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64-471: VPg was first described in initial investigations of poliovirus RNA as a protein covalently attached to the 5' end of the genome. and later seen in caliciviruses. VPg must undergo post-translational uridylylation before it can act as a primer for replication. 3Dpol (the RdRp) is able to synthesize VPg-pUpU-OH by using a polyA sequence within a stem-loop structure ( cis-acting replication element ) of 2C-ATPase as

128-454: 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. Genetic mutations in this region prevent viral protein production. The first IRES to be discovered

192-404: A distinct secondary or even tertiary structure , but similar structural features at the levels of either primary or secondary structure that are common to all IRES segments have not been reported to date. Use of IRES sequences in molecular biology soon became common as a tool for expressing multiple genes from a single transcriptional unit in a genetic vector . In such vectors, translation of

256-486: A human pathogen, and does not naturally infect any other species (although chimpanzees and Old World monkeys can be experimentally infected). The CD155 gene appears to have been subject to positive selection . 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 enterovirus . Infection occurs via

320-455: A matter of dispute. A number of these cellular IRES elements are located within mRNAs encoding proteins involved in stress survival , and other processes critical to survival. As of September 2009, there are 60 animal and 8 plant viruses reported to contain IRES elements and 115 mRNA sequences containing them as well. IRESs are often used by viruses as a means to ensure that viral translation

384-564: A neurovirulent form causing paralytic polio. Researchers have developed a poliovirus type 2 vaccine strain that is genetically more stable and less likely to regain virulence than the original Sabin2 strain, with three key genetic modifications. The vaccine derived from this strain, novel oral polio virus type 2 (nOPV2), was granted emergency licencing in 2021, and subsequently full licensure in December 2023. Genetically stabilsed vaccines targeting poliovirus types 1 and 3 are in development, with

448-621: A procapsid which can survive outside the host cell), including, respectively: Fully assembled poliovirus leaves the confines of its host cell by lysis 4 to 6 hours following initiation of infection in cultured mammalian cells. The mechanism of viral release from the cell is unclear, but each dying cell can release up to 10,000 polio virions . Drake demonstrated that poliovirus is able to undergo multiplicity reactivation. That is, when polioviruses were irradiated with UV light and allowed to undergo multiple infections of host cells, viable progeny could be formed even at UV doses that inactivated

512-494: A result of a change in cellular receptor specificity from 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 nerve tissue. The mutation rate in the virus is relatively high even for an RNA virus, with a synonymous substitution rate of 1.0 × 10 substitutions/site/year and a non-synonymous substitution rate of 3.0 × 10 substitutions/site/year. Base distribution within

576-485: 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

640-976: A slightly different capsid protein. Capsid proteins define cellular receptor specificity and virus antigenicity. PV-1 is the most common form encountered in nature, but all three forms are extremely infectious . As of March 2020, wild PV-1 is highly localized to regions in Pakistan and Afghanistan. Certification of the eradication of indigenous transmission of wild PV-2 occurred in September 2015, after last being detected in 1999, and in October 2019 for wild PV-3 after last being detected in 2012. However, circulating vaccine-derived poliovirus (variant poliovirus, cVDPV) of all three serotypes continues to circulate and cause paralysis, having been detected in 32 countries in 2023. Specific strains of each serotype are used to prepare vaccines against polio . Inactive polio vaccine

704-474: A small animal model of poliomyelitis was developed by two laboratories. Mice were engineered to express a human receptor to poliovirus (hPVR). Unlike normal mice, transgenic poliovirus receptor (TgPVR) mice are susceptible to poliovirus injected intravenously or intramuscularly , and when injected directly into the spinal cord or the brain . Upon infection, TgPVR mice show signs of paralysis that resemble those of poliomyelitis in humans and monkeys, and

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768-467: A standard technology used to study many other viruses. In 2002, Eckard Wimmer 's group at Stony Brook University succeeded in synthesizing poliovirus from its chemical code, producing the world's first synthetic virus. Scientists first converted poliovirus's published RNA sequence, 7741 bases long, into a DNA sequence, as DNA was easier to synthesize. Short fragments of this DNA sequence were obtained by mail-order, and assembled. The complete viral genome

832-426: A template. Furthermore, a 5' terminal cloverleaf is required in cis to form the 3Dpol preinitiation RNA replication complex involved in uridylylating VPg. 3CDpro (a protease ) cleaves VPg from membrane-bound 3AB. Studies that used proteinase K to cleave VPg from the viral genome discovered that calicivirus vesicular exanthema virus lacking VPg is no longer infectious whereas poliovirus retains infectivity even with

896-432: Is a very rare event in babies, who still have anti-poliovirus antibodies acquired from their mothers. 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. In many respects, the neurological phase of infection

960-488: Is accomplished by vaccination . There are two kinds of polio vaccine —oral polio vaccine (OPV), which uses weakened poliovirus , and inactivated polio vaccine (IPV), which is injected. OPV is less expensive and easier to administer, and can spread immunity beyond the person vaccinated, creating contact immunity . It has been the predominant vaccine used. However, under conditions of long-term vaccine virus circulation in under-vaccinated populations, mutations can reactivate

1024-452: Is active when host translation is inhibited. These mechanisms of host translation inhibition are varied, and can be initiated by both virus and host, depending on the type of virus. However, in the case of most picornaviruses, such as poliovirus , this is accomplished by viral proteolytic cleavage of eIF4G so that it cannot interact with the 5'cap binding protein eIF4E . Interaction between these two eukaryotic initiation factors (eIFs) of

1088-436: Is an RNA element that allows for translation initiation in a cap-independent manner, as part of the greater process of protein synthesis . Initiation of eukaryotic translation nearly always occurs at and is dependent on the 5' cap of mRNA molecules, where the translation initiation complex forms and ribosomes engage the mRNA. IRES elements, however allow ribosomes to engage the mRNA and begin translation independently of

1152-456: Is attached to the CRE directly and specifically. Because of its presence VPg can bind the CRE properly and primary production proceeds without problems. 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. In the assembly of new virus particles (i.e. the packaging of progeny genome into

1216-418: Is composed of an RNA genome and a protein capsid . The genome is a single-stranded positive-sense RNA (+ssRNA) genome that is about 7500 nucleotides long. The viral particle is about 30 nm in diameter with icosahedral symmetry . Because of its short genome and its simple composition—only a strand of RNA and a nonenveloped icosahedral protein coat encapsulating it—poliovirus is widely regarded as

1280-401: 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. 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

1344-408: Is prepared by formalin inactivation of three wild, virulent reference strains: Mahoney or Brunenders (PV-1), MEF-1/Lansing (PV-2), and Saukett/Leon (PV-3). Oral polio vaccine contains live attenuated (weakened) strains of the three serotypes of poliovirus. Passaging the virus strains in monkey kidney epithelial cells introduces mutations in the viral IRES, and hinders (or attenuates) the ability of

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1408-409: Is still under investigation. Testing of sequences for potential IRES function has generally relied on the use of bicistronic reporter assays . In these tests, a candidate IRES segment is introduced into a plasmid between two cistrons encoding two different reporter proteins. A promoter upstream of the first cistron drives transcription of both cistrons in a single mRNA. Cells are transfected with

1472-489: Is structurally similar to other human enteroviruses ( coxsackieviruses , echoviruses , and rhinoviruses ), which also use immunoglobulin-like molecules to recognize and enter host cells. Phylogenetic analysis of the RNA and protein sequences of poliovirus suggests that it may have evolved from a C-cluster Coxsackie A virus ancestor through a mutation in the capsid. The distinct speciation of poliovirus probably occurred as

1536-451: Is taken up by endocytosis. Immediately after internalization of the particle, the viral RNA is released. 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. Unlike

1600-878: Is the aim of a multinational public health effort begun in 1988, led by the World Health Organization (WHO), the United Nations Children's Fund (UNICEF) and the Rotary Foundation . These organizations, along with the U.S. Centers for Disease Control and Prevention (CDC) and The Gates Foundation , have spearheaded the campaign through the Global Polio Eradication Initiative (GPEI). Successful eradication of infectious diseases has been achieved twice before, with smallpox in humans and rinderpest in ruminants. Prevention of disease spread

1664-525: Is thought to be an accidental diversion of the normal gastrointestinal infection. The mechanisms by which poliovirus enters the CNS are poorly understood. Three nonmutually exclusive hypotheses have been suggested to explain its entry. All theories require primary viremia. The first hypothesis predicts that virions pass directly from the blood into the central nervous system by crossing the blood–brain barrier independent of CD155. A second hypothesis suggests that

1728-414: The eIF4F complex is necessary for 40S ribosomal subunit recruitment to the 5' end of mRNAs, which is further thought to occur with mRNA 5'cap to 3' poly(A) tail loop formation. The virus may even use partially-cleaved eIF4G to aid in initiation of IRES-mediated translation. Cells may also use IRESs to increase translation of certain proteins during mitosis and programmed cell death . In mitosis,

1792-457: The eukaryotic initiation factors (eIFs) eIF2 , eIF3 , eIF5 , and eIF5B , but do not require the factors eIF1 , eIF1A , and the eIF4F complex. In contrast, picornavirus IRESs do not bind the 40S subunit directly, but are recruited instead through the eIF4G -binding site. Many viral IRES (and cellular IRES) require additional proteins to mediate their function, known as IRES trans -acting factors (ITAFs). The role of ITAFs in IRES function

1856-525: The fecal–oral route , meaning that one ingests the virus and viral replication occurs in the gastrointestinal tract . Virus is shed in the feces of infected individuals. In 95% of cases only a primary, transient presence of viremia (virus in the bloodstream) occurs, and the poliovirus infection is asymptomatic . In about 5% of cases, the virus spreads and replicates in other sites such as brown fat , reticuloendothelial tissue, and muscle . The sustained viral replication causes secondary viremia and leads to

1920-434: The 5' cap. IRES sequences were first discovered in 1988 in the poliovirus (PV) and encephalomyocarditis virus (EMCV) RNA genomes in the laboratories of Nahum Sonenberg and Eckard Wimmer , respectively. They are described as distinct regions of RNA molecules that are able to recruit the eukaryotic ribosome to the mRNA. This process is also known as cap-independent translation. It has been shown that IRES elements have

1984-483: The absence of VPg. Because VPg sits at the 5' end of the genome, similar to eukaryotic 5' mRNA caps , several experiments were performed to explore its function in translation. Poliovirus utilizes an internal ribosome entry site (IRES) instead of a cap for translation initiation, abrogating the requirement of VPg in initial infection whereas studies with feline calicivirus confirmed that the VPg protein interacts directly with

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2048-531: The apparent IRES function observed in bicistronic reporter tests. A promoter or splice acceptor within a test sequence can result in the production of monocistronic mRNA from which the downstream cistron is translated by conventional cap-dependent, rather than IRES-mediated, initiation. A later study that documented a variety of unexpected aberrant mRNA species arising from reporter plasmids revealed that splice acceptor sites can mimic both IRES and promoter elements in tests employing such plasmids, further highlighting

2112-491: The cap-binding protein of the ribosome , eIF4E, and that this interaction is essential for viral translation. Principles of Virology by S.J. Flint, L.W. Enquist, V.R. Racaniello, A.M. Skalka ( ISBN   1-55581-259-7 ) Poliovirus Poliovirus , the causative agent of polio (also known as poliomyelitis), is a serotype of the species Enterovirus C , in the family of Picornaviridae . There are three poliovirus serotypes , numbered 1, 2, and 3. Poliovirus

2176-406: The cell dephosphorylates eIF4E so that it has little affinity for the 5'cap . As a result, the 40S ribosomal subunit , and the translational machinery is diverted to IRES within the mRNA. Many proteins involved in mitosis are encoded by IRES mRNA. In programmed cell death, cleavage of eIF-4G, such as performed by viruses, decreases translation. Lack of essential proteins contributes to the death of

2240-432: The cell, as does translation of IRES mRNA sequences coding proteins involved in controlling cell death. To date, the mechanism of viral IRES function is better characterized than the mechanism of cellular IRES function, which is still a matter of debate. HCV -like IRESs directly bind the 40S ribosomal subunit to position their initiator codons are located in ribosomal P-site without mRNA scanning. These IRESs still use

2304-497: 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. Three distinct types of TgPVR mice have been well studied: The development of the TgPVR mouse has had a profound effect on oral poliovirus vaccine (OPV) production. Previously, monitoring

2368-432: The development of minor symptoms such as fever, headache, and sore throat. Paralytic poliomyelitis occurs in less than 1% of poliovirus infections. Paralytic disease occurs when the virus enters the central nervous system (CNS) and replicates in motor neurons within the spinal cord , brain stem , or motor cortex , resulting in the selective destruction of motor neurons leading to temporary or permanent paralysis . This

2432-570: The first cistron is initiated at the 5' cap, and translation of any downstream cistron is enabled by an IRES element appended at its 5' end. IRES elements are most commonly found in the 5' untranslated region , but may also occur elsewhere in mRNAs. The mRNA of viruses of the Dicistroviridae family possess two open reading frames (ORFs), and translation of each is directed by a distinct IRES. It has also been suggested that some mammalian cellular mRNAs also have IRESs, although this has been

2496-411: The genome is not random; adenosine is less common than expected at the 5' end and higher at the 3' end. Codon use is not random; codons ending in adenosine are favoured, and those ending in cytosine or guanine are avoided. Codon use differs between the three genotypes, and appears to be driven by mutation rather than selection. The three serotypes of poliovirus, PV-1, PV-2, and PV-3, each have

2560-416: 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 3CD that is an RNA binding protein. It

2624-463: The genus Enterovirus was changed from Poliovirus to (Human) Enterovirus C . 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 primates , and Old World monkeys . Poliovirus is, however, strictly

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2688-547: 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

2752-408: The host's immune response. Individuals who are exposed to poliovirus, either through infection or by immunization with polio vaccine , develop immunity . In immune individuals, antibodies against poliovirus are present in the tonsils and gastrointestinal tract (specifically IgA antibodies) and are able to block poliovirus replication; IgG and IgM antibodies against poliovirus can prevent

2816-731: The intention that these will eventually completely replace the Sabin vaccines. Poliovirus was first isolated in 1909 by Karl Landsteiner and Erwin Popper . The structure of the virus was first elucidated in 1958 using X-ray diffraction by a team at Birkbeck College led by Rosalind Franklin , showing the polio virus to have icosahedral symmetry. In 1981, the poliovirus genome was published by two different teams of researchers: by Vincent Racaniello and David Baltimore at MIT and by Naomi Kitamura and Eckard Wimmer at Stony Brook University . The three-dimensional structure of poliovirus

2880-425: The need for caution in the interpretation of reporter assay results in the absence of careful RNA analysis. IRES sequences are often used in molecular biology to co-express multiple genes under the control of the same promoter, thereby mimicking a polycistronic mRNA. Within the past decades, IRES sequences have been used to develop hundreds of genetically modified rodent animal models. The advantage of this technique

2944-667: The plasmid and assays are subsequently performed to quantitate expression of the two reporters in the cells. An increase in the ratio of expression of the downstream reporter relative to the upstream reporter is taken as evidence for IRES activity in the test sequence. However, without characterization of the mRNA species produced from such plasmids, other explanations for the increase in this ratio cannot be ruled out. For example, there are multiple known cases of suspected IRES elements that were later reported as having promoter function. Unexpected splicing activity within several reported IRES elements have also been shown to be responsible for

3008-421: 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

3072-432: 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. A modification of the poliovirus, called PVSRIPO ,

3136-427: The simplest significant virus. Poliovirus is one of the most well-characterized viruses, and has become a useful model system for understanding the biology of RNA viruses . Poliovirus infects human cells by binding to an immunoglobulin -like receptor, CD155 (also known as the poliovirus receptor or PVR) on the cell surface. Interaction of poliovirus and CD155 facilitates an irreversible conformational change of

3200-404: The spread of the virus to motor neurons of the central nervous system. Infection with one serotype of poliovirus does not provide immunity against the other serotypes; however, second attacks within the same individual are extremely rare. Polio eradication , the goal of permanent global cessation of circulation of the poliovirus and hence elimination of the poliomyelitis (polio) it causes,

3264-488: 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. In mice expressing CD155 (through genetic engineering) but lacking

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3328-486: The three strains of WPV, the last recorded wild case caused by type   2 (WPV2) was in 1999, and WPV2 was declared eradicated in 2015. Type   3 (WPV3) is last known to have caused polio in 2012, and was declared eradicated in 2019. All wild-virus cases since that date have been due to type   1 (WPV1). 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,

3392-460: 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. Poliovirus has two key mechanisms to evade the immune system . First, it can survive the highly acidic conditions of the stomach, allowing ingested viruses to infect the host and spread throughout the body via the lymphatic system . Second, because it can replicate very quickly,

3456-458: The viral particle necessary for viral entry. 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 . Recent experimental evidence supports the latter hypothesis and suggests that poliovirus binds to CD155 and

3520-412: The virions are transported from peripheral tissues that have been bathed in the viremic blood, for example muscle tissue, to the spinal cord through nerve pathways via retrograde axonal transport . A third hypothesis is that the virus is imported into the CNS via infected monocytes or macrophages . Poliomyelitis is a disease of the central nervous system. However, CD155 is believed to be present on

3584-538: The virus in single infections. Poliovirus can undergo genetic recombination when at least two viral genomes are present in the same host cell. Kirkegaard and Baltimore presented evidence that RNA-dependent RNA polymerase (RdRP) catalyzes recombination by a copy choice mechanism in which the RdRP switches between (+)ssRNA templates during negative strand synthesis. Recombination in RNA viruses appears to be an adaptive mechanism for repairing genome damage. Poliovirus

3648-437: The virus overwhelms the host's organs before an immune response can be mounted. 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

3712-411: The virus to infect nerve tissue. Polioviruses were formerly classified as a distinct species belonging to the genus Enterovirus in the family Picornaviridae . In 2008, Poliovirus ceased to be recognized as a species, 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

3776-523: The virus to produce a polio-inducing strain, while OPV can also, in rare circumstances, induce polio or persistent asymptomatic infection in vaccinated individuals, particularly those who are immunodeficient . IPV, being inactivated, does not carry these risks, but does not induce contact immunity. IPV is more costly and the logistics of its delivery are more challenging. Nigeria is the latest country to have officially stopped endemic transmission of wild poliovirus, with its last reported case in 2016. Of

3840-469: Was determined in 1985 by James Hogle at Scripps Research Institute using X-ray crystallography. 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. Creation of the infectious clone propelled understanding of poliovirus biology, and has become

3904-517: Was found in poliovirus RNA. 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 3D are produced than those of capsid proteins, VP1–4. These individual viral proteins are: After translation, transcription and genome replication which involve

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3968-428: 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. Internal ribosome entry site An internal ribosome entry site , abbreviated IRES ,

4032-532: Was tested in early clinical trials as a possible treatment for cancer. As of September 2022 , a number of clinical trials are under way. A drawback of the attenuated virus used in the Sabin oral polio vaccine is its potential to cause vaccine-associated paralytic poliomyelitis (VAPP) in approximately one individual per every 2.7   million doses administered. In addition, the live virus can also circulate in under-vaccinated populations (circulating vaccine-derived poliovirus, cVDPV) and over time can revert to

4096-480: Was then assembled by a 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

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