• 3D polymerase
• innate immunity
• interactions
• nuclear localization signal
• picornavirus
• virus replication

• Humans
• Virus Replication/genetics
• Picornaviridae Infections
• Picornaviridae/genetics
• Viral Proteins/genetics
• RNA, Viral/genetics

The phosphatidylinositol-4 kinase IIIβ (PI4KB)/oxysterol-binding protein (OSBP) family I pathway serves as an essential host pathway for the formation of viral replication complex for viral plus-strand RNA synthesis; however, poliovirus (PV) could evolve toward substantial independence from this host pathway with four mutations. Recessive epistasis of the two mutations (3A-R54W and 2B-F17L) is essential for viral RNA replication. Quantitative analysis of effects of the other two mutations (2B-Q20H and 2C-M187V) on each step of infection reveals functional couplings between viral replication, growth, and spread conferred by the 2B-Q20H mutation, while no enhancing effect was conferred by the 2C-M187V mutation. The effects of the 2B-Q20H mutation occur only via another recessive epistasis between the 3A-R54W/2B-F17L mutations. These mutations confer enhanced replication in PI4KB/OSBP-independent infection concomitantly with an increased ratio of viral plus-strand RNA to the minus-strand RNA. This work reveals the essential roles of the functional coupling and high-order, multi-tiered recessive epistasis in viral evolution toward independence from an obligatory host pathway.

IMPORTANCE Each virus has a different strategy for its replication, which requires different host factors. Enterovirus, a model RNA virus, requires host factors PI4KB and OSBP, which form an obligatory functional axis to support viral replication. In an experimental evolution system in vitro, virus mutants that do not depend on these host factors could arise only with four mutations. The two mutations (3A-R54W and 2B-F17L) are required for the replication but are not sufficient to support efficient infection. Another mutation (2B-Q20H) is essential for efficient spread of the virus. The order of introduction of the mutations in the viral genome is essential (known as “epistasis”), and functional couplings of infection steps (i.e., viral replication, growth, and spread) have substantial roles to show the effects of the 2B-Q20H mutation. These observations would provide novel insights into an evolutionary pathway of the virus to require host factors for infection.

• OSBP
• PI4KB
• enterovirus
• epistasis
• evolution
• evolutionary biology
• resistance
• virus
• virus-host interactions

• EV-D111
• EV-D120
• EV-D68
• EV-D70
• EV-D94
• Enterovirus
• Enterovirus D
• Picornavirus

• 310030_184777 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
• 812673 Horizon 2020

Picornaviruses are a diverse and major cause of human disease, and their genomes replicate with intracellular membranes. The functionality of these replication organelles depends on the activities of both viral nonstructural proteins and co-opted host proteins. The mechanism by which viral-host interactions generate viral replication organelles and regulate viral RNA synthesis is unclear. To elucidate this mechanism, enterovirus A71 (EV-A71) was used here as a virus model to investigate how these replication organelles are formed and to identify the cellular components that are critical in this process. An immunoprecipitation assay was combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to identify 172 cellular proteins and four viral proteins associating with viral 3A protein. Secretory carrier membrane protein 3 (SCAMP3) was one of the host proteins we selected for further investigation. Here, we demonstrate by immunoprecipitation assay that SCAMP3 associates with 3A protein and colocalizes with 3A protein during virus infection. SCAMP3 knockdown or knockout in infected cells decreases synthesis of EV-A71 viral RNA, viral proteins, and viral growth. Furthermore, the viral 3A protein associates with SCAMP3 and phosphatidylinositol-4-kinase type III β (PI4KIIIβ) as shown by immunoprecipitation assay and colocalizes to the replication complex. Upon infection of cells with a SCAMP3 knockout construct, PI4KIIIβ and phosphatidylinositol-4-phosphate (PI4P) colocalization with EV-A71 3A protein decreases; viral RNA synthesis also decreases. SCAMP3 is also involved in the extracellular signal-regulated kinase (ERK) signaling pathway to regulate viral replication. The 3A and SCAMP3 interaction is also important for the replication of coxsackievirus B3 (CVB3). SCAMP3 also associates with 3A protein of CVB3 and enhances viral replication but does not regulate dengue virus 2 (DENV2) replication. Taken together, the results suggest that enterovirus 3A protein, SCAMP3, PI4KIIIβ, and PI4P form a replication complex and positively regulate enterovirus replication.

IMPORTANCE Virus-host interaction plays an important role in viral replication. 3A protein of enterovirus A71 (EV-A71) recruits other viral and host factors to form a replication complex, which is important for viral replication. In this investigation, we utilized immunoprecipitation combined with proteomics approaches to identify 3A-interacting factors. Our results demonstrate that secretory carrier membrane protein 3 (SCAMP3) is a novel host factor that associates with enterovirus 3A protein, phosphatidylinositol-4-kinase type III β (PI4KIIIβ), and phosphatidylinositol-4-phosphate (PI4P) to form a replication complex and positively regulates viral replication. SCAMP3 is also involved in the extracellular signal-regulated kinase (ERK) signaling pathway to regulate viral replication.

• 3A protein
• PI4KIIIβ
• PI4P
• SCAMP3
• enterovirus
• replication complex

Picornaviruses are comprised of a positive-sense RNA genome surrounded by a protein shell (or capsid). They are ubiquitous in vertebrates and cause a wide range of important human and animal diseases. The genome encodes a single large polyprotein that is processed to structural (capsid) and non-structural proteins. The non-structural proteins have key functions within the viral replication complex. Some, such as 3D^pol (the RNA dependent RNA polymerase) have conserved functions and participate directly in replicating the viral genome, whereas others, such as 3A, have accessory roles. The 3A proteins are highly divergent across the Picornaviridae and have specific roles both within and outside of the replication complex, which differ between the different genera. These roles include subverting host proteins to generate replication organelles and inhibition of cellular functions (such as protein secretion) to influence virus replication efficiency and the host response to infection. In addition, 3A proteins are associated with the determination of host range. However, recent observations have challenged some of the roles assigned to 3A and suggest that other viral proteins may carry them out. In this review, we revisit the roles of 3A in the picornavirus life cycle. The 3AB precursor and mature 3A have distinct functions during viral replication and, therefore, we have also included discussion of some of the roles assigned to 3AB.

• RNA replication
• lipid droplets
• membrane interactions
• phosphatidylinositol 4-kinase
• protein interactions
• protein trafficking
• replication organelles
• virus host-range
• virus replication

• Genome, Viral
• Humans
• Picornaviridae/chemistry
• Picornaviridae/classification
• Picornaviridae/genetics
• Picornaviridae/physiology
• Protein Transport
• RNA, Viral/genetics
• Viral Proteins/classification
• Viral Proteins/genetics
• Viral Proteins/metabolism
• Virus Replication/physiology

Bovine viral diarrhea virus (BVDV) is a cause of substantial economic loss to the cattle industry worldwide, and there are currently no effective treatment or preventive measures. Bovine enterovirus (BEV) has a broad host range with low virulence and is a good candidate as a viral vaccine vector. In this study, we explored new insertion sites for the expression of exogenous genes in BEV, and developed a recombinant infectious cDNA clone for BEV BJ101 strain expressing BVDV E0 protein.

A recognition site for the viral proteinase 3C^pro was inserted in the GpBSK-BEV plasmid at the 2C/3A junction by overlapping PCR. Subsequently, the optimized full-length BVDV E0 gene was inserted to obtain the recombinant infectious plasmid GpBSK-BEV-E0. The rescued recombinant virus was obtained by transfection with linearized plasmid. Expression of BVDV E0 in the recombinant virus was confirmed by PCR, western blotting, and immunofluorescence analysis, and the genetic stability was tested in MDBK cells over 10 passages. We further tested the ability of the recombinant virus to induce an antibody response in mice infected with BVDV and immunized them with the recombinant virus and parental strain.

The rescued recombinant virus rBEV-E0 was identified and confirmed by western blot and indirect immunofluorescence. The sequencing results showed that the recombinant virus remained stable for 10 passages without genetic changes. There was also no significant difference in growth dynamics and plaque morphology between the recombinant virus and parental virus. Mice infected with both recombinant and parental viruses produced antibodies against BEV VP1, while the recombinant virus also induced antibodies against BVDV E0.

A new insertion site in the BEV vector can be used for the prevention and control of both BEV and BVDV, providing a useful tool for future research on the development of viral vector vaccines.

• 2C/3A junction
• Bovine enterovirus
• Bovine viral diarrhea virus
• E0 gene
• Viral vector

• cardiovirulence
• coxsackievirus B2
• myocarditis
• pathogenesis

• E6AP/UBE3A
• Encephalomyocarditis virus
• Picornavirus
• Virus replication
• ubiquitin-protein ligase

• ACBD3
• Aichi virus
• OSBP
• PI4KB
• PI4P
• SAC1
• VAP
• cholesterol
• picornavirus

• Animals
• DNA Replication/genetics
• Foot-and-Mouth Disease Virus/genetics
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mutation/genetics
• RNA, Viral/genetics
• RNA, Viral/metabolism
• Receptors, Cytoplasmic and Nuclear/genetics
• Receptors, Cytoplasmic and Nuclear/metabolism
• Viral Proteins/metabolism
• Virus Replication/genetics

• G0901002 Medical Research Council
• BB/E010709/1 Biotechnology and Biological Sciences Research Council
• BBS/E/I/00007039 Biotechnology and Biological Sciences Research Council
• C20035 Biotechnology and Biological Sciences Research Council
• BB/H007849/1 Biotechnology and Biological Sciences Research Council
• BBS/E/I/00007037 Biotechnology and Biological Sciences Research Council
• BBS/E/I/00007034 Biotechnology and Biological Sciences Research Council

• 2B
• Eukaryotic translation elongation factor 1 gamma
• Foot-and-mouth disease virus
• Virus–host interactions

• Autoinduction
• Immunoassays
• Poliovirus
• Protein expression

Enteroviruses induce the formation of membranous structures (replication organelles [ROs]) with a unique protein and lipid composition specialized for genome replication. Electron microscopy has revealed the morphology of enterovirus ROs, and immunofluorescence studies have been conducted to investigate their origin and formation. Yet, immunofluorescence analysis of fixed cells results in a rather static view of RO formation, and the results may be compromised by immunolabeling artifacts. While live-cell imaging of ROs would be preferred, enteroviruses encoding a membrane-anchored viral protein fused to a large fluorescent reporter have thus far not been described. Here, we tackled this constraint by introducing a small tag from a split-GFP system into an RO-resident enterovirus protein. This new tool bridges a methodological gap by circumventing the need for immunolabeling fixed cells and allows the study of the dynamics and formation of enterovirus ROs in living cells.

Like all other positive-strand RNA viruses, enteroviruses generate new organelles (replication organelles [ROs]) with a unique protein and lipid composition on which they multiply their viral genome. Suitable tools for live-cell imaging of enterovirus ROs are currently unavailable, as recombinant enteroviruses that carry genes that encode RO-anchored viral proteins tagged with fluorescent reporters have not been reported thus far. To overcome this limitation, we used a split green fluorescent protein (split-GFP) system, comprising a large fragment [strands 1 to 10; GFP(S1-10)] and a small fragment [strand 11; GFP(S11)] of only 16 residues. The GFP(S11) (GFP with S11 fragment) fragment was inserted into the 3A protein of the enterovirus coxsackievirus B3 (CVB3), while the large fragment was supplied by transient or stable expression in cells. The introduction of GFP(S11) did not affect the known functions of 3A when expressed in isolation. Using correlative light electron microscopy (CLEM), we showed that GFP fluorescence was detected at ROs, whose morphologies are essentially identical to those previously observed for wild-type CVB3, indicating that GFP(S11)-tagged 3A proteins assemble with GFP(S1-10) to form GFP for illumination of bona fide ROs. It is well established that enterovirus infection leads to Golgi disintegration. Through live-cell imaging of infected cells expressing an mCherry-tagged Golgi marker, we monitored RO development and revealed the dynamics of Golgi disassembly in real time. Having demonstrated the suitability of this virus for imaging ROs, we constructed a CVB3 encoding GFP(S1-10) and GFP(S11)-tagged 3A to bypass the need to express GFP(S1-10) prior to infection. These tools will have multiple applications in future studies on the origin, location, and function of enterovirus ROs.

IMPORTANCE Enteroviruses induce the formation of membranous structures (replication organelles [ROs]) with a unique protein and lipid composition specialized for genome replication. Electron microscopy has revealed the morphology of enterovirus ROs, and immunofluorescence studies have been conducted to investigate their origin and formation. Yet, immunofluorescence analysis of fixed cells results in a rather static view of RO formation, and the results may be compromised by immunolabeling artifacts. While live-cell imaging of ROs would be preferred, enteroviruses encoding a membrane-anchored viral protein fused to a large fluorescent reporter have thus far not been described. Here, we tackled this constraint by introducing a small tag from a split-GFP system into an RO-resident enterovirus protein. This new tool bridges a methodological gap by circumventing the need for immunolabeling fixed cells and allows the study of the dynamics and formation of enterovirus ROs in living cells.

• correlative light electron microscopy
• enterovirus
• live-cell imaging
• viral replication

• ER
• ERAD
• LC3
• RNA virus
• SEL1L
• autophagy
• coxsackievirus
• enterovirus
• membranes
• pancreas

• Animals
• DNA Repair Enzymes/genetics
• DNA Repair Enzymes/metabolism
• DNA-Binding Proteins
• Enterovirus/growth & development
• Enterovirus/physiology
• Enterovirus B, Human/growth & development
• Enterovirus B, Human/physiology
• Enterovirus Infections/enzymology
• Enterovirus Infections/virology
• HeLa Cells
• Host-Pathogen Interactions
• Humans
• Mice
• Phosphoric Diester Hydrolases/genetics
• Phosphoric Diester Hydrolases/metabolism
• Poliovirus/enzymology
• Poliovirus/growth & development
• Poliovirus/physiology
• RNA, Viral/metabolism
• Rhinovirus/enzymology
• Rhinovirus/growth & development
• Rhinovirus/physiology
• Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/genetics
• Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/metabolism
• Viral Proteins/metabolism
• Virus Replication

• 16771 Cancer Research UK
• R01 AI110782 NIAID NIH HHS
• AI110782 NIAID NIH HHS

Cardioviruses, including encephalomyocarditis virus (EMCV) and the human Saffold virus, are small non-enveloped viruses belonging to the Picornaviridae, a large family of positive-sense RNA [(+)RNA] viruses. All (+)RNA viruses remodel intracellular membranes into unique structures for viral genome replication. Accumulating evidence suggests that picornaviruses from different genera use different strategies to generate viral replication organelles (ROs). For instance, enteroviruses (e.g. poliovirus, coxsackievirus, rhinovirus) rely on the Golgi-localized phosphatidylinositol 4-kinase III beta (PI4KB), while cardioviruses replicate independently of the kinase. By which mechanisms cardioviruses develop their ROs is currently unknown. Here we show that cardioviruses manipulate another PI4K, namely the ER-localized phosphatidylinositol 4-kinase III alpha (PI4KA), to generate PI4P-enriched ROs. By siRNA-mediated knockdown and pharmacological inhibition, we demonstrate that PI4KA is an essential host factor for EMCV genome replication. We reveal that the EMCV nonstructural protein 3A interacts with and is responsible for PI4KA recruitment to viral ROs. The ensuing phosphatidylinositol 4-phosphate (PI4P) proved important for the recruitment of oxysterol-binding protein (OSBP), which delivers cholesterol to EMCV ROs in a PI4P-dependent manner. PI4P lipids and cholesterol are shown to be required for the global organization of the ROs and for viral genome replication. Consistently, inhibition of OSBP expression or function efficiently blocked EMCV RNA replication. In conclusion, we describe for the first time a cellular pathway involved in the biogenesis of cardiovirus ROs. Remarkably, the same pathway was reported to promote formation of the replication sites of hepatitis C virus, a member of the Flaviviridae family, but not other picornaviruses or flaviviruses. Thus, our results highlight the convergent recruitment by distantly related (+)RNA viruses of a host lipid-modifying pathway underlying formation of viral replication sites.

All positive-sense RNA viruses [(+)RNA viruses] replicate their viral genomes in tight association with reorganized membranous structures. Viruses generate these unique structures, often termed “replication organelles” (ROs), by efficiently manipulating the host lipid metabolism. While the molecular mechanisms underlying RO formation by enteroviruses (e.g. poliovirus) of the family Picornaviridae have been extensively investigated, little is known about other members belonging to this large family. This study provides the first detailed insight into the RO biogenesis of encephalomyocarditis virus (EMCV), a picornavirus from the genus Cardiovirus. We reveal that EMCV hijacks the lipid kinase phosphatidylinositol-4 kinase IIIα (PI4KA) to generate viral ROs enriched in phosphatidylinositol 4-phosphate (PI4P). In EMCV-infected cells, PI4P lipids play an essential role in virus replication by recruiting another cellular protein, oxysterol-binding protein (OSBP), to the ROs. OSBP further impacts the lipid composition of the RO membranes, by mediating the exchange of PI4P with cholesterol. This membrane-modification mechanism of EMCV is remarkably similar to that of the distantly related flavivirus hepatitis C virus (HCV), while distinct from that of the closely related enteroviruses, which recruit OSBP via another PI4K, namely PI4K IIIβ (PI4KB). Thus, EMCV and HCV represent a striking case of functional convergence in (+)RNA virus evolution.

• 1-Phosphatidylinositol 4-Kinase/metabolism
• Animals
• Blotting, Western
• Cardiovirus Infections/metabolism
• Encephalomyocarditis virus/physiology
• Hepacivirus/physiology
• Host-Parasite Interactions/physiology
• Humans
• Immunoprecipitation
• Lipid Metabolism/physiology
• Microscopy, Fluorescence
• Phosphatidylinositol Phosphates/metabolism
• Picornaviridae
• RNA Viruses
• RNA, Small Interfering
• Receptors, Steroid/metabolism
• Transfection
• Virus Replication/physiology

• Aureusvirus
• Auxiliary replicase
• Endoplasmic reticulum
• Tombusviridae

• Amino Acid Sequence
• Endoplasmic Reticulum/enzymology
• Endoplasmic Reticulum/metabolism
• Gene Expression Regulation, Viral/physiology
• Molecular Sequence Data
• Protein Structure, Tertiary
• RNA-Dependent RNA Polymerase/metabolism
• Nicotiana
• Tombusviridae/enzymology
• Tombusviridae/genetics
• Tombusviridae/physiology
• Viral Proteins/genetics
• Viral Proteins/metabolism
• Virus Replication

• Lipoprotein
• Liposomes
• Membrane Bilayer
• Membrane Biophysics
• Membrane Reconstitution
• Positive-strand RNA Viruses
• Viral Protein
• Viral Replication

Plus-strand RNA virus replication occurs in tight association with cytoplasmic host cell membranes. Both, viral and cellular factors cooperatively generate distinct organelle-like structures, designated viral replication factories. This compartmentalization allows coordination of the different steps of the viral replication cycle, highly efficient genome replication and protection of the viral RNA from cellular defense mechanisms. Electron tomography studies conducted during the last couple of years revealed the three dimensional structure of numerous plus-strand RNA virus replication compartments and highlight morphological analogies between different virus families. Based on the morphology of virus-induced membrane rearrangements, we propose two separate subclasses: the invaginated vesicle/spherule type and the double membrane vesicle type. This review discusses common themes and distinct differences in the architecture of plus-strand RNA virus-induced membrane alterations and summarizes recent progress that has been made in understanding the complex interplay between viral and co-opted cellular factors in biogenesis and maintenance of plus-strand RNA virus replication factories.

• Viral replication factory
• Viral replication complex
• Plus-strand RNA virus
• Membrane remodeling
• Virus-host interaction
• Alphavirus
• Enterovirus
• Coronavirus
• Flavivirus
• Hepatitis C virus

• Carrier Proteins/metabolism
• Gene Expression Regulation, Viral
• Lipid Bilayers/metabolism
• Models, Biological
• Poliovirus/enzymology
• Poliovirus/physiology
• Protein Binding
• Protein Multimerization
• Viral Nonstructural Proteins/metabolism
• Virus Replication

• R01 AI059130 NIAID NIH HHS
• R37 AI059130 NIAID NIH HHS
• R01 AI-059130 NIAID NIH HHS

RNA viruses are ubiquitous in nature, infecting every known organism on the planet. These viruses can also be notorious human pathogens with significant medical and economic burdens. Central to the lifecycle of an RNA virus is the synthesis of new RNA molecules, a process that is mediated by specialized virally encoded enzymes called RNA‐dependent RNA polymerases (RdRps). RdRps directly catalyze phosphodiester bond formation between nucleoside triphosphates in an RNA‐templated manner. These enzymes are strikingly conserved in their structural and functional features, even among diverse RNA viruses belonging to different families. During host cell infection, the activities of viral RdRps are often regulated by viral cofactor proteins. Cofactors can modulate the type and timing of RNA synthesis by directly engaging the RdRp and/or by indirectly affecting its capacity to recognize template RNA. High‐resolution structures of RdRps as apoenzymes, bound to RNA templates, in the midst of catalysis, and/or interacting with regulatory cofactor proteins, have dramatically increased our understanding of viral RNA synthetic mechanisms. Combined with elegant biochemical studies, such structures are providing a scientific platform for the rational design of antiviral agents aimed at preventing and treating RNA virus‐induced diseases. WIREs RNA 2013, 4:351–367. doi: 10.1002/wrna.1164

This article is categorized under: 1

RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes

• Agrobacterium tumefaciens/genetics
• Amino Acid Sequence
• Endoplasmic Reticulum/metabolism
• Endoplasmic Reticulum/virology
• Green Fluorescent Proteins/chemistry
• Green Fluorescent Proteins/genetics
• Green Fluorescent Proteins/metabolism
• Intracellular Membranes/metabolism
• Intracellular Membranes/virology
• Molecular Sequence Data
• Mutation
• Plant Diseases
• Protein Structure, Tertiary
• RNA, Viral/biosynthesis
• RNA, Viral/genetics
• RNA-Dependent RNA Polymerase/chemistry
• RNA-Dependent RNA Polymerase/genetics
• RNA-Dependent RNA Polymerase/metabolism
• Recombinant Fusion Proteins/chemistry
• Recombinant Fusion Proteins/genetics
• Recombinant Fusion Proteins/metabolism
• Nicotiana/virology
• Tombusviridae/physiology
• Trifolium/virology
• Viral Proteins/chemistry
• Viral Proteins/genetics
• Viral Proteins/metabolism
• Virus Replication

• 3C Viral Proteases
• Cysteine Endopeptidases/metabolism
• HeLa Cells
• Heterogeneous Nuclear Ribonucleoprotein D0
• Heterogeneous-Nuclear Ribonucleoprotein D/metabolism
• Host-Pathogen Interactions
• Humans
• Poliovirus/physiology
• Proteolysis
• RNA, Viral/metabolism
• Rhinovirus/physiology
• Viral Proteins/metabolism
• Virus Replication

• AI026765 NIAID NIH HHS
• R01 AI026765 NIAID NIH HHS
• U54 AI065357 NIAID NIH HHS
• P30 CA062203 NCI NIH HHS
• R56 AI026765 NIAID NIH HHS
• AI065357 NIAID NIH HHS
• P30CA062203 NCI NIH HHS

• Animals
• Cell Line
• Cricetinae
• Epitopes/biosynthesis
• Epitopes/genetics
• Female
• Foot-and-Mouth Disease Virus/genetics
• Foot-and-Mouth Disease Virus/metabolism
• Gene Expression Regulation, Viral
• Genetic Vectors
• Mice
• Protein Structure, Tertiary
• Recombinant Fusion Proteins/biosynthesis
• Recombinant Fusion Proteins/genetics
• Transduction, Genetic
• Viral Nonstructural Proteins/biosynthesis
• Viral Nonstructural Proteins/genetics

• cellbio
• microbio

Viral ion channels are short membrane proteins with 50–120 amino acids and play an important role either in regulating virus replication, such as virus entry, assembly and release or modulating the electrochemical balance in the subcellular compartments of host cells. This review summarizes the recent advances in viral encoded ion channel proteins (or viroporins), including PBCV-1 KcV, influenza M2, HIV-1 Vpu, HCV p7, picornavirus 2B, and coronavirus E and 3a. We focus on their function and mechanisms, and also discuss viral ion channel protein serving as a potential drug target.

• poliovirus
• oligomer
• polymerase
• complementation
• antiviral

• Antiviral Agents/pharmacology
• Catalytic Domain/genetics
• Drug Resistance, Viral
• Genetic Complementation Test
• HeLa Cells
• Humans
• Macromolecular Substances
• Models, Molecular
• Mutagenesis, Site-Directed
• Mutation
• RNA Viruses/drug effects
• RNA Viruses/genetics
• RNA Viruses/metabolism
• RNA Viruses/physiology
• RNA, Viral/chemistry
• RNA, Viral/genetics
• RNA, Viral/metabolism
• RNA-Dependent RNA Polymerase/chemistry
• RNA-Dependent RNA Polymerase/genetics
• RNA-Dependent RNA Polymerase/metabolism
• Recombinant Proteins/chemistry
• Recombinant Proteins/genetics
• Recombinant Proteins/metabolism
• Transduction, Genetic
• Virus Replication/drug effects

• AI-25166 NIAID NIH HHS

Picornaviruses cause several diseases, not only in humans but also in various animal hosts. For instance, human enteroviruses can cause hand-foot-and-mouth disease, herpangina, myocarditis, acute flaccid paralysis, acute hemorrhagic conjunctivitis, severe neurological complications, including brainstem encephalitis, meningitis and poliomyelitis, and even death. The interaction between the virus and the host is important for viral replication, virulence and pathogenicity. This article reviews studies of the functions of viral and host factors that are involved in the life cycle of picornavirus. The interactions of viral capsid proteins with host cell receptors is discussed first, and the mechanisms by which the viral and host cell factors are involved in viral replication, viral translation and the switch from translation to RNA replication are then addressed. Understanding how cellular proteins interact with viral RNA or viral proteins, as well as the roles of each in viral infection, will provide insights for the design of novel antiviral agents based on these interactions.

• Animals
• Cell Line
• Foot-and-Mouth Disease/physiopathology
• Foot-and-Mouth Disease/virology
• Foot-and-Mouth Disease Virus/metabolism
• Foot-and-Mouth Disease Virus/pathogenicity
• Foot-and-Mouth Disease Virus/physiology
• RNA, Viral/metabolism
• Viral Nonstructural Proteins/metabolism
• Virus Replication/drug effects
• Virus Replication/physiology

• Animals
• Brefeldin A/pharmacology
• Cell Line
• Cricetinae
• Enterovirus B, Human/metabolism
• Enterovirus B, Human/pathogenicity
• Foot-and-Mouth Disease Virus/metabolism
• Foot-and-Mouth Disease Virus/pathogenicity
• Host-Pathogen Interactions
• Kidney/cytology
• Kidney/ultrastructure
• Kidney/virology
• Mesocricetus
• Microscopy, Confocal
• Microscopy, Fluorescence
• Subcellular Fractions/metabolism
• Vesicular stomatitis Indiana virus/metabolism
• Vesicular stomatitis Indiana virus/pathogenicity
• Viral Proteins/genetics
• Viral Proteins/metabolism

• Animals
• Cattle
• China
• Foot-and-Mouth Disease/virology
• Foot-and-Mouth Disease Virus/classification
• Foot-and-Mouth Disease Virus/genetics
• Genome, Viral
• Molecular Sequence Data
• Sequence Homology, Nucleic Acid