Polio virus life cycle

IPV does not contain live virus, so people who receive this vaccine do not shed the virus and cannot infect others, and the vaccine cannot cause disease. IPV does not stop transmission of the virus. OPV is used wherever a polio outbreak needs to be contained, even in countries which rely exclusively on IPV for their routine immunization program.

Poliovirus containment is focused on eradicated polioviruses. Containment measures external icon are being put in place for laboratories or other facilities that handle or store eradicated polioviruses.

Polio, or poliomyelitis, is a crippling and potentially deadly infectious disease. Learn more about the symptoms and how the virus is spread from person-to-person. Polio vaccine provides the best protection against polio disease. Two types of vaccines are used to prevent polio disease— inactivated polio vaccine IPV external icon and oral polio vaccine OPV. In influenza A, the hemagglutinin glycoprotein spike provides the site for binding to its cellular receptor sialic acid residues on glycoproteins and glycolipids on the cell surface and serves as the fusion protein.

The hemagglutinin is first synthesized as a precursor HA 0 and is cleaved late in assembly to form two chains, HA 1 and HA 2. When the virus binds to its cellular receptor, it is taken up into endosomes. Upon acidification of the endosomes, the hemagglutinin undergoes a massive conformational change that results in the exposure of the fusion peptide, its insertion into the membrane of the endosome, the fusion of the viral envelope with the endosome, and the release of the nucleocapsid into the cytoplasm.

Thus, for influenza the receptor plays a single role, namely to concentrate virus at the surface of susceptible cells, and the trigger that releases the hemagglutinin from its metastable state is acidification of the endosome. In other enveloped viruses the receptor also serves as the trigger that induces the conformational changes required for entry, in which case the virus envelope may fuse directly with the plasma membrane. High-resolution structures of ectodomains of HA 0 21 , the mature HA , and of the fusogenic form of HA 2 , which is produced by proteolytic removal of HA 1 from HA subsequent to acidification 18 , have been solved in Don Wiley's laboratory at Harvard University.

The hemagglutinin is a trimer that is held together largely by coil-coil interactions between long helices in the HA 2 subunit Figure 1. The globular head of the trimer comprises much of the HA 1 chain and contains the receptor-binding sites. In HA 0 and HA at neutral pH, the fusion peptide is located at the base of the molecule near the site of attachment to the viral envelope. The fusion peptide is contained in an exposed loop in HA 0 Figure 1 a , and upon cleavage to produce HA the newly freed fusion peptide is inserted between the helices and is not exposed Figure 1 b.

Acidification induces a massive conformational rearrangement that moves both the fusion peptide and the C terminus of the ectodomain of HA 2 which in the intact protein is anchored in the viral envelope to a point near the top cell-proximal end of the molecule Figure 1 c. At this point the fusion peptide and the cell membrane to which it is attached, and the C terminus of HA 2 and the viral envelope to which it is attached, are in close proximity, allowing fusion of the two membranes to proceed.

The detailed mechanism of induction of fusion is still poorly understood. Structural changes on maturation and acidification of the influenza A virus hemagglutinin.

The hemagglutinin is a homotrimer. The newly generated amino terminus of HA 2 yellow facilitates fusion and is called the fusion peptide. In HA 0 the fusion peptide is in an exposed loop near the base of the molecule indicated by the 1 in Figure 1 a. In the fusogenic form c the fusion peptide and the C terminus of HA 2 which anchors the molecule in the viral membrane and the fusion peptide which is believed to insert into the cell membrane are both near the top of the molecule.

This would bring the viral membrane and cell membrane into close proximity. The HA of influenza A is the only protein where both the metastable and fusogenic forms of the glycoprotein have been characterized structurally. However, similar conformational changes have been proposed for the envelope glycoproteins of a number of other viruses based on structures of analogues of the fusogenic form 5 , 20 , 32 , 61 , 71 , 72 , , , Using poliovirus as an example, we demonstrate that similar mechanisms in which receptor binding releases virus from a metastable state and exposes hydrophobic sequences may also occur in nonenveloped viruses.

Poliovirus is a member of the picornavirus family, which includes a number of significant pathogens of humans e. Despite their simple organization, the viruses have a complex life cycle [reviewed in 92 ].

Because the process is cyclic we may start at any point. We choose viral assembly as our starting point to develop the parallel with the model described above. Upon release into the cytoplasm, the viral RNA is translated in a single open reading frame to produce a polyprotein that is processed cotranslationally by viral proteases to yield the viral proteins 57 , The polyprotein is myristoylated at its N terminus An early cotranslational cleavage of the polyprotein by the viral 2A protease releases a precursor protein myristoyl-P1 from the N terminus of the polyprotein.

This cleavage may occur in cis. The P1 protein contains all the capsid protein sequences. This cleavage is associated with the assembly of the proteins into a pentameric assembly intermediate, which spontaneously assembles into empty capsid containing 60 copies each of VP0, VP3, and VP1.

The empty capsids and pentamers are apparently in equilibrium within the cell, and therefore it has not been possible to determine whether RNA is encapsidated by pentamers or by insertion into the preformed empty capsids.

Regardless, the encapsidation appears to be tightly linked to RNA replication, as there is an absolute dependence of encapsidation on de novo synthesis of progeny RNA 77 , There is no known protease requirement for this cleavage, and it is thought to be autocatalytic, depending only on the capsid proteins themselves and perhaps the viral RNA.

The cleavage of VP0 to form the virion is associated with a significant increase in the stability of the particle. The mechanism of release of the virus from the cell is unclear. The life cycle of poliovirus and related picornaviruses. Infection is initiated by attachment to receptor, which induces conformational changes in the virus that facilitate translocation of the viral RNA into the cytoplasm where it is replicated to yield progeny RNAs and translated to yield viral proteins.

Translation produces a long polyprotein that is processed by viral proteases. Assembly of the virus is linked to processing of the polyprotein and proceeds through a series of intermediates including a protomer, a pentamer, an empty capsid, a provirion, and ultimately the virus. Adapted from Principles of Virology , S.

Flint, V. Racaniello, L. Enquist, A. Krug with permission. The receptors for a number of picornaviruses have been identified 11 - 14 , 43 , 51 , 76 , 98 , There is no known requirement for a coreceptor for poliovirus entry. The cellular function for Pvr is not known, but two paralogs in humans, called Nectin-1 and Nectin-2, are homotrophic adhesion proteins that interact with the actin skeleton through a cytoplasmic protein called afadin Mice lacking the mouse homolog of Nectin-2 show specific defects in spermatogenesis It is not clear whether Pvr plays similar roles, as it lacks sequence motifs in its cytoplasmic domain that mediate interactions with afadin.

Interestingly, Pvr, Nectin-1, and Nectin-2 are coreceptors for alpha herpesviruses 38 , Several lines of evidence suggest that the first N-terminal domain of Pvr is responsible for poliovirus binding and infection.

This functionality is independent of the cytoplasmic domain or the nature of the transmembrane anchor, suggesting that intracellular signaling is not critical for Pvr's function as a receptor.

Indeed, the ectodomain fused to a GPI anchor is a functional receptor M. Chow, personal communication. Indeed, the characterization of the entry mechanism is complicated by the relatively high particle-to-pfu plaque-forming-unit ratio for polio and its relatives ranging from 10 2 to 10 3. Thus, when virus or viral-derived particles are detected in a given compartment during entry it is not clear whether the particles are involved in productive or nonproductive events.

Early experiments with monensin and lysomotrophic amines which do measure infectious units suggested that poliovirus entry requires acidification However, subsequent studies with bafilomycin A demonstrated that poliovirus entry is independent of acidification of endosomes 88 and suggested that the contradictory results of the earlier studies were an artifact of inhibition of downstream events in infection, most likely RNA replication.

Similar studies indicate that most enteroviruses and some 8 , but not all 91 , rhinoviruses enter via mechanisms that do not depend on acidification of endosomes. Others and we have taken advantage of the recent development of dominant-negative mutants of dynamin 28 to further probe the route of entry of poliovirus and several closely related entero- and rhinoviruses.

Recent data suggest that dynamin also is required for internalization via caveoli. Mittler, J. Hogle, manuscript in preparation. These studies showed that closely related viruses differ in their dependence on dynamin for cell entry.

Thus, echovirus 1 and the RD strain Coxsackievirus B3 were shown to be dynamin dependent, whereas echovirus 7, the Nancy strain of Coxsackievirus B3 which is the parent of the RD strain , and Coxsackievirus B4 were not. Dynamin dependence seemed to be correlated with the receptor used, but it was not correlated with the nature of the transmembrane anchor of the receptor or the presence of known clathrin-recruiting signals in the cytoplasmic domain of the receptor.

Mittler et al. They showed that while infection mediated by full-length five domain ICAM-1 was dynamin dependent, infection mediated by mutant receptors with deletions of domain 5 membrane proximal , domains 4 and 5 or domain 3 were not.

The results suggest that dynamin dependence is not an intrinsic property of the virus itself. Thus, the enteroviruses and rhinoviruses are not obligatorily dependent on dynamin-requiring pathways such as endocytosis for cell entry and may be promiscuous in their choice of pathways. In the course of a typical experimental infection, a significant fraction of the A particle subsequently elutes from cells in what is thought to represent an abortive infection.

However, the A particle is also the predominant cell-associated form of the virus early in infection within the first min At later times post infection the levels of A particles begin to decrease.

The timing of the disappearance of the A particle is correlated with the timing of the appearance of a second altered form of the virus that has lost its RNA and now sediments at 80S.

The trigger for conversion to the 80S form is not known, but it does not require receptor. The native-to-A particle conversion can also be induced by solubilized forms of the receptor 40 , 55 and by the soluble ectodomain of the receptor in the absence of cells 3 , The A particle has altered sedimentation behavior sedimenting at S versus S for the native virion and altered antigenicity.

In contrast to the virion which is stable to the proteases and quite soluble , the A particle is sensitive to proteases and is hydrophobic partitioning into detergent micelles. The A particle has externalized myristoyl-VP4 and the N-terminal extension of the capsid protein VP1 36 , both of which are in the interior of the native virion.

The receptor-induced conversion to the A particle is apparently irreversible. The breathing provides striking evidence for the dynamic nature of the poliovirus structure and suggests that the virus is literally primed to undergo larger, concerted, and irreversible changes associated with receptor binding. Breathing also occurs in other nonenveloped viruses such as Flock House virus 16 and rhinoviruses Insertion of the N terminus of VP1 and perhaps the myristoyl group of VP4 may facilitate cell entry either by disrupting a membrane or by forming a pore in a membrane This observation, together with unpublished data that show that the channels become pores in the presence of receptor M.

Chow, personal communication , would support a model in which the inserted sequences formed a pore in the membrane through which the RNA could be extruded into the cytoplasm. Although there is still considerable controversy concerning the role of the two altered particles, it is generally thought that the A particle may be an intermediate in the cell entry pathway and that the 80S empty particle is the final protein product that accumulates after the RNA is released into the cytoplasm to initiate translation and replication.

There are several lines of evidence that the A particle is indeed an intermediate: a The antiviral activity of compounds that bind to the capsid correlates well with their ability to inhibit the formation of the A particle in vitro Although the efficiency of infection with the A particle is nearly four orders of magnitude lower than virions, this inefficiency is largely attributable to the lack of a receptor to bring the particle to high concentration at the cell surface.

Although this observation raises an important caveat concerning the role of the A particle, the failure to observe an intermediate in a steady-state process in cell entry does not necessarily imply that the intermediate does not exist.

In fact, in a steady-state process, an intermediate is expected to accumulate to appreciable levels only if a rate-limiting step in the pathway occurs downstream of the putative intermediate. Thus, the A particle would not be expected to accumulate in infections at low temperature, and it or perhaps a similar particle remains a viable candidate as a cell entry intermediate.

In the absence of calcium the reaction proceeds directly to the 80S particles, suggesting that calcium is required to stabilize the A particle and that depletion of calcium at some stage during the normal entry process may serve as a trigger for RNA release. Like the receptor-mediated native-to-A particle conversion, the thermal-mediated conversion is inhibited by capsid-binding antiviral agents , The ability to recapitulate the conformational alterations by simply warming the virion provides a convenient means for production of large amounts of the altered particles in vitro from purified virus.

It also provides a convenient assay system for studying the kinetics of the virion-to-A particle conversion as a function of temperature. These kinetic studies have led to several observations that support the general model for cell entry discussed in the introduction and that provide additional insights into the role of the receptor in mediating the virion-to-A particle conversion. This would be consistent with the model in which the virus is kinetically trapped in a metastable state.

Analysis of the kinetics of both the thermal-induced and the receptor-induced virion-to-A particle conversion as a function of temperature supports this model Analysis of the kinetics of the receptor-mediated conversion as a function of temperature confirms that the receptor produces a significant enhancement of the rate, such that the rate becomes biologically relevant at physiological temperatures.

Thus, the receptor behaves like a classical transition-state catalyst A model based on this prediction suggests that the antiviral agents act like a peg to rigidify the capsid. Surprisingly, kinetic studies of the thermal-mediated transition show that the capsid-binding antiviral agents have no effect on the activation barrier an enthalpic term and suggest that the drugs act via entropic stabilization of the virion These experimental studies are consistent with computational studies of rhinovirus by Post and colleagues that show that binding the drugs increases rather than decreases the compressibility of the virus, and stabilizes the virus by providing a higher density of low-energy states to the virion 89 , 90 , These results can only be explained if the receptor-mediated pathway proceeds via an intermediate not present in the receptor-independent pathway.

By analogy with classic enzyme kinetic models, we propose that this intermediate represents an activated virus-receptor complex in which the virus and receptor?

This proposal is also consistent with the observation that soluble receptor has two affinities for the virus, with the low-affinity mode dominating at low temperature and the high-affinity mode becoming more prevalent as the temperature is increased In contrast, the tight-binding mode for the Pvr-poliovirus complex is characterized by a significant increase in k on , which more than compensates for a small increase in k off This suggests that the tight-binding mode for the Pvr-poliovirus complex is the result of an opening of the receptor-binding site, making it more accessible to receptor binding.

The structural snapshots begin with the virus structure, which has been determined at high resolution by X-ray crystallographic methods 52 , and a high-resolution structure of the empty capsid assembly intermediate which has not yet undergone the maturation cleavage of the immature capsid protein precursor VP0 7.

The structures of the Mahoney strain of type 1 poliovirus 52 and of the closely related rhinovirus 14 94 were first reported in Since then, structures of several other picornaviruses have been described 1 , 34 , 35 , 41 , 48 , 56 , 62 , 65 - 67 , 84 , 85 , , , , The protein shell of the virion is composed of 60 copies of the 4 capsid proteins, VP1, VP2, VP3, and VP4, that are arranged on an icosahedral surface.

The three large capsid proteins VP1, VP2, and VP3 share a common fold an eight-stranded beta-barrel that is also seen in a number of other plant, insect, and animal viruses Figure 3 a.

A striking feature of infection is lifelong disabilities that may affect survivors of the acute disease. Transmitted by the fecal—oral and oral—oral route, this virus three serotypes was one of the most feared pathogens in industrialized countries during the 20th century affecting hundreds of thousands of children every year, via outbreaks during warm summer months.

Although there are highly effective vaccines to control poliomyelitis, it remains endemic in a few countries, from which spread and outbreaks continue to occur throughout the world. Since its discovery in , poliovirus has been intensively studied to better understand and control this formidable pathogen.

The history of poliovirus is not, however, limited to the fight against the disease. Poliovirus replication studies also have played important roles in the development of modern virology since poliovirologists and, more generally, picornavirologists have been pioneers in many domains of molecular virology. Poliovirus was, for example, the first animal RNA virus to have its complete genome sequence determined, the first RNA animal virus for which an infectious clone was constructed, and, along with the related rhinovirus, the first human virus that had its three-dimensional structure solved by X-ray crystallography.

Indeed, the history of over half a century of poliovirus replication studies is marked by major discoveries, many of which are summarized here and illustrated in Fig 1. In , John Enders, Thomas Weller, and Frederick Robbins performed a landmark study showing that poliovirus could be propagated in cultured, non-neural human cells that did not correspond to the tissues infected during the disease [ 1 ].

Not only did these Nobel Prize-winning studies pave the way for the development of highly effective vaccines against poliovirus, but they also opened the door for virologists to study the molecular mechanisms of poliovirus replication in cultured cells that were much more readily manipulated than neural tissue. Isolated poliovirus genomic RNA was then shown to be infectious for susceptible HeLa cells in monolayers, demonstrating that the viral genome itself is the carrier of the biological activity responsible for infection [ 2 ].

John Holland and coworkers then reproduced this experiment with normally nonsusceptible cells, demonstrating that the block to poliovirus growth in nonpermissive, nonprimate cells was due to the absence of specific receptors, defining cell determinants of poliovirus infection [ 3 ].

Studies on another picornavirus, mengovirus, revealed the existence of an actinomycin D-resistant replication activity in the cytoplasm of infected cells that was later also identified in poliovirus-infected cells [ 4 ]. This virus-specific enzyme was isolated eight years later [ 5 ].

In the late s, Summers and Maizel [ 6 ], and others [ 7 , 8 ], showed that the genomic RNA of poliovirus is translated to produce very large polypeptides that are then specifically cleaved into smaller functional proteins. This discovery was the first demonstration that picornavirus proteins were produced from large precursors proteolytically processed in infected cells [ 6 ]. At the same time, cellular fractionation studies revealed that poliovirus RNAs are synthesized in replication complexes bound to distinct membranous structures in the cytoplasm of infected cells [ 9 ].

This period corresponds to several major advances in understanding the mechanisms of translation and replication of poliovirus genomic RNA. In , a small protein of 22 amino acids, called VPg, was discovered to be covalently linked to the 5' end of poliovirus RNA [ 10 ]. This hypothesis was confirmed later by Paul et al. Experiments with dicistronic vectors subsequently led to the discovery of a novel mechanism of initiation of translation through ribosome binding to RNA secondary structures within the long 5' nontranslated region of the virus genome.

Since infection by poliovirus and many other picornaviruses leads to the shut off of cap-dependent translation [ 15 , 16 ], the IRES allows the virus to effectively compete for the cellular translation machinery via cap-independent mechanisms.

Finally, a cis-acting replication element or cre was identified in picornavirus genomic RNAs. Cre sequences are RNA stem-loop structures almost exclusively located within the coding region, and they are required for viral RNA replication. These elements bind viral proteins involved in RNA replication complex formation, allowing specific recognition of viral RNAs in the cytoplasm of infected cells among a myriad of poly A -containing host cellular mRNAs.

Their functions appear to be strand-specific, since the cre is required for positive-strand RNA synthesis but may not be essential for negative-strand RNA synthesis. Since then, similar types of internal recognition elements have been detected for other positive-strand RNA viruses. The complete sequence of poliovirus genomic RNA was reported in by two different groups [ 19 , 20 ]. This single ORF encodes the viral polyprotein that is ultimately cleaved into more than 15 intermediate and mature viral polypeptides.

Transfection of this clone into mammalian cells produced infectious poliovirus and, via genetic manipulation, led to new insights about the functions of viral proteins and RNA sequences and their roles in the picornavirus intracellular replication cycle [ 21 ]. These extracts contain all essential elements for poliovirus replication, including cytoplasmic membranes and components required for virion assembly [ 22 ].

Based upon X-ray crystallography studies, poliovirus and its relative, HRV, were the first animal viruses for which the three-dimensional virus structure was solved in by the groups of Hogle and Rossmann [ 24 , 25 ]. And in , Racaniello and coworkers identified CD, a member of the immunoglobulin superfamily, as the poliovirus receptor [ 26 ]. This finding was followed by the generation of mice carrying CD as a transgene, allowing studies of poliovirus infection and pathogenesis in vivo in a nonprimate model [ 27 ].

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