Poliovirus

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Poliovirus
TEM micrograph of poliovirus virions. Scale bar, 50 nm.
TEM micrograph of poliovirus virions. Scale bar (white): 50 nm
A type 3 poliovirus capsid coloured by chains
A type 3 poliovirus capsid, protein side chains coloured
Virus classification Edit this classification
(unranked): Virus
Realm: Riboviria
Kingdom: Orthornavirae
Phylum: Pisuviricota
Class: Pisoniviricetes
Order: Picornavirales
Family:
Picornaviridae
Genus: Enterovirus
Species:
Enterovirus C
Virus:
Poliovirus
Serotypes

Poliovirus, the causative agent of

Picornaviridae.[1] There are three poliovirus serotypes
: types 1, 2, and 3.

Poliovirus is composed of an

single-stranded positive-sense RNA (+ssRNA) genome that is about 7500 nucleotides long.[2] The viral particle is about 30 nm in diameter with icosahedral symmetry. Because of its short genome and its simple composition—only RNA and a nonenveloped icosahedral protein coat that encapsulates it—poliovirus is widely regarded as the simplest significant virus.[3]

Poliovirus was first isolated in 1909 by

Birkbeck College led by Rosalind Franklin,[5][6] showing the polio virus to have icosahedral symmetry.[7]

In 1981, the poliovirus genome was published by two different teams of researchers: by Vincent Racaniello and David Baltimore at MIT[8] and by Naomi Kitamura and Eckard Wimmer at Stony Brook University.[9]

The three-dimensional structure of poliovirus was determined in 1985 by

Scripps Research Institute using X-ray crystallography.[10]

Poliovirus is one of the most well-characterized viruses, and has become a useful model system for understanding the biology of

RNA viruses
.

Replication cycle

The replication cycle of poliovirus is initiated by binding to the cell surface receptor CD155 (1). The virion forms a pore in the cell membrane through which viral RNA is released into the cytoplasm (2). Translation of the viral RNA occurs by an IRES-mediated mechanism (3). The polyprotein is cleaved, yielding mature viral proteins (4). The positive-sense RNA serves as template for complementary negative-strand synthesis, producing double-stranded replicative form (RF) RNA (5). Many positive strand RNA copies are produced from the single negative strand (6). The newly synthesized positive-sense RNA molecules can serve as templates for translation of more viral proteins (7) or can be enclosed in a capsid (8), which ultimately generates progeny virions. Lysis of the infected cell results in release of infectious progeny virions (9).[11]

Poliovirus infects human cells by binding to an

immunoglobulin-like receptor, CD155 (also known as the poliovirus receptor or PVR)[12][13] on the cell surface.[14] Interaction of poliovirus and CD155 facilitates an irreversible conformational change of the viral particle necessary for viral entry.[15][16] Following attachment to the host cell membrane, entry of the viral nucleic acid was thought to occur one of two ways: via the formation of a pore in the plasma membrane through which the RNA is then "injected" into the host cell cytoplasm, or via virus uptake by receptor-mediated endocytosis.[17] Recent experimental evidence supports the latter hypothesis and suggests that poliovirus binds to CD155 and is taken up by endocytosis. Immediately after internalization of the particle, the viral RNA is released.[18]

Poliovirus is a positive-stranded RNA virus. Thus, the genome enclosed within the viral particle can be used as messenger RNA and immediately translated by the host cell. On entry, the virus hijacks the cell's translation machinery, causing inhibition of cellular protein synthesis in favor of virus-specific protein production.[19] Unlike the host cell's mRNAs, the 5' end of poliovirus RNA is extremely long—over 700 nucleotides—and highly structured. This region of the viral genome is called an internal ribosome entry site (IRES). This region consists of many secondary structures and 3 or 4 domains. Domain 3 is a self folding RNA element that contains conserved structural motifs in various stable stem loops linked by two four-way junctions. As IRES consists of many domains, these domains themselves consist of many loops that contribute to modified translation without a 5’ end cap by hijacking ribosomes. The interaction loop of domain 3 is known as GNRA tetraloop. The residues of adenosines A180 and A181 in the GUAA tetraloop form hydrogen bonds via non canonical base pairing interactions with the base pairs of the receptors C230/G242 and G231/C241, respectively.[20] Genetic mutations in this region prevent viral protein production.[21][22][23] The first IRES to be discovered was found in poliovirus RNA.[24]

Poliovirus mRNA is translated as one long

polypeptide. This polypeptide is then autocleaved by internal proteases into about 10 individual viral proteins. Not all cleavages occur with the same efficiency. Therefore, the amounts of proteins produced by the polypeptide cleavage vary: for example, smaller amounts of 3Dpol are produced than those of capsid proteins, VP1–4.[25][26] These individual viral proteins are:[3][27]

The genomic structure of poliovirus type 1[11]
  • 3Dpol, an
    RNA dependent RNA polymerase
    whose function is to make multiple copies of the viral RNA genome
  • 2Apro and 3Cpro/3CDpro, proteases which cleave the viral polypeptide
  • VPg (3B), a small protein that binds viral RNA and is necessary for synthesis of viral positive and negative strand RNA
  • 2BC, 2B, 2C (an ATPase)[28], 3AB, 3A, 3B proteins which comprise the protein complex needed for virus replication.
  • VP0, which is further cleaved into VP2 and VP4, VP1 and VP3, proteins of the viral capsid

After translation, transcription and genome replication which involve a single process, synthesis of (+) RNA) is realized. For the infecting (+)RNA to be replicated, multiple copies of (−)RNA must be transcribed and then used as templates for (+)RNA synthesis. Replicative intermediates (RIs), which are an association of RNA molecules consisting of a template RNA and several growing RNAs of varying length, are seen in both the replication complexes for (−)RNAs and (+)RNAs. For synthesis of each negative-strand and positive-strand RNAs, VPg protein in the poliovirus works as a primer. RNA-dependent RNA polymerase of the poliovirus adds two uracil nucleotides (UU) to VPg protein utilizing the poly(A) tail at the 3′-end of the +ssRNA genome as a pattern for synthesis of the negative-strand antigenomic RNA. To initiate this −ssRNA synthesis, the tyrosine hydroxyl of VPg is needed. But for the initiation of positive strand RNA synthesis, CRE-dependent VPg uridylylation is needed. Which means that VPg is once more utilized as a primer however this time it adds the two uridine triphosphates using a cis-acting replication element (CRE) as a template.[29][30]

The CRE of poliovirus is identified as an unachieved base-paired stem and a final loop consisting of 61 nt. The CRE is found in enteroviruses. It is a highly preserved secondary RNA structural element and bedded in the genome's polyprotein-coding region. The complex can be translocated to the 5' region of the genome that have no coding activity, at least 3.7-kb distant from the initial location. This process can occurs without negatively influencing activity. CRE copies do not influence replication negatively. Uridylylation process of VPg that takes place at CRE needs the presence of 3CDpro that is an RNA binding protein. It is attached to the CRE directly and specifically. Because of its presence VPg can bind the CRE properly and primary production proceeds without problems.[31]

Some of the (+) RNA molecules are used as templates for further (−) RNA synthesis, some function as mRNA, and some are destined to be the genomes of progeny virions.[25]

In the assembly of new virus particles (i.e. the packaging of progeny genome into a procapsid which can survive outside the host cell), including, respectively:[32]

  • Five copies each of VP0, VP3, and VP1 whose N termini and VP4 form interior surface of capsid, assemble into a 'pentamer' and 12 pentamers form a procapsid. (The outer surface of capsid is consisting of VP1, VP2, VP3; C termini of VP1 and VP3 form the canyons which around each of the vertices; around this time, the 60 copies of VP0 are cleaved into VP4 and VP2.)
  • Each procapsid acquires a copy of the virus genome, with VPg still attached at the 5' end.

Fully assembled poliovirus leaves the confines of its host cell by

virions.[34]

Drake demonstrated that poliovirus is able to undergo multiplicity reactivation.

(+)ssRNA templates during negative strand synthesis. Recombination in RNA viruses appears to be an adaptive mechanism for repairing genome damage.[37][38]

Origin and serotypes

Poliovirus is structurally similar to other human enteroviruses (

intercellular adhesion molecule-1 (ICAM-1), used by C-cluster Coxsackie A viruses, to CD155
; leading to a change in pathogenicity, and allowing the virus to infect nervous tissue.

The mutation rate in the virus is relatively high even for an RNA virus with a synonymous substitution rate of 1.0 x 10−2 substitutions/site/year and non synonymous substitution rate of 3.0 x 10−4 substitutions/site/year.

Codon use is not random with codons ending in adenosine being favoured and those ending in cytosine or guanine being avoided. Codon use differs between the three genotypes and appears to be driven by mutation rather than selection.[42]

The three

infectious.[4] As of March 2020, wild PV-1 is highly localized to regions in Pakistan and Afghanistan. Certification of the eradication of indigenous transmission occurred in September 2015 for wild PV-2, after last being detected in 1999,[43] and in October 2019 for wild PV-3, after last being detected in 2012.[44]

Specific strains of each serotype are used to prepare

Passaging the virus strains in monkey kidney epithelial cells introduces mutations in the viral IRES, and hinders (or attenuates) the ability of the virus to infect nervous tissue.[34]

Polioviruses were formerly classified as a distinct species belonging to the genus Enterovirus in the family Picornaviridae. In 2008, the Poliovirus species was eliminated and the three serotypes were assigned to the species Human enterovirus C (later renamed Enterovirus C), in the genus Enterovirus in the family Picornaviridae. The type species of the genus Enterovirus was changed from Poliovirus to (Human) Enterovirus C.[45]

Pathogenesis

Main article: Polio
Electron micrograph
of poliovirus

The primary determinant of infection for any virus is its ability to enter a cell and produce additional infectious particles. The presence of CD155 is thought to define the animals and tissues that can be infected by poliovirus. CD155 is found (outside of laboratories) only on the cells of humans, higher

chimpanzees and Old World monkeys can be experimentally infected).[46]

The CD155 gene appears to have been subject to

positive selection.[47]
The protein has several domains of which domain D1 contains the polio virus binding site. Within this domain, 37 amino acids are responsible for binding the virus.

Poliovirus is an

brain stem, or motor cortex, resulting in the selective destruction of motor neurons leading to temporary or permanent paralysis. This is a very rare event in babies, who still have anti-poliovirus antibodies acquired from their mothers.[50] In rare cases, paralytic poliomyelitis leads to respiratory arrest and death. In cases of paralytic disease, muscle pain and spasms are frequently observed prior to onset of weakness and paralysis. Paralysis typically persists from days to weeks prior to recovery.[51]

In many respects, the

retrograde axonal transport.[53][54][55] A third hypothesis is that the virus is imported into the CNS via infected monocytes or macrophages.[11]

Poliomyelitis is a disease of the central nervous system. However, CD155 is believed to be present on the surface of most or all human cells. Therefore, receptor expression does not explain why poliovirus preferentially infects certain tissues. This suggests that tissue tropism is determined after cellular infection. Recent work has suggested that the type I interferon response (specifically that of interferon alpha and beta) is an important factor that defines which types of cells support poliovirus replication.[56] In mice expressing CD155 (through genetic engineering) but lacking the type I interferon receptor, poliovirus not only replicates in an expanded repertoire of tissue types, but these mice are also able to be infected orally with the virus.[57]

Immune system avoidance

CD155 molecules complexed with a poliovirus particle. Reconstructed image from cryo-electron microscopy.

Poliovirus uses two key mechanisms to evade the

acidic conditions of the stomach, allowing the virus to infect the host and spread throughout the body via the lymphatic system.[3] Second, because it can replicate very quickly, the virus overwhelms the host organs before an immune response can be mounted.[58] If detail is given at the attachment phase; poliovirus with canyons on the virion surface have virus attachment sites located in pockets at the canyon bases. The canyons are too narrow for access by antibodies, so the virus attachment sites are protected from the host's immune surveillance, while the remainder of the virion surface can mutate to avoid the host's immune response.[59]

Individuals who are exposed to poliovirus, either through infection or by

IgM antibodies against poliovirus can prevent the spread of the virus to motor neurons of the central nervous system.[34] Infection with one serotype of poliovirus does not provide immunity against the other serotypes; however, second attacks within the same individual are extremely rare.[60]

PVR transgenic mouse

Although humans are the only known natural hosts of poliovirus, monkeys can be experimentally infected and they have long been used to study poliovirus. In 1990–91, a small animal model of poliomyelitis was developed by two laboratories. Mice were engineered to express a human receptor to poliovirus (hPVR).[61][62]

Unlike normal mice,

intramuscularly, and when injected directly into the spinal cord or the brain.[63] Upon infection, TgPVR mice show signs of paralysis that resemble those of poliomyelitis in humans and monkeys, and the central nervous systems of paralyzed mice are histocytochemically similar to those of humans and monkeys. This mouse model of human poliovirus infection has proven to be an invaluable tool in understanding poliovirus biology and pathogenicity.[64]

Three distinct types of TgPVR mice have been well studied:[65]

Recently, a fourth TgPVR mouse model was developed. These "cPVR" mice carry hPVR

bulbar form of polio after intranasal inoculation.[66]

The development of the TgPVR mouse has had a profound effect on oral

poliovirus vaccine (OPV) production. Previously, monitoring the safety of OPV had to be performed using monkeys, because only primates are susceptible to the virus. In 1999, the World Health Organization approved the use of the TgPVR mouse as an alternative method of assessing the effectiveness of the vaccine against poliovirus type-3. In 2000, the mouse model was approved for tests of vaccines against type-1 and type-2 poliovirus.[67]

Cloning and synthesis

Model of poliovirus-binding CD155 (shown in purple)

In 1981, Racaniello and Baltimore used recombinant DNA technology to generate the first infectious clone of an animal RNA virus, poliovirus. DNA encoding the RNA genome of poliovirus was introduced into cultured mammalian cells and infectious poliovirus was produced.[68] Creation of the infectious clone propelled understanding of poliovirus biology, and has become a standard technology used to study many other viruses.

In 2002,

gene synthesis company. Nineteen markers were incorporated into the synthesized DNA, so that it could be distinguished from natural poliovirus. Enzymes were used to convert the DNA back into RNA, its natural state. Other enzymes were then used to translate the RNA into a polypeptide, producing functional viral particle. This whole painstaking process took two years. The newly minted synthetic virus was injected into PVR transgenic mice, to determine if the synthetic version was able to cause disease. The synthetic virus was able to replicate, infect, and cause paralysis or death in mice. However, the synthetic version was between 1,000 and 10,000 times weaker than the original virus, probably due to one of the added markers.[70]

Modification for therapies

A modification of the poliovirus, called PVSRIPO, was tested in early clinical trials as a possible treatment for cancer.[71][needs update]

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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Poliovirus&oldid=1192024000"