Picornaviruses are a family of nonenveloped RNA viruses that infect vertebrates. They contain a single-sense positive-sense RNA genome within a 30 nm icosahedral capsid.
Many picornaviruses gain entry to cells by binding to cellular receptors, initiating a process called uncoating. The structures of several of these viral particles have been determined at near-atomic resolution.
Viruses
The Picornaviridae are a diverse group of viruses that cause various diseases in humans and other mammals. These viruses are so-called “small” RNA viruses because the RNA genome is much smaller than that of most other RNA viruses. The Picornaviridae include nine currently recognized genera with more to be added as research progresses and new viruses are found. The virus species within each genus are further subclassified by serotypes, which is important to distinguish between different infections caused by the same virus.
The picornavirus RNA genome is covalently linked to the viral protein VPg at its 5′ end, which serves as an initiation primer for RNA synthesis. The 3′ end of the RNA is poly-adenylated. The genomic RNA of most picornaviruses is transcribed to mRNA in the virus-specific direction (i.e., the opposite direction from that of most cellular mRNAs).
During virion assembly, the VP0 precursor is cleaved in trans to VP2 and VP4 by the viral proteases 2Apro and 3Cpro or their proforms (3CDpro and 3Dpol). In some picornaviruses, including poliovirus and rhinovirus, a second sequence element known as the cre element is also inserted in the VP0 precursor. This element forms a cloverleaf structure that binds the cleavage products of 2Apro/3Cpro and may function to regulate synthesis of viral RNA.
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Picornavirus proteins are involved in forming an icosahedral capsid, which is a highly dynamic structure with T=3 symmetry and a diameter of about 30nm. Each capsid consists of 60 copies of each of the four different capsid proteins VP1-4, which are assembled in a relatively tight, symmetrical arrangement around a central core particle.
In humans, a number of picornaviral RNAs are associated with infections that result in clinical symptoms such as gastrointestinal upset and respiratory illness. In particular, a large number of viruses in the enterovirus genus are responsible for epidemic gastroenteritis; these include rotaviruses such as RVC and RVC, coxsackieviruses including CV-A21, EV-C104, EV-C105 and EV-D68, and echoviruses such as EV-A71 and EV-D68.
Other picornaviral RNAs are associated more specifically with the diseases of rodents, such as EMC virus, which causes encephalomyocarditis in mice and has been extensively studied as a model for multiple sclerosis in humans. Several other picornaviral RNAs have been used in experiments to generate polycistronic mRNAs or expressed proteins in a cap-independent manner using the IRES system, and the EV-A71 virus has been tested as a possible vaccine candidate.
Molecular biology
Picornaviruses are among the simplest vertebrate viruses with a single-stranded positive-sense RNA genome enclosed in an icosahedral protein capsid. Well-characterised members of the family include poliovirus (PV), human rhinovirus (HRV) and foot-and-mouth disease virus (FMDV). These small, non-enveloped viruses can enter cells via endocytosed vesicles or directly through the plasma membrane. Entry to the cytoplasm typically occurs by a receptor-mediated process in which the virus particles become incorporated into host endosomal vesicles, a process involving the recruitment of the host protein clathrin and a complex interplay between viral and host proteins.
The picornavirus RNA genome is flanked by 5′- and 3′ untranslated regions and encodes a polyprotein precursor that undergoes a series of proteolytic cleavages to generate mature virus proteins, the number of which varies between 11 and 15. In addition, most picornaviruses contain a type I internal ribosome entry site (IRES) in their 5′ UTRs to facilitate translation initiation.
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Unlike other members of the Herpesviridae, poliovirus and other members of the genus Picornaviridae do not code for a leader protein. Instead, the P2 region of the PV genome codes for a proteinase known as 2Apro or 3Cpro, which is structurally similar to other viral proteinases and reportedly binds to and cleaves transcription factors and regulators such as TATA-box binding protein, octamer-binding protein 1 and 2, cyclic AMP-responsive element binding protein and histone H3.
In contrast to enteroviruses, rhinoviruses, parechoviruses and hepatitis A virus, many of the other members of the genus Picornaviridae code for an L protein at the amino terminus of their uncleaved polyprotein precursors. These proteins are also called VPg and have been shown to interact with poliovirus polymerase-3D, allowing VPg to be uridylated and utilized as a primer for both positive- and negative-strand synthesis.
The structures of a variety of Picornaviridae viruses have been determined at close to atomic resolution by X-ray crystallography and at a lower resolution by cryo-electron microscopy. These structures reveal that the viral RNA genome is capped by an m7GpppN nucleotide residue, and that the genome has a stem structure with two polarised domains that are contacted by the 3C subdomains of the viral protein 3CD.
Pathogenesis
Picornaviruses are icosahedral viruses with single-stranded plus-sense RNA genomes. The RNA genome encodes structural proteins and nonstructural proteins (NSPs) required for viral replication and capsid assembly. The 3′ end of the RNA genome has a short stretch of polyadenine (polyA) that ranges in length from 35 to 100 nt, which is important for directing ribosome binding and translation initiation. Picornavirus mRNAs do not contain a 5′-methyl-guanine cap and instead depend on an internal ribosomal entry site (IRES) to direct ribosome assembly and transcription of viral genes.
Viruses bind to and infect cells by targeting specific cell surface receptors. Picornaviruses also use co-receptors and alternative receptors to enter cells. Detailed studies of the mechanisms of cell entry are only available for enteroviruses and rhinoviruses, while working models are being developed for other members of the family.
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Infection of cells by picornaviruses triggers cellular antiviral defense mechanisms. Viruses have evolved several strategies to interfere with these responses. Picornaviruses inhibit cellular protein secretion and alter the cellular transcriptome to repress cellular gene expression. In addition, some viruses have been shown to enter the nucleus and cleave host-cell transcription factors and regulators, which can lead to blocking of cellular gene transcription during infection.
Viral proteins have been found to bind to a variety of cellular NSPs and can interact with various subunits of the NNS. Some of these interactions are known to be important for viral replication and capsid assembly. For example, the 3A protein of PV can interact with cellular phosphorylated NNSs and bind to a polyadenine sequence in the 61 nt cis-acting replication element (CR) region of the RNA genome. This interaction may help virions initiate replication by binding to the CR site of the RNA genome and stimulating NNS phosphorylation.
Infection of cells by picornaviruses leads to the production of viral RNA and proteins that form the capsid. The 2A proteins of some picornaviruses function as proteases that separate the capsid precursor P1 from the P2 protein during synthesis. In contrast, the 2A protein of FMDV, a hepatovirus, acts as an RNA-dependent RNA polymerase and requires the 3CD pro domain to function properly. The functions of 2Cpro, which is homologous to the 2A protein of some hepatitis A viruses, are less well understood.
Serodiagnosis
Picornaviruses are nonenveloped viruses that bind to cells and cause infections in both humans and animals. They are responsible for a wide range of clinical symptoms, from mild diarrhea to encephalitis. In some cases, infection with a specific serotype causes more than one disease syndrome, and the virulence of different strains can be closely related. This variability makes it difficult to determine the etiology of disease in many cases. Therefore, laboratory tests are required to identify the virus and the serotype. These tests can also be used to distinguish between asymptomatic and symptomatic infections.
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Picornaviridae consists of five genera: Enterovirus, Hepatovirus, and Rhinovirus, which infect humans; Apthovirus (foot-and-mouth disease virus), which infects cloven-hoofed animals; and Cardiovirus, which infects rodents. Despite the close phylogenetic and genetic similarities, the genus Picornaviridae contains many antigenic differences, which may lead to the emergence of new strains that can infect different species or genera.
The genome of a picornavirus is a positive-sense, single-stranded RNA molecule 7.1-8.9 kb in size, with a poly(A) tail at the 5′ end. It encodes a large polyprotein precursor that undergoes a series of viral protease-mediated cleavage events to produce the mature proteins VP1, VP2, VP3, and VP4. These proteins form the capsid, and the remainder participate in viral replication and in the synthesis of VPg.
Viral protein 3Cpro has been shown to cleave several cellular transcription factors and regulators, including TBPI, OCT-1, CREB, and DNA polymerase III. It may play an important role in the inhibition of cellular transcription by picornaviruses. The 3Cpro protease domain contains conserved catalytic triads of cysteine, histidine, and glutamic acid residues.
The cleavage activity of the virus-encoded protein 3Cpro varies among members of the family Picornaviridae. For example, the cleavage of enteroviral 1AB, which accompanies RNA encapsidation, is catalyzed by 2A in all enteroviruses; whereas the cleavage of avihepatovirus, aphthovirus, hepatitis C virus, and Ljungan virus of the genus Parechovirus is catalyzed by 3Cpro. This protease is also capable of entering nuclei and displaying nuclear localization. The cleavage of the 3Cpro domain by host chymotrypsin-like cysteine proteases has been reported in some species.
