Biology of viruses ppt

SU stands for more Because of the error rate of the enzymes involved in RNA replication, these viruses usually show much higher mutation rates than do the DNA viruses. Mutation rates of 10 -4 lead to the continuous generation of virus variants which show great adaptability to new hosts.

The viral RNA may be single-stranded ss or double-stranded ds , and the genome may occupy a single RNA segment or be distributed on two or more separate segments segmented genomes. In addition, the RNA strand of a single-stranded genome may be either a sense strand plus strand , which can function as messenger RNA mRNA , or an antisense strand minus strand , which is complementary to the sense strand and cannot function as mRNA protein translation see Ch.

Sense viral RNA alone can replicate if injected into cells, since it can function as mRNA and initiate translation of virus-encoded proteins. Antisense RNA, on the other hand, has no translational function and cannot per se produce viral components.

Schemes of 21 virus families infecting humans showing a number of distinctive criteria: presence of an envelope or double- capsid and internal nucleic acid genome. DsRNA viruses, e. Each segment consists of a complementary sense and antisense strand that is hydrogen bonded into a linear ds molecule.

The replication of these viruses is complex; only the sense RNA strands are released from the infecting virion to initiate replication. The retrovirus genome comprises two identical, plus-sense ssRNA molecules, each monomer 7—11 kb in size, that are noncovalently linked over a short terminal region. Retroviruses contain 2 envelope proteins encoded by the env-gene, 4—6 nonglycosylated core proteins and 3 non-structural functional proteins reverse transcriptase, integrase, protease: RT, IN, PR specified by the gag-gene Fig.

This DNA, mediated by the viral integrase, becomes covalently bonded into the DNA of the host cell to make possible the subsequent transcription of the sense strands that eventually give rise to retrovirus progeny. After assembly and budding, retroviruses show structural and functional maturation.

In immature virions the structural proteins of the core are present as a large precursor protein shell. After proteolytic processing by the viral protease the proteins of the mature virion are rearranged and form the dense isometric or cone-shaped core typical of the mature virion, and the particle becomes infectious. Most DNA viruses Fig. The papovaviruses, comprising the polyoma- and papillomaviruses, however, have circular DNA genomes, about 5. Three or 2 structural proteins make up the papovavirus capsid: in addition, nonstructural proteins are encoded that are functional in virus transcription, DNA replication and cell transformation.

Single-stranded linear DNA, 4—6 kb in size, is found with the members of the Parvovirus family that comprises the parvo-, the erythro- and the dependoviruses.

The virion contains 2—4 structural protein species which are differently derived from the same gene product see Ch. The adeno-associated virus AAV, a dependovirus is incapable of producing progeny virions except in the presence of helper viruses adenovirus or herpesvirus.

It is therefore said to be replication defective. Circular single-stranded DNA of only 1. The isometric capsid measures 17 nm and is composed of 2 protein species only. On the basis of shared properties viruses are grouped at different hierarchical levels of order, family, subfamily, genus and species. More than 30, different virus isolates are known today and grouped in more than 3, species, in genera and 71 families. Viral morphology provides the basis for grouping viruses into families.

A virus family may consist of members that replicate only in vertebrates, only in invertebrates, only in plants, or only in bacteria. Certain families contain viruses that replicate in more than one of these hosts. This section concerns only the 21 families and genera of medical importance. Besides physical properties, several factors pertaining to the mode of replication play a role in classification: the configuration of the nucleic acid ss or ds, linear or circular , whether the genome consists of one molecule of nucleic acid or is segmented, and whether the strand of ss RNA is sense or antisense.

Also considered in classification is the site of viral capsid assembly and, in enveloped viruses, the site of nucleocapsid envelopment. Table lists the major chemical and morphologic properties of the families of viruses that cause disease in humans.

The use of Latinized names ending in -viridae for virus families and ending in -virus for viral genera has gained wide acceptance.

The names of subfamilies end in -virinae. Vernacular names continue to be used to describe the viruses within a genus. In this text, Latinized endings for families and subfamilies usually are not used. Table shows the current classification of medically significant viruses. In the early days of virology, viruses were named according to common pathogenic properties, e.

From the early s until the mids, when many new viruses were being discovered, it was popular to compose virus names by using sigla abbreviations derived from a few or initial letters.

Thus the name Picornaviridae is derived from pico small and RNA; the name Reoviridae is derived from respiratory, enteric, and orphan viruses because the agents were found in both respiratory and enteric specimens and were not related to other classified viruses; Papovaviridae is from papilloma, polyoma, and vacuolating agent simian virus 40 [SV40] ; retrovirus is from reverse transcriptase; Hepadnaviridae is from the replication of the virus in hepatocytes and their DNA genomes, as seen in hepatitis B virus.

Hepatitis A virus is classified now in the family Picornaviridae, genus Hepatovirus. Although the current rules for nomenclature do not prohibit the introduction of new sigla, they require that the siglum be meaningful to workers in the field and be recognized by international study groups. The latter are translated into structural proteins and accessory proteins. During infection by some coronaviruses, but not others, a fraction of S protein that has not been assembled into virions ultimately reaches the plasma membrane.

At the cell surface S protein can cause the fusion of an infected cell with adjacent, uninfected cells, leading to the formation of large, multinucleate syncytia. This enables the spread of infection independent of the action of extracellular virus, thereby providing some measure of escape from immune surveillance. Key aspects of the coronavirus replication cycle are discussed in more detail in the remainder of this section and in the next section Section V.

Viruses very closely related to BCoV had been isolated from wild ruminants Tsunemitsu et al. Nevertheless, the interaction between S protein and receptor remains the principal, if not sole, determinant of coronavirus host species range and tissue tropism.

At the cellular level, this has been demonstrated by manipulation of each of the interacting partners. First, expression of an identified receptor in nonpermissive cells, often of a heterologous species, invariably has rendered those cells permissive for the corresponding coronavirus Delmas , Dveksler , Li , Li , Mossel , Tresnan , Yeager Similarly, exchange of the relevant regions of S protein ectodomains was shown to transform a strictly respiratory isolate of TGEV into a more virulent, enterotropic strain Sanchez et al.

Table III lists the known cellular receptors for coronaviruses of groups 1 and 2; to date no receptors have been identified for coronaviruses of group 3. Group 2 coronavirus receptors include the earliest and the most recent of the items in Table III.

CEACAM1 was the first receptor discovered for a coronavirus, and, indeed, it was one of the first receptors found for any virus Williams , Williams This diversity of MHV receptor isoforms was found to be generated by multiple alleles of the Ceacam1 gene as well as by the existence of multiple alternative splicing variants of its mRNA Compton , Dveksler a , Dveksler b , Ohtsuka , Ohtsuka , Yokomori This was initially suggested by an early experiment showing that in vivo administration of a monoclonal antibody to CEACAM1 greatly enhanced the frequency of survival of mice subsequently given a lethal challenge of MHV Smith et al.

More definitively, it was demonstrated that homozygous Ceacam1 knockout mice were totally resistant to infection by high doses of MHV Hemmila et al. The CEACAM1 structure now provides the basis for beginning to understand the relative affinities of receptor variants for different S protein ligands.

Other group 2 coronaviruses use different receptors. BCoV is phylogenetically close to MHV, but the two viruses neither share common hosts nor are they supported by any of the same cell lines in tissue culture.

Although this finding raised the possibility of a means to interfere with the initiation of infection, the inhibitor does not affect S protein binding or receptor function of ACE2 Li et al. In all cases tested, nonpermissive cells were shown to be made permissive by expression of human ACE2 Mossel et al.

However, neither the use of specific APN inhibitors, nor the mutational disruption of the catalytic site of pAPN, affected its TGEV receptor activity, indicating that the enzymatic activity of APN, per se, is not required for initiation of infection Delmas et al.

However, chimera construction has not revealed a single linear determinant for virus binding. Rather, two different regions of the molecule have been found to influence receptor activity with respect to a given coronavirus. Not all group 1 coronaviruses use APN as a receptor, however.

This situation can currently be ascribed to an amazing coincidence, but it may later be found to have deeper significance. The more variable of the two portions of the spike molecule, S1, is the part that binds to the receptor. Binding leads to a conformational change that results in the more highly conserved portion of the spike molecule, S2, mediating fusion between virion and cell membranes.

Just as different coronaviruses can bind to different receptors, coronaviruses also appear to use different regions of S1 with which to do so. For MHV, persistent infection in tissue culture was shown to lead to the selection of variant viruses with an extended host range Baric , Baric , Schickli Analysis and engineered reconstruction of one of these selected variants showed that a relatively small number of amino acid changes in the S protein RBD accounted for its extended host range Schickli , Thackray Mutations in some of these residues were lethal or resulted in viruses that formed very small plaques; in particular, a tyrosine at position of the RBD was proposed as a candidate element in a key interaction with the receptor.

However, only the TOR2 virus efficiently adapted to humans. Inspection of the interface of this contact revealed that an astonishingly small number of RBD amino acid changes were critical to the adaptation of the virus from one species homolog of ACE2 to another. The binding of spike to its cellular receptor triggers a major conformational change in the S molecule.

In some cases, induction of this conformational change may also require a shift to an acidic pH. There may be a very fine balance between these two states. Such treatment enhanced the infectivity of the virus by orders of magnitude, and this enhancement was receptor dependent. Such treatment caused the dissociation and release of the cleaved S1 subunit and the aggregation of S2 subunits; the accompanying conformational changes in S1 were monitored by differential access of a panel of monoclonal antibodies at neutral and alkaline pH Weismiller et al.

Disulfide bond formation plays an important role in S protein folding, and disulfides in S1 may become rearranged during the conformational transitions of S1 following receptor binding Lewicki , Opstelten , Sturman The conformational change that separates S1 from the rest of the molecule, in turn, transmits a major change to S2. This secondary change has been monitored by the differential susceptibility of S2 to protease treatment before and after the binding of S1 to soluble receptor Matsuyama and Taguchi, Additionally, the same changes were shown to be caused, in the absence of receptor, by mild alkaline pH, which induced a fusogenic state in S2 that could be measured by a liposome flotation assay Zelus et al.

It has been realized that the coronavirus S protein is a type I viral fusion protein with functional similarities to the fusion proteins of phylogenetically distant RNA viruses such as influenza virus, HIV, and Ebola virus Bosch et al. Similar to its counterparts in other viruses, the coronavirus S2 domain contains two separated heptad repeats, HR1 and HR2, with a fusion peptide upstream of HR1 and the transmembrane domain immediately downstream of HR2 Fig.

Unlike its counterparts, however, the coronavirus S protein does not require cleavage to be fusogenic, and it contains an internal fusion peptide, although the exact assignment of this domain is not agreed upon Guillen , Sainz Even for MHV S and other cleaved S proteins, the fusion peptide is not the amino terminus of S2 created by cleavage Luo and Weiss, , as is the case in other type I fusion proteins.

The result is the juxtaposition of the viral and cellular membranes in sufficient proximity to allow the mixing of their lipid bilayers and the delivery of the contents of the virion into the cytoplasm. There is no contact between the HR2 monomers, each of which associates with the HR1 grooves through hydrophobic interactions.

In addition to the mechanisms of the conformational rearrangements of S1 and S2, other factors influence coronavirus fusion and entry, in ways that are not yet well understood.

For two coronaviruses, the role of cholesterol in virus entry has been investigated. Cholesterol supplementation was found to augment MHV replication, while cholesterol depletion was inhibitory; these effects were shown to occur at the earliest stages of infection Thorp and Gallagher, Contrary to expectations, the basis for the action of cholesterol was not through clustering of CEACAM receptors into lipid rafts, either before or after the binding of virus to receptor Choi , Thorp For those coronaviruses that bring about syncytia formation, cell—cell fusion appears to have different requirements than virus—cell fusion.

Studies with MHV have long noted a correlation between the degree of S protein cleavage and the amount of cell—cell fusion, both of which could be enhanced by trypsin treatment Sturman et al. The extent and kinetics of S protein cleavage were shown to vary among different cell lines, implicating the involvement of a cellular, rather than viral, protease Frana et al.

Treatment of cells with a specific furin inhibitor blocked both cleavage and cell—cell fusion, but it had no effect on virus—cell fusion. Once the full program of viral gene expression is underway, through transcription, translation, and genome replication, progeny viruses can begin to assemble. The M protein is a party to most, if not all, of these interactions and has come to be recognized as the central organizer of the assembly process.

Despite its dominant role, however, M protein alone is not sufficient for virion formation. These observations suggested that some factor, in addition to M, must determine the site of virion assembly and budding. Such studies showed that, for MHV, coexpression of both M protein and the minor virion component, E protein, was necessary and sufficient for the formation of particles Bos , Vennema The resulting VLPs were morphologically identical to virions minus spikes and were released from cells by a pathway similar to that used by virions.

Notably, neither the S protein nor the nucleocapsid was found to be required for VLP formation. This latter contradiction remains to be resolved. Since VLPs contain very little E protein, it is assumed that lateral interactions between M protein monomers are the driving force for virion envelope formation.

These interactions have been explored through examination of the ability of constructed M protein mutants to support or to interfere with VLP formation. In particular, the carboxy terminus of M was extremely sensitive to small deletions or even to point mutations of the final residue of the molecule. Construction of many of these latter mutations in the viral genome revealed a consistent set of effects on viral viability.

This finding, coupled with results from coimmunoprecipitation analyses, provided the basis for further work, which concluded that monomers of M interact via multiple contacts throughout the molecule and particularly in the transmembrane domains de Haan et al. Moreover, the interaction of M with S was demonstrated to be specific; complexes of M did not impede the progress of a heterologous glycoprotein the VSV G protein to the plasma membrane.

Additionally, kinetic experiments revealed that the folding and oligomerization of S protein in the ER is rate limiting in the M—S interaction, in which nascent M protein immediately participates Opstelten et al.

The simplest picture to be drawn from all this evidence, then, is that S protein is entirely passive in assembly but becomes trapped by M protein upon passage through the ER. Nevertheless, there are indications that, in some cases, S cooperates in its own capture. By the criterion of acquisition of endo H resistance, independently expressed S protein was found to be transported to the cell surface with much slower kinetics than S protein that was incorporated into virions.

This led to the proposal that free S protein harbors intracellular retention signals that become hidden during virion assembly Vennema et al. VLP manipulations thus made it possible to begin to dissect the molecular basis for the specific selection of S protein by M protein. As for M—M homotypic interactions, the sites within M protein that bind to S protein have not yet been pinpointed. The residues of S protein that interact with M protein, on the other hand, have been much more precisely localized.

This type of exchange showed that the incorporation of S protein into VLPs of a given species was determined by the presence of merely the transmembrane domain and endodomain of S protein from the same species.

The source of the S ectodomain did not matter. As predicted, this mutant gained the ability to grow in feline cells, while losing the ability to grow in mouse cells. The fMHV chimera provided the basis for powerful selections, based on host cell species restriction, that have been used with the reverse genetic system of targeted RNA recombination Section VI Kuo , Masters , Masters More detailed dissection of the transmembrane domain and endodomain of the MHV S protein has been carried out to further localize the determinants of S incorporation into virions Bosch , Ye In one study, the S protein transmembrane domain, or the endodomain, or both, were swapped with the corresponding region s of a heterologous transmembrane protein, which was expressed as an extra viral gene product Ye et al.

Mutations were constructed in this surrogate virion structural protein, or, alternatively, directly in the S protein. Thus, the precise nature of the interaction between the S protein endodomain and the M protein remains to be resolved. The interaction of the viral nucleocapsid with M protein was originally examined by the fractionation of purified MHV virions Sturman et al. C Narayanan et al. Additionally, it was shown that the transfer of N protein domain 3 to a heterologous protein allowed incorporation of that protein into MHV virions.

In contrast to the more overt structural roles of the M, S, and N proteins, the part played by E protein in assembly is enigmatic. On discovery of the essential nature of E in VLP formation, it was speculated that the low amount of E protein in virions and VLPs indicated a catalytic, rather than structural, function for this factor. E protein might serve to induce membrane curvature in the ERGIC, or it might act to pinch off the neck of the viral particle in the final stage of the budding process Vennema et al.

This phenotype clearly supported a critical role for E protein in virion assembly. This indicated that, for MHV, the E protein is important, but not absolutely essential, to virion assembly. By contrast, for TGEV, two independent reverse genetic studies showed that knockout of the E gene was lethal. Viable virus could be recovered only if E protein was provided in trans Curtis , Ortego This discordance may point to basic morphogenic differences between group 2 coronaviruses such as MHV and group 1 coronaviruses such as TGEV.

Alternatively, it is possible that E protein has multiple activities, one of which is essential for group 1 coronaviruses but is largely dispensable for group 2 coronaviruses. The information available about E protein at this time is not sufficiently complete to allow us to understand the function of this tiny molecule.

One of the most intriguing questions is whether it is necessary for E protein to directly physically interact with M protein, or whether E acts at a distance. If E protein has multiple roles, then perhaps both of these possibilities are applicable. Direct interaction between the E and M proteins is implied by the observation that, at least in some cases, coexpression of E and M proteins from different species does not support VLP formation Baudoux et al.

Contrary to this, some data appear to argue that E acts independently of M. Some indirect evidence may also be taken to indicate that E does not directly contact other viral proteins. Multiple revertant searches with E gene mutants failed to identify any suppressor mutations that map in M or in any gene other than E Fischer et al.

Such an activity made be the basis for an independent mode of action of E protein. This may be accomplished with varying degrees of stringency by different members of the family. By contrast, similarly purified virions of BCoV Hofmann et al. In those viruses in which it has been mapped, the RNA element that specifies selective packaging falls, as would be expected, in a region of the genome that is not found in any of the subgenomic mRNAs.

DI RNAs are extensively deleted variants of the genome that propagate as molecular parasites, using the replicative machinery of a helper virus. Dissection of particular members of the former class revealed that a relatively small span of internal sequence could account for packaging competence Makino , van der Most The MHV packaging element is thus embedded in the coding sequence of nsp15, at the distal end of the replicase gene.

This functional homology does not appear to extend across group boundaries, though. For the group 1 coronavirus TGEV, the packaging signal was also shown to be retained in particular DI RNAs, which were found to be incorporated into defective virions that could be separated from helper virus by density gradient centrifugation Mendez et al.

It will be interesting to see whether the packaging signals of viruses in the three coronavirus groups, once they are completely characterized, are found to retain structural similarities despite differences in sequence and location.

The mechanism by which packaging signals operate is not yet clear, and results with MHV have in fact taken an unanticipated turn. In this context, it is important to note the distinction between encapsidation and packaging, two terms that are often used interchangeably in the coronavirus literature. Encapsidation is the process of formation of the nucleocapsid, that is, the cooperative binding of N protein to viral RNA. Packaging is the incorporation of the nucleocapsid into virions. For enveloped viruses, the two processes are not necessarily the same.

For coronaviruses, it was logical to assume that encapsidation is initiated by the N protein. A possible resolution of this paradox has come from findings that reveal a role for M protein in the selectivity of packaging. If this discovery turns out to generalize to all coronaviruses, then it will mean that M protein orchestrates every single interaction necessary for virion assembly.

Coronavirus RNA synthesis proceeds by a complex and incompletely understood mechanism, portions of which involve interactions between distant segments of the genome Lai , Lai , van der Most Coronavirus RNA synthesis.

Manipulations of naturally occurring and artificially constructed DI RNAs, which are studied by transfection into infected cells, enabled the mapping of elements from the genome that participate in replication and transcription Brian and Baric, The exact magnitude of this value appears to have been dependent on which MHV genomic regions were present in the individual DI RNA with which a particular analysis was begun.

Consistent with this latter finding, it was shown for engineered mutants of MHV that translocation of the N gene to an upstream genomic position had no effect on replication Goebel et al.

If any such region does exist, it must be able to act at a distance of nearly 1. It has thus been proposed that they constitute components of a molecular switch that is operative at some stage of RNA synthesis, although a target of their putative regulation has not yet been identified Goebel et al. The group 1 coronaviruses all contain a highly conserved pseudoknot Williams et al. Only the group 2 coronaviruses have both elements, and, in all cases, the elements overlap in the same fashion.

Numerous investigations have focused on the intriguing nature of coronavirus sgRNA transcription. TRSs are fairly well conserved within each coronavirus group. Not every TRS in a given virus conforms exactly to the consensus sequence; a number of allowable variant bases are found in individual TRSs.

However, studies with DI RNAs containing authentic and mutated TRSs led many investigators to conclude that, beyond a minimum threshold of potential base pairing, other factors must predominate Hiscox , Makino , van der Most It was proposed that the polymerase pauses near the end of the leader sequence and detaches with the nascent free leader RNA.

This work made use of a robust system in which both the leader copy and one or multiple body copies of the TRS were singly or simultaneously mutated in the genome; RNA synthesis in this system was able to be assayed in the initial passage of infectious RNA Pasternak , Pasternak , Pasternak , van Marle It will also be necessary to extend to the coronaviruses principles that have been more clearly established for the arteriviruses.

An important feature of coronavirus RNA synthesis is the high rate of homologous and nonhomologous RNA—RNA recombination that has been demonstrated to occur among selected and unselected markers during the course of infection. Although most experimental work in this area has been performed with MHV Keck , Keck a , Keck b , Makino , Makino , a high frequency of homologous recombination is clearly an attribute of the entire coronavirus family, given that it has been observed in other viruses in all three groups: TGEV Sanchez et al.

In addition, nonhomologous recombination was likely, in all three groups, to be the mechanism of acquisition of the various accessory protein genes.

In this scheme, the viral polymerase, with its nascent RNA strand intact, detaches from one template and resumes elongation at the identical position, or a similar position, on another template.

On a fine scale, the sites of recombination were seen to be random Banner and Lai, , although strong selective pressures were able to create the appearance of local clustering of recombinational hot spots in one study Banner et al.

Most evidence supports a model for viral RNA recombination having three mechanistic requirements Lai, First, the RNA polymerase must pause during synthesis. This may be an intrinsic property of the enzyme, or it may result from the enzyme encountering a template secondary structure that exceeds a certain stability threshold.

Second, a new template must be in physical proximity. Third, some property of the new template must allow the transfer of the nascent RNA strand and the resumption of RNA synthesis.

Alternatively, strand transfer could result from a processive mechanism that does not require polymerase dissociation Jarvis and Kirkegaard, Such a disruption, followed by resumption of replicative antigenome synthesis, would leave a partial copy of the leader sequence embedded at an internal point in the genome, near the junction between two genes. This type of recombinant was selected repeatedly in revertants of a severely impaired MHV M protein mutant.

However, similar transcriptional collapse events may have been a significant factor in coronavirus evolution. Each of these leader remnants occurs at a site where there is an apparent deletion of an entire accessory gene, with respect to the genomic layouts of the closest relatives of this virus, MHV and BCoV.

The replicase complex that carries out the intricacies of viral RNA replication and transcription is encoded by the first gene of the coronavirus genome. The discovery of coronavirus ribosomal frameshifting resulted from the completion of the sequence of IBV, the first member of the family for which an entire genomic sequence was obtained Brierley et al. This revealed a small 43 nt overlap between ORF 1a This arrangement was subsequently found to exist for all coronaviruses.

Thus, ribosomal frameshifting, which had previously been seen only in retroviruses Jacks et al. It should be noted, however, that the efficiency of in vivo frameshifting occurring in cells infected with IBV, or any other coronavirus, has not yet been quantitated; nor is it known whether that value remains constant over the course of infection.

In addition, the spacing between these elements is critical. It is thought that the pseudoknot impedes the progress of the elongating ribosome. Normal translational elongation then resumes. Studies of the kinetics of translation, using a model mRNA based on the IBV frameshifting region, support the idea of ribosomal pausing at the pseudoknot Somogyi et al.

Moreover, mutational studies of IBV frameshifting Brierley et al. The reason why coronaviruses employ ribosomal frameshifting as a gene expression strategy is less well established at this time. The explanation most commonly given is that, as for retroviruses, the frameshifting mechanism provides a fixed ratio of translation products, in the necessary proximity of one another, for assembly into a macromolecular complex.

It could also be speculated that frameshifting forestalls expression of the enzymatic products of ORF 1b until a platform and a cellular environment for them have been prepared by the products of ORF 1a. RNA elements required for ribosomal frameshifting. The expanded region shows RNA sequences and secondary structures that program the frameshift, using IBV as an example. The two genomic components required for ribosomal frameshifting have been investigated in considerable detail.

However, although some heptanucleotides showed a frameshifting efficiency nearly as high as that of the wild type, it must be noted that, to date, all known coronaviruses have been found to contain a slippery sequence of UUUAAAC Brian , Plant The second component, the pseudoknot, has similarly been examined through exhaustive mutagenesis Brierley et al. Although the involvement of a downstream RNA secondary structural element in ribosomal frameshifting was first recognized with retroviruses Jacks et al.

This demonstration was initially by classic stem replacement mutagenesis, and, subsequently, by intensive modification of pseudoknot elements; all of the results of both types of studies supported the proposed structure.

It was also revealed that the length of stem 1 is very important for frameshifting efficiency Napthine et al. The frameshifting signals of other coronaviruses have been found to generally conform to the rules defined for IBV, although additional complexities have emerged. It is currently unresolved whether the group 1 elaborated pseudoknot is the operative structure in frameshifting, as suggested by some mutational evidence Herold and Siddell, The role of stem 3 in ribosomal frameshifting is, as yet, unclear.

On the other hand, the complete deletion of stem 3 is not detrimental to frameshifting. This seeming discrepancy has led to the suggestion that stem 3 plays an as yet undiscovered regulatory role, perhaps in the switch from genome translation to replication Plant et al. These range from to kDa and from to kDa, respectively, and they are cotranslationally processed by two or three internally contained proteinase activities. The Herculean task of mapping all of the polyprotein processing events began at a time before investigators were even aware of the full sizes of coronavirus genomes Denison , Denison , Soe Only relatively recently have replicase cleavage maps been completed for at least one representative from each coronavirus group Bonilla , Kanjanahaluethai , Lim , Liu , Lu , Pinon , Schiller , Xu , Ziebuhr , Ziebuhr The final products of the autoproteolytic cleavage of pp1a and pp1ab are 16 nonstructural proteins, designated nsp1—nsp16 Fig.

Nsp1—nsp11 are derived from pp1a, whereas nsp1—nsp10 and nsp12—nsp16 are derived from pp1ab. Thus, all products processed from pp1a are common to those processed from pp1ab, except for nsp11, which is an oligopeptide generated when ribosomal frameshifting does not occur. For IBV, which lacks a counterpart of nsp1, there are 15 final products of polyprotein cleavage.

These are numbered beginning with nsp2, in order to maintain correspondence with their homologs in the other coronaviruses. Comparative layouts and processing schemes for the replicase genes of all three coronavirus groups can be found in the review by Ziebuhr and references therein.

It should be noted that partial proteolytic products may also be significant in the processing scheme. The efficiency of cleavage at particular polyprotein sites may be regulated by both the exact primary sequence at the site and the site's accessibility to the proteinase Ziebuhr , Ziebuhr Protein products of the replicase gene.

Cleavage sites and processed products of pp1a nsp1—nsp11 and of pp1ab nsp1—nsp10, nsp12—nsp16 are shown. Elucidation of the precise roles of nsp1—nsp16 will be the next major undertaking. While knowledge about many of the replicase proteins is still at a very early stage, substantial progress has been made for others.

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