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PubMed1995

Evolutionary analysis of the picornavirus family.

An exhaustive evolutionary analysis of the picornavirus family has been carried out using the amino acid sequences of several proteins of the viruses including: the capsid proteins (1D, 1B, and 1C) situated at the 5' end of the genome and responsible for the serotype of the viruses, and the viral polymerase (3D), located at the 3' end of the genome. The evolutionary relationships found among the viruses studied support the new classification, recently suggested, in contrast to the classical one, and the existence of a new genus for the picornavirus family. In the new taxonomic organization, five genera form the picornavirus family: (1) aphthoviruses, (2) cardioviruses, (3) hepatoviruses (previously classified as enteroviruses), (4) renteroviruses (which mainly constitute a combination of the previous genera rhinovirus and enterovirus), and (5) a new genus, with a new and unique representative: the echovirus 22. Our analysis also allowed us, for the first time, to propose the most probable sequence of speciation events to have given rise to the current picornavirus family. The bootstrap procedure was used to check the reliability of the phylogenetic trees obtained. The application of the method of the statistical geometry in distance space to internal branches of the tree revealed a high degree of evolutionary "noise," which makes the resolution of some internal branching points difficult.

Capsid↗

PubMed1996

Epitope mapping of monoclonal antibodies raised to recombinant Mengo 3D polymerase.

The cDNA coding sequence of the RNA-dependent RNA polymerase (3Dpol) of Mengovirus was cloned and expressed in a bacterial system. Eleven monoclonal antibodies were raised against the recombinant Mengo 3Dpol (rM3D). All of them recognized the recombinant and the viral-induced form of the protein. The panel of monoclonals belonged to the IgG1 and IgG2a isotypes and were mapped to four different epitopes in the 3D molecule by competition assays. All monoclonals recognized Mengo 3Dpol in western blots and cross-reacted with the homologous polymerases of seven other cardioviruses but failed to react with 3Dpol from poliovirus type 1 and 3 or rhinovirus type 14 and 16.

Antibodies, Monoclonal↗

PubMed2003

The human rhinovirus internal cis-acting replication element (cre) exhibits disparate properties among serotypes.

It has been reported previously that the Human rhinovirus 14 (HRV-14) RNA genome contains a cis-acting replication element (cre) that maps to the capsid coding (P1) sequence [19]. Further characterization of the HRV-14 cre in the present study established that by moving the cre stem-loop structure downstream, adjacent to the 3'NCR, that its position is not critical for function. When the P1 sequences of two closely related serotypes of HRV-14 were analyzed for the presence of a cre, both HRV-3 and HRV-72 were found to contain similar sequence at the same positions as HRV-14. Moreover, sequence at these positions produced structures from MFOLD analysis that closely resembled the HRV-14 cre. It was also discovered that neither HRV serotypes 1a or 16 harbor replication elements that map to the P1 segments of their genomes. Computer and mutational analyses suggest that the cre in these latter HRV serotypes map instead to the 2A gene, as has been reported for HRV-2. The putative HRV-3 cre was determined to be unable to support replication when placed in an HRV-14 replicon background. Similarly, the previously identified HRV-2 cre was unable to support replication of the HRV-14 genome. This finding is in contrast to the cardiovirus cre, which has been shown to be functionally active between two members of its family, and further suggests that there is a close link between the evolution of the human rhinoviruses and the mechanisms of RNA replication.

3' Untranslated Regions↗

PubMed1989

A theoretical study of the acidification of the rhinovirus capsid.

Electrostatic calculations for human rhinovirus 14 indicate that histidine-base residue pairs in the region of a beta-strand interaction between pentamers may be involved in a pH-induced process that leads to the release of viral RNA. Other picornavirus sequences are examined for these residue pairs, a subset of which is present in enteroviruses. Foot and mouth disease virus possesses one of the residue pairs, and cardioviruses, which undergo a separate pH and halide ion-induced capsid dissociation, possess none.

Capsid↗

PubMed1988

Molecular cloning and sequence determination of DA strain of Theiler's murine encephalomyelitis viruses.

Theiler's murine encephalomyelitis viruses (TMEV) belong to the Picornaviridae, and are divided into two subgroups. TO subgroup strains produce a persistent demyelinating central nervous system infection in mice, while GDVII subgroup strains cause acute polioencephalomyelitis. We generated three overlapping clones of the genome of DA strain, a member of TO subgroup. Sequence analysis revealed that the genome is 8093 nucleotides long with a poly(A) tail. The 5' noncoding region stretches from nucleotides 1 to 1065 and lacks a poly(C) tract. The open reading frame stretches from 1066 to 7968 and encodes 2301 amino acids. DA strain sequence is more closely related to members of the Cardiovirus genus than to members of other Picornavirus genera. Comparison with sequence of BeAn strain, another TO subgroup strain, showed that the P1 area has the greatest number of differences, while the noncoding regions are more well-conserved. The three overlapping clones will be important in recombinant infectious cDNA studies between strains of both subgroups.

Amino Acid Sequence↗

PubMed1991

Genetic variability within the 5' nontranslated region of hepatitis A virus RNA. Implications for secondary structure and function.

The RNA genome of hepatitis A virus (HAV) contains a lengthy and relatively well conserved 5' nontranslated region (5'NTR). In other picornaviruses, the 5'NTR has been shown to have important functions related to the initiation of viral translation and replication of viral RNA, functions which are critically dependent on both primary and secondary RNA structure. We have utilized a phylogenetic approach to construct a model of the secondary structure of the HAV 5'NTR. By comparing the nucleotide sequences of genetically divergent simian and human HAV strains, we identified a series of covariant nucleotide substitutions which are predictive of conserved, double-stranded helical structures within the 5'NTR, and which thus permitted improved thermodynamic modeling of the secondary structure. The model was further refined based on the observed sites of cleavage of synthetic RNA by single- and double-strand specific RNAses. The results of these studies suggest that the 5'NTR of HAV has a general organization similar to that of other picornaviruses, and shares certain structural features and perhaps specific functions with the 5'NTRs of the cardioviruses and aphthoviruses.

Base Composition↗

PubMed1995

Unusual folding regions and ribosome landing pad within hepatitis C virus and pestivirus RNAs.

A statistically significant folding region is identified in the 5' untranslated region (5'-UTR) of hepatitis C virus (HCV), bovine viral diarrhea virus and hog cholera virus. This unusual folding region (UFR) detected in HCV encompasses 199 nucleotides (nt) and coincides with the reported internal ribosome entry site or ribosome landing pad (RLP), as determined by the 5' and 3' deletions [Tsukiyama-Kohara et al., J. Virol. 66 (1992) 1476-1483]. The RNA structure predicted in the UFR of HCV consists of a large stem-loop and a pseudoknot. The proposed structural model is consistent with RNase sensitivity studies [Brown et al., Nucleic Acids Res. 20 (1992) 5041-5045]. Moreover, the structure is highly conserved among these divergent HCV and pestivirus RNAs. The covariation of paired bases in the helical regions offers support for the proposed structural models. The pseudoknot predicted in these UFR shares a similar structural feature to those proposed in the RLP of cardioviruses, aphthoviruses and hepatitis A virus. Based on the common structural motif, a putative base-pairing model between HCV RNA and 18S rRNA, as well as pestiviral RNAs and 18S rRNA are suggested. Intriguingly, the proposed base-pairing models in this study are comparable to those proposed in picornaviruses in terms of their folded shape and location of the predicted complementary sequences between viral RNAs and 18S rRNA. Taken together, we suggest that the common base-pairing model between the UFR detected in the 5'-UTR of pestivirus and HCV and 18S rRNA have a general function in the internal initiation of cap-independent translation.

Base Sequence↗

PubMed2004

Phylogeny of the Picornaviridae and differential evolutionary divergence of picornavirus proteins.

A rooted phylogenetic analysis of the viral family Picornaviridae identified several major clusters within this viral family. The genus Parechovirus, including Ljungan virus, was found to be basal to the family. Within the family, there were two major subgroups: (1) a cluster including viruses assigned to the genera Enterovirus and Rhinovirus; and (2) a cluster including Teschovirus, Cardiovirus, Erbovirus, Aphthovirus, and probably Kobuvirus. Within the former cluster, the genera Enterovirus and Rhinovirus were found not to be monophyletic. Principal components analysis was used to identify different patterns with regard to the relative sequence divergence of the 11 polyproteins encoded by the picornavirus genome. In comparisons of closely related pairs of viruses, the nonstructural proteins were generally more conserved than the capsid proteins 1B, 1C, and 1D. This pattern is most likely explained by the predominance of host antibody-driven selection on the differentiation of closely related viral genomes. However, the same pattern was not seen in more distantly related pairs of viruses, which showed a number of distinct patterns with regard to the relative conservation of the 11 proteins.

Biological Evolution↗

PubMed2003

Genomic evidence that simian virus 2 and six other simian picornaviruses represent a new genus in Picornaviridae.

Analysis of the VP1 capsid protein coding region of simian virus (SV) 2, SV16, SV18, SV42, SV44, SV45, and SV49 demonstrates that they are clearly distinct from members of the Enterovirus genus and from members of other existing picornavirus genera. To further characterize this group of viruses and to clarify their classification within the Picornaviridae, we have determined the complete genomic sequence of SV2 (8126 nucleotides). The genome was typical of members of Picornaviridae, encoding a single open reading frame. The putative polyprotein contained typical picornavirus protease cleavage sites, yielding mature proteins homologous to each of the known picornavirus proteins. SV2 contained an amino-terminal extension of the reading frame, which was analogous to the leader protein of members of the Aphthovirus, Cardiovirus, Erbovirus, Kobuvirus, and Teschovirus genera, but there was no significant amino acid homology with any of these known leader proteins. The 2A protein also aligned poorly with the 2A proteins of other picornaviruses. The deduced amino acid sequences of the SV2 structural and nonstructural proteins were related to but phylogenetically distinct from those of enteroviruses and human rhinoviruses. The major distinguishing features of SV2 were the presence of a type 2 internal ribosome entry site in the 5'-NTR, a putative leader protein encoded upstream of the structural proteins, and an unusually large 2A protein. On the basis of the molecular analysis, we propose that SV2, SV16, SV18, SV42, SV44, SV45, SV49, and porcine enterovirus 8 be classified as members of a new genus in Picornaviridae and that SV2 (strain 2383) be designated as the type strain.

5' Untranslated Regions↗

PubMed1988

Aetiological association of a virus-like particle with enterically transmitted non-A, non-B hepatitis.

Virus-like particles, approximately 27 nm in diameter, were identified in faeces from an Indian patient with enterically transmitted non-A, non-B (ENANB) hepatitis. They were serologically distinct from hepatitis A virus (HAV). Nucleic acid extracted from the particles did not hybridize with cDNA probes representing the genomes of HAV, enteroviruses, and cardioviruses. Chimpanzees were experimentally inoculated with faecal suspensions containing this 27 nm particle or with faeces from another case of ENANB hepatitis. Mild histological and biochemical hepatitis developed in these animals and there was serological evidence of infection with the virus-like particle as shown by immunoelectronmicroscopy (IEM). Serological analysis by IEM suggested that this agent or an antigenically similar virus was the aetiological agent of two epidemics and a sporadic case of ENANB hepatitis in India and of an epidemic of the illness in the USSR. Antibody to the particle was found in sera from patients with ENANB hepatitis from various geographic areas over a 30-year period.

Animals↗

PubMed2002

Synthesis of new 3-methylthio-5-aryl-4-isothiazolecarbonitriles with broad antiviral spectrum.

The isothiazole derivative 3-methylthio-5-(4-OBn-phenyl)-4-isothiazolecarbonitrile, coded IS-50, which in previous studies had exhibited a broad antipicornavirus spectrum of action, was selected as the model for the synthesis of a new series of 3-methylthio-5-aryl-4-isothiazolecarbonitriles. These compounds were prepared in good yield (from 66 to 82%) by alkylation of 3-methylthio-5-(4-hydroxyphenyl)-4-isothiazolecarbonitrile with suitable bromides in the presence of acetone; only the 4-cyanophenoxy derivatives were obtained in a yield of less than 30%. All the compounds were screened against a panel of 17 representative human rhinovirus (HRV) serotypes belonging to both A and B groups, enteroviruses polio 1, ECHO 9 and Coxsackie B1, cardiovirus EMC, measles virus, and herpes simplex virus type 1 (HSV-1). Our results demonstrate that HRV 86 (group A) and HRVs 39 and 89 (group B) are the rhinovirus serotypes more susceptible to the action of these compounds. Isothiazole derivatives with a longer intermediate alkyl chain exhibited good activity against polio 1 and ECHO 9. The compound bearing a butyl group between the two phenoxy rings showed the lowest IC(50) against Coxsackie B1 and measles viruses. No activity against HSV-1 was detected with any of the compounds screened.

Antiviral Agents↗

PubMed2002

Phylogenetic analysis of Ljungan virus and A-2 plaque virus, new members of the Picornaviridae.

In addition to the viruses belonging to the nine proposed genera of the Picornaviridae, Enterovirus, Rhinovirus, Cardiovirus, Aphtovirus, Hepatovirus, Parechovirus, Kobuvirus, Erbovirus and Teschovirus, two new members of this family have recently been discovered. Three strains of Ljungan virus (LV) were isolated from bank voles (Clethrionomys glareolus) and A-2 plaque virus (A-2) was isolated from human sera. To study the genetic relationship between these recently discovered viruses and the members of the family Picornaviridae, an evolutionary analysis has been carried out using the amino acid sequences of the two nonstructural proteins 2C and 3D. Phylogenetic analysis using prime members of the nine genera support the division of picornaviruses into the proposed genera. The study also supports a previous suggestion based on analysis of partial sequences of the structural proteins that LV is more related to the genus of Parechovirus than to other picornaviruses, but also shows that the three LV strains used in the comparison constitute a distinct monophyletic group, clearly separated from the parechoviruses. The analyses using the 2C and 3D sequences clearly showed that A-2 was related to the genera of Rhinovirus and Enterovirus, but it was not possible to group the A-2 with high confidence into one of the genera. Comparison using the VP1 protein sequences of Enterovirus and Rhinovirus showed that although the A-2 virus is positioned between the two genera, the virus is more related to the genus of Enterovirus than to Rhinovirus. Our analysis of the three LV strains based on the phylogenetic analysis of the 2C and 3D proteins suggests that the strains used in this study constitute a monophyletic group clearly related to Parechovirus of Picornaviridae. The taxonomic position of the A-2 virus is presently uncertain but available data indicate that this virus may be classified as a member of the genus of Enterovirus.

Animals↗

PubMed2003

Encephalomyocarditis viral protein 2A localizes to nucleoli and inhibits cap-dependent mRNA translation.

Panels of monoclonal antibodies were raised against viral non-structural proteins of encephalomyocarditis virus (EMCV) and used to probe infected cells in laser confocal microscopy experiments and Western analyses. Surprisingly, all Mengovirus and EMCV-infected cells showed strong targeting of protein 2A, 3B(VPg), 3C(pro), and 3D(pol) signals to cellular nuclei, in particular to nucleoli, from the earliest times of infection. Viral capsid proteins (1AB, 1C, and 1D) and other non-structural proteins (2B, 2C, and 3A) did not target nuclei and remained cytoplasmic throughout the infection. The cardioviral 2A protein (subject of this article) has a novel 143 amino acid sequence, terminating in a 19 amino acid COOH-terminal processing cassette (PCC) that participates in autocatalytic, co-translational primary cleavage of the viral polyprotein. The remainder of the 2A protein shares only limited similarity with other viral or cellular sequences, except for a short motif (KRvRPFRLP) near PCC resembling the nuclear localization signals (NLS) common to many yeast ribosomal proteins. Deletions within the EMCV 2A protein that impinge on this region have been reported to diminish the ability of virus to inhibit cap-dependent translation of cellular mRNAs. We have now observed that these same deletions prevented nuclear localization. Cellular expression of 2A protein from RNA transcripts or cDNAs confirmed that it does not require other viral proteins or activities for nuclear transport; even when expressed as a single protein, 2A protein effectively shuts off translation from capped reporter mRNAs. Within infected, transfected, or DNA vector-transformed cells, the 2A protein was always found in close association with the nucleolar ribosomal chaperone protein B23, which may help the traffic 2A into nucleoli like a surrogate ribosomal protein, by virtue of the putative nucleolar localization signal (NoLS). The data are consistent with a novel mechanism for virus-induced host protein shut off in cardioviruses, whereby 2A helps to upregulate the synthesis of new and modified ribosomes that have an inherent preference for internal ribosomal entry site (IRES)-dependent viral genome translation over cap-dependent host mRNA translation.

Amino Acid Sequence↗

PubMed1997

Application of genome sequence information to the classification of bovine enteroviruses: the importance of 5'- and 3'-nontranslated regions.

Comparative genomics of viruses in evolutionary and phylogenetic studies is well established. Previous nucleic acid sequence analyses have demonstrated that enteroviruses and rhinoviruses of the family Picornaviridae exhibit a similar structure of the 5'-nontranslated region (NTR) differing significantly from the 5'-NTR of cardiovirus, aphthovirus, hepatovirus, and echovirus 22 (provisionally parechovirus 1). Available nucleotide sequence information of the 5'- and 3'-nontranslated regions of more than 70 serotypes of enteroviruses, bovine enteroviruses and rhinoviruses has been compared and correlated with previous findings obtained after analysis of the coding and noncoding genome regions. As a result, the 5'- and 3'-NTRs of all three virus groups are characterized by group-specific nucleotide sequences. Focusing on bovine enterovirus (BEV) serotypes, unique characteristics in all secondary structures of the NTRs were observed. These features clearly separate the BEVs from the human enteroviruses and rhinoviruses. Concerning the 5'-NTR, the most remarkable property is an insertion of about 110 nucleotides between the putative cloverleaf structure at the very 5'-end of the viral genome and the IRES element. This insertion was demonstrated for BEV 1 and 2 and has a predicted folding pattern which is very similar to the 5'-cloverleaf structure. One stem-loop of this second cloverleaf is almost identical to the 3CDpro-binding domain of rhinoviral 5'-cloverleafs. It was also demonstrated that the IRES elements and the 3'-NTRs of both, enteroviruses and rhinoviruses, have group-specific features which differ significantly from the corresponding genome regions of BEV. These results suggest that bovine enteroviruses hold an exceptional taxonomic position besides the established genera Enterovirus and Rhinovirus. Within the Enterovirus and Rhinovirus genera, the existence of virus clusters representing subgenera was previously proposed. Whereas the 5'-NTRs of the four human enterovirus clusters fall into two groups, all four clusters have characteristic secondary structures at the 3'-NTR supporting the concept of enterovirus clusters. For rhinoviruses, the existence of two virus clusters was confirmed.

Animals↗

PubMed1990

Attenuation of Mengo virus through genetic engineering of the 5' noncoding poly(C) tract.

The murine cardioviruses, such as the Mengo and encephalomyocarditis viruses, and the bovine aphthoviruses, such as foot-and-mouth disease virus, are distinguished among positive-strand RNA viruses by the presence of long homopolymeric poly(C) tracts within their 5' noncoding sequences. Although the specific lengths (60-350 bases) and sequence discontinuities (for example, uridine residues) that sometimes disrupt the homopolymer have served to characterize natural viral isolates, the biological function of the poly(C) region has never been clear. We now report that complementary DNA-mediated truncation of the Mengo virus poly(C) tract dramatically attenuates the pathogenicity of the virus in mice. Animals injected with viruses with short tracts not only survived inoculation of up to 50 micrograms live virus (10(11) plaque-forming units) but consistently produced high titres of neutralizing antibodies, which conferred long-term immunogenic protection from (normally) lethal virus challenge. We propose that analogous synthetic strains of foot and mouth disease virus could serve as the basis for new attenuated vaccines.

Animals↗

PubMed2006

A picornavirus protein interacts with Ran-GTPase and disrupts nucleocytoplasmic transport.

Active nucleocytoplasmic transport of protein and RNA in eukaryotes depends on the Ran-GTPase system to regulate cargo-receptor interactions. Several viruses, including the RNA picornaviruses, encode factors that alter nuclear transport with the aim of suppressing synthesis of antiviral factors and promoting viral replication. Picornaviruses in the cardiovirus genus express a unique 67-aa Leader protein (L), known to alter the subcellular distribution of IFN regulatory proteins targeted to the nucleus. We report here that L binds directly to Ran and blocks nuclear export of new mRNAs. In Xenopus egg extracts, recombinant L also inhibits mitotic spindle assembly, a RanGTP function crucial to cell-cycle progression. We propose that L inhibits nucleocytoplasmic transport during infection by disrupting the RanGDP/GTP gradient. This inhibition triggers an efflux of nuclear proteins necessary for viral replication and causes IFN suppression. To our knowledge, L is the first viral picornaviral protein to interact directly with Ran and modulate the Ran-dependent nucleocytoplasmic pathway.

Active Transport, Cell Nucleus↗

PubMed1992

A distinct picornavirus group identified by sequence analysis.

Although echovirus 22 is presently classified as a member of the enterovirus group in the family of picornaviruses, it has been reported to have exceptional biological properties when compared with other representatives of the group. We have determined the complete nucleotide sequence of the echovirus 22 (Harris strain) genome, which appears to be significantly different from all the other studied picornaviruses. However, the organization of the genome [7339 nucleotides, excluding the poly(A) tract] is similar to that of previously sequenced picornaviruses. This genome includes a 5' untranslated region, relatively well-conserved when compared with aphtho- and cardioviruses, followed by an open reading frame coding for a 2180-amino acid-long polyprotein. The amino termini of capsid polypeptides VP1 and VP3 were determined by direct sequencing, and the other proteolytic cleavage sites in the polyprotein were predicted by comparison with other picornavirus proteins. The amino acid identities of echovirus 22 polypeptides with the corresponding proteins of other picornaviruses are in the 14-35% range, similar to those percentages seen when representatives of the five picornavirus groups (entero-, rhino-, cardio-, aphtho-, and hepatoviruses) are compared. Our results suggest that echovirus 22 belongs to an independent group of picornaviruses.

Amino Acid Sequence↗

PubMed2002

Encephalomyocarditis and Mengo viruses productively infect murine T-lymphocyte cell lines but not fresh ex vivo derived T lymphocytes.

Encephalomyocarditis virus (EMCV) and Mengo virus are highly virulent murine cardioviruses that are found in abundant quantities in the spleen and lymph nodes after infection. T lymphocytes are pivotal mediators of humoral and cellular immunity against cardioviral challenge, and are highly suspect candidates of EMCV and Mengo virus infection. We found T lymphocyte-like cell lines CTLL-2, EL-4, LY1+2/9, and LBRM33 were susceptible to productive viral infection and exhibited cytopathology after infection with virulent EMCV-R or attenuated Mengo virus strains vMC0 and vMC24. Flow cytometric analysis demonstrated progressive intracellular accumulation of viral proteins, such as the replication-dependent 3D viral polymerase, in EL-4 cells during infection. Conversely, freshly isolated and mitogen-stimulated CD4+ and CD8+ T cells were resistant to productive infection with these viruses, exhibiting no viral-induced cytopathic effects or intracellular presence of viral proteins. These data indicate that although T-lymphocyte-like tumor cell lines are highly susceptible to viral infection and cytopathic effects, primary/freshly isolated T cells are resistant to infection by EMCV-R or Mengo virus.

Animals↗