1998, 435: 79-83. 10.1016/S0014-5793(98)01027-8.
Westrop GD, Wareham KA, Evans DM, Dunn G, Minor PD, Magrath DI, Taffs F, Marsden S, Skinner MA, Schild GC, Almond JW: Genetic basis of attenuation of the Sabin type 3 oral poliovirus vaccine. J Virol. 1989, 63: 1338-1344.
Wetz K: Cross-linking of poliovirus with bifunctional reagents: biochemical and immunological identification of protein neighbourhoods. J Virol Methods. 1987, 18: 143-151. 10.1016/0166-0934(87)90119-4.
Wimmer E: Genome-linked proteins of viruses. Cell. 1982, 28: 199-201. 10.1016/0092-8674(82)90335-X.
Wimmer E, Hellen CU, Cao X: Genetics of poliovirus. Annu Rev Genet. 1993, 27: 353-436. 10.1146/annurev.ge.27.120193.002033.
Xiang W, Harris KS, Alexander L, Wimmer E: Interaction between the 5'-terminal cloverleaf and 3AB/3CDpro of poliovirus is essential for RNA replication. J Virol. 1995, 69: 3658-3667.
Yalamanchili P, Harris K, Wimmer E, Dasgupta A: Inhibition of basal transcription by poliovirus: a virus-encoded protease (3Cpro) inhibits formation of TBP-TATA box complex in vitro. J Virol. 1996, 70: 2922-2929.
Yang WX, Terasaki T, Shiroki K, Ohka S, Aoki J, Tanabe S, Nomura T, Terada E, Sugiyama Y, Nomoto A: Efficient delivery of circulating poliovirus to the central nervous system independently of poliovirus receptor. Virology. 1997, 229: 421-428. 10.1006/viro.1997.8450.
Medical Microbiology. Edited by: Baron S. 1996, Galveston, TX:The University of Texas Medical Branch at Galveston, [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.chapter.2833]4
Yogo Y, Wimmer E: Sequence studies of poliovirus RNA. III. Polyuridylic acid and polyadenylic acid as components of the purified poliovirus replicative intermediate. J Mol Biol. 1975, 92: 467-477. 10.1016/0022-2836(75)90292-2.
Ypma-Wong MF, Dewalt PG, Johnson VH, Lamb JG, Semler BL: Protein 3CD is the major poliovirus proteinase responsible for cleavage of the P1 capsid precursor. Virology. 1988, 166: 265-270. 10.1016/0042-6822(88)90172-9.
The author thanks Dr. Eckard Wimmer for critical review of this manuscript, and acknowledges support from NIH Training grant 5 T32 CA09176 as well as a Medical Scientist Training grant.
The author declares that she has no competing interests.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
Rights and permissions
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
De Jesus, N.H. Epidemics to eradication: the modern history of poliomyelitis. Virol J 4, 70 (2007). https://doi.org/10.1186/1743-422X-4-70
- Internal Ribosomal Entry Site
- Human Enterovirus
- Paralytic Poliomyelitis