In viruses such as HIV, this modification sometimes called maturation occurs after the virus has been released from the host cell. Viruses can be released from the host cell by lysis, a process that kills the cell by bursting its membrane and cell wall if present. This is a feature of many bacterial and some animal viruses. The viral genome is then known as a provirus or, in the case of bacteriophages a prophage. Whenever the host divides, the viral genome is also replicated.
The viral genome is mostly silent within the host; however, at some point the provirus or prophage may give rise to active virus, which may lyse the host cells. Enveloped viruses e. The genetic material within virus particles, and the method by which the material is replicated, varies considerably between different types of viruses.
Viral infection involves the incorporation of viral DNA into a host cell, replication of that material, and the release of the new viruses. A virus must use cell processes to replicate. The viral replication cycle can produce dramatic biochemical and structural changes in the host cell, which may cause cell damage.
These changes, called cytopathic causing cell damage effects, can change cell functions or even destroy the cell. The symptoms of viral diseases result from the immune response to the virus, which attempts to control and eliminate the virus from the body and from cell damage caused by the virus.
Many animal viruses, such as HIV Human Immunodeficiency Virus , leave the infected cells of the immune system by a process known as budding, where virions leave the cell individually. During the budding process, the cell does not undergo lysis and is not immediately killed. However, the damage to the cells that the virus infects may make it impossible for the cells to function normally, even though the cells remain alive for a period of time.
Most productive viral infections follow similar steps in the virus replication cycle: attachment, penetration, uncoating, replication, assembly, and release. Pathway to viral infection : In influenza virus infection, glycoproteins attach to a host epithelial cell. As a result, the virus is engulfed. RNA and proteins are made and assembled into new virions.
A virus attaches to a specific receptor site on the host cell membrane through attachment proteins in the capsid or via glycoproteins embedded in the viral envelope.
The specificity of this interaction determines the host and the cells within the host that can be infected by a particular virus. This can be illustrated by thinking of several keys and several locks where each key will fit only one specific lock.
The nucleic acid of bacteriophages enters the host cell naked, leaving the capsid outside the cell. Plant and animal viruses can enter through endocytosis, in which the cell membrane surrounds and engulfs the entire virus. Some enveloped viruses enter the cell when the viral envelope fuses directly with the cell membrane.
Once inside the cell, the viral capsid is degraded and the viral nucleic acid is released, which then becomes available for replication and transcription. The replication mechanism depends on the viral genome. The viral mRNA directs the host cell to synthesize viral enzymes and capsid proteins, and to assemble new virions.
Of course, there are exceptions to this pattern. If a host cell does not provide the enzymes necessary for viral replication, viral genes supply the information to direct synthesis of the missing proteins. Reverse transcription never occurs in uninfected host cells; the needed enzyme, reverse transcriptase, is only derived from the expression of viral genes within the infected host cells. The fact that HIV produces some of its own enzymes not found in the host has allowed researchers to develop drugs that inhibit these enzymes.
This approach has led to the development of a variety of drugs used to treat HIV and has been effective at reducing the number of infectious virions copies of viral RNA in the blood to non-detectable levels in many HIV-infected individuals. The last stage of viral replication is the release of the new virions produced in the host organism. They are then able to infect adjacent cells and repeat the replication cycle. As you have learned, some viruses are released when the host cell dies, while other viruses can leave infected cells by budding through the membrane without directly killing the cell.
A tropism is a biological phenomenon, indicating growth or turning movement of a biological organism in response to an environmental stimulus. In tropisms, this response is dependent on the direction of the stimulus as opposed to nastic movements which are non-directional responses. Host tropism is the name given to a process of tropism that determines which cells can become infected by a given pathogen. Host tropism is determined by the biochemical receptor complexes on cell surfaces that are permissive or non-permissive to the docking or attachment of various viruses.
Various factors determine the ability of a pathogen to infect a particular cell. If so, this would render the capsid accessible to TIM-1, which undergoes constitutive endocytosis and trafficking to late endosomes and lysosomes 26 , as well as to anti-HAV. Many details of eHAV entry and neutralization remain to be explained.
However, TRIM tripartite motif-containing 21 , which is implicated in intracellular neutralization of other viruses 27 , seems to have no function in neutralization of eHAV Supplementary Fig.
Left, intracellular; right, extracellular. For post-treatment, JC was added to the medium on refeeding after removal of the inoculum. The host membrane enveloping eHAV is likely to facilitate its spread within the liver. Antibodies restrict the replication of eHAV when added to cultures several hours after infection, but further studies will be needed to determine how this happens and whether this can explain why immune globulin and vaccines protect against hepatitis when administered long after exposure, when virus is already circulating in blood 5.
Chemical reagents were purchased from Sigma unless otherwise noted. The sources of other anti-HAV mAbs have been described previously All chimpanzee materials were archived samples collected during previous studies 5 conducted prior to 15 December Proteins were extracted from gradient fractions by precipitation with trichloroacetic acid.
Immunoblots were performed with standard procedures and the indicated antibodies. Images were collected with a Zeiss Meta laser-scanning confocal microscope. Approximately 20 fractions were collected from the top of the gradient; density was determined with a refractometer. Beads were extensively washed with lysis buffer, and captured immunoprecipitates were subjected to RNA extraction for qRT—PCR, or immunoblotting, as above.
PCR-derived fragments were sequenced to ensure sequence fidelity. Gradient fractions 2. Harrison, S. Google Scholar. Feng, Z. Lemon, S. Type A viral hepatitis: new developments in an old disease. Martin, A. Ou, J. Book Google Scholar. Lanford, R. Natl Acad. USA , — Victor, J. Bobrie, A.
Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 12 , — Hurley, J. Jansen, R. Virology , — Counihan, N. Infrared fluorescent immunofocus assay IR-FIFA for the quantitation of non-cytopathic and minimally cytopathic viruses. Methods , 62—69 Ping, L. Cohen, L. Graff, J. Schulman, A. This finding clearly warrants further investigation into an intraviral protein interaction which has not been investigated yet.
Protein 7a, a structural protein unique to SARS-CoV, is incorporated into mature virions and plays an important part in the pathogenesis of SARS-CoV, where it functions to induce apoptosis, arrest the cell cycle, and promote the production of pro-inflammatory cytokines [ , , , , ].
In a mammalian two hybrid system, SARS-CoV E was found to interact with 7a, but the importance of this interaction has not yet been determined [ ]. However, despite this interaction with E, 7a still appears to be dispensable for SARS-CoV replication both in vivo and in vitro [ 30 , , , ].
Viruses lack the necessary machinery to self-replicate and are, therefore, dependent on the host cell machinery for propagation. The PDZ domain is a protein-protein recognition sequence found in cellular adaptor proteins that coordinate host cell signalling pathways by binding to other proteins that have a complementary PBM.
A number of these signalling pathways and processes are exploited by viruses for replication, propagation, and pathogenesis [ , , , , ]. To date, E has only been reported to interact with five host proteins, i. Some context has been offered as to the relevance of each interaction, but it is not yet fully understood. By infecting mice with recombinant SARS-CoV viruses, they demonstrated that E caused syntenin to be redistributed to the cytoplasm where it triggered an overexpression of inflammatory cytokines.
This would give rise to an exacerbated immune response, resulting in tissue damage, oedema, and culminate in the characteristic acute respiratory distress syndrome ARDS. Aside from this, it is of therapeutic importance that more E interaction partners be identified as inhibitors of p38 mitogen-activated protein kinase MAPK were shown to increase the survival rate of mice, protecting them from a lethal infection [ 18 , ]. Identifying more interaction partners for CoV E could provide a more targeted therapeutic approach where licensed coronaviral treatments are currently ineffective [ 26 , 27 , 28 ].
Partial amino acid sequences of the E protein C-terminus for the different CoV genera. Red blocks represent the potential location of the predicted PBM motif [ 18 ]. Despite its enigmatic nature, research conducted to date has been able to propose three roles for the CoV E protein.
The interaction between the cytoplasmic tails of the M and E proteins drives VLP production, suggesting that E participates in 1 viral assembly [ 56 , 61 , 89 ]. The hydrophobic TMD of E is also crucial to the 2 release of virions [ 40 , 53 , ].
The progress made in these three aspects of E will be reviewed accordingly. Coronaviruses are unique among enveloped viruses in that assembly of the viral envelope occurs at the ERGIC. From there, virions bud into the lumen, navigate their way through the host secretory pathway, and ultimately egress from the cell [ 89 , 90 , , ]. Although assembly of the viral envelope is coordinated by M, both M and E are required for the production and release of VLPs [ 51 , 55 , 56 , 60 , 61 , 62 , 63 , 64 , , , , ].
Still, deleting the E gene from several recombinant CoVs does not halt virus production but rather cripples viral production severely or produces replication-competent but propagation-defective virions [ 35 , 39 , 40 , 67 , 68 , , , ].
Clearly then E is involved in the CoV assembly and release, but the exact role is not yet fully understood. The coronaviral envelope consists predominantly of M while only a small portion of E is incorporated into the viral envelope of virions [ , , ]. Extensive electron microscopy EM studies conducted on M from a variety of CoVs provided no indication that M is capable of inducing membrane curvature on its own [ 51 , , ].
When C-terminus residues of MHV E were mutated to alanine, virions became temperature sensitive and took on pinched, elongated shapes rather than the typical spherical particles observed among wild type virions [ ]. This material was proposed to be the result of the aborted viral assembly process that gave rise to immature virions [ 35 ]. The absence of TGEV E arrested virus trafficking and, thereby, blocking full virion maturation [ 40 ].
In comparison, the phenotype of VLPs made up of M and E are described as smooth and indistinguishable from, or resembling, wild type virions, placing this morphology in stark contrast to that observed of virions lacking E [ 37 , 63 , 64 ]. Most likely then, instead of coordinating viral assembly, the function of E is rather to induce membrane curvature of the viral envelope, thereby allowing CoV particles to acquire their characteristic spherical shape and morphology. Coronavirus-infected cells contain several different membranous structures, including double-membrane vesicles DMVs and convoluted membranes CMs [ , , , ].
The luminal loops present in full-length nsp3 and nsp4 are essential for the formation of the replicative structures seen in SARS-CoV-infected cells [ , ]. Moreover, the cysteine residues located in the luminal loop nsp4 appear to be particularly important in the process of ER membrane rearrangement [ ].
Hagemeijer, Monastyrska [ ] proposed a model in which the luminal loops located between the transmembrane regions of nsp3 and 4 interact with one another to initiate the rearrangement of ER membranes and induce membrane curvature to form DMVs Fig. Model proposed by Hagemeijer, Monastyrska [ ] for the induction of ER membrane curvature.
This underpins the importance of establishing a unanimous topology for the E protein as this model could be applied to the induction of membrane curvature by E, provided E can assume multiple topologies during an infection.
Should it be demonstrated that E can take on a topology with a luminal loop, this would not be inconceivable as a possible mechanism for the induction of membrane curvature initiated by E or in which E participates. Equally, as heterotypic interactions of nsp3 and 4 are required to induce ER membrane curvature, and the expression of both M and E is required for the formation of smooth, spherical CoV VLPs, it would be interesting to see if a heterotypic interaction between M and E could drive membrane curvature by a similar mechanism [ , , ].
Alternatively, no research exists on the exact purpose of the N-terminus of E. Perhaps homotypic interactions mediated by the N-termini of alternating E proteins could be responsible for inducing membrane curvature by a similar mechanism. It is also worth noting that the mutation of each of the cysteine residues located in the nsp4 luminal loop abrogated the ability of nsp4 to rearrange the ER membranes [ ].
This is interesting because cysteine residues are substrates for the palmitoylation of proteins associated with membranes [ ]. Perhaps this corroborates the requirement of E palmitoylation, not in assembly per se, but rather by anchoring E during the induction of membrane curvature. It is quite evident that although a lot of progress has been made in determining the role of E in assembly, much still remains unknown. The role of E has also been proposed to be merely catalytic by functioning to pinch off, or in the scission of, the viral particle from the ER membrane during the terminal phase of budding [ 63 ].
The viral envelope is formed primarily during assembly and culminates when the virion buds from the host membrane, a process known as scission [ ]. In the absence of scission machinery, the budding process begins but ultimately stops, and render budding virions attached to the membrane by a small membranous neck. This is clearly and elegantly demonstrated in the mutation of the matrix-2 M2 protein, a viral protein responsible for the budding and scission of the influenza virus.
Virions that have failed to undergo scission remain attached to the host cell membrane by a membranous neck. The budding process is reinitiated at the site where scission failed, and a new virion is formed.
However, the new virion also remains attached to the membrane as well as the previous virion by a small membranous neck. The continuation of this cycle and repeated initiation of budding results in the formation of consecutive scission-defective virions that resemble beads on a string [ , ].
The same morphology has been reported for the Moloney murine leukaemia virus upon deletion and mutation of p12 protein that functions in its assembly and release [ ]. It is, therefore, essential that host cell candidates capable of interacting with CoV E be identified as they could be potential therapeutic targets for CoV antivirals to stop CoV scission.
The amphipathic helix located in the cytoplasmic tail of the M2 protein is both required and sufficient for the detachment of vesicle buds in an in vitro model system [ ]. Mutation of the hydrophobic region of the helix also significantly reduced viral release in vivo, confirming the importance of the amino-acid-helix in the release of the influenza virus in vivo as well.
In the absence of the M2 protein, buds formed inside infected cells but failed to detach and such cells exhibited the beads-on-a-string morphology. It appears that no attempts have been made to determine whether E of any of the CoVs is responsible for the scission of CoV virions during budding.
However, expression of E alone has been reported to produce and secrete vesicles from cells but no further research has been done to determine how this is possible [ 60 , ]. Mutational studies would certainly benefit from EM analysis to determine what effects TMD mutations of E would have on virion budding.
Electron microscopy can clearly demonstrate the consequences of mutated scission proteins and can even prove useful to ascertain what effects complete gene deletion have on viral budding. While the accumulation of E at the ERGIC points largely to a role in assembly and budding, only a small portion is incorporated into the viral envelope, suggesting that E has additional functions centred around the ER and Golgi region [ 66 , 92 , , ].
Viroporins are viral-encoded membrane pore-forming proteins that can modulate cellular ion channels and have been suggested to regulate and function in multiple stages of the viral life cycle, from viral entry to assembly and release, and even pathogenesis [ , , , , , , , , , , ].
Although viroporins are not essential to viral replication, their absence does weaken or attenuate the virus and diminishes its pathogenic effects [ 35 , , , , ]. The hydrophobic residues line the outside of the structure, oriented toward the phospholipids, while the inside of the pore is made up of the hydrophilic resides [ , , , , , ]. Illustration of a typical viroporin structure and motifs.
Conformational changes in the structure regulate the flow ions through the viroporin by opening left and closing right the pore [ ]. Although preferentially selective for cations, viroporins can also transport anions. The preference simply appears to be for cations over anions [ , , ].
It is, however, interesting to note that, at a neutral pH, the ion selectivity of the respiratory syncytial virus RSV small hydrophobic SH protein can change from cationic to anionic [ ]. This suggests that viroporins are sensitive to changes in the cellular environment, a property that could be of therapeutic value.
After all, the influenza A virus M2 protein is pH-gated and activates upon acidification of the endosome following receptor-mediated endocytosis of the virus [ ]. In the same study, Schnell and Chou [ ] showed that the anti-viral drug rimantadine exerts its anti-viral property by stabilising the M2 viroporin in its closed conformation and in doing so inhibits viral replication [ , ].
Similarly, the E protein of several CoVs possesses ion channel activity, though the only structural data of the CoV viroporin has been derived from SARS-CoV using synthetic peptides [ 75 , , , , , ].
Computational predictions and spectroscopic studies show that the SARS-CoV E TMD undergoes oligomerisation, characteristic of ion-channelling proteins, to form a stable pentamer [ 75 , , , ].
Viroporin formation appears to be mediated by ionic interactions rather than disulphide bonds as mutation of the porcine reproductive and respiratory syndrome virus PRRSV E protein cysteine residues appears to be dispensable for oligomerisation [ ]. Research into the mechanism of viroporin formation is hampered by the hydrophobic nature of the TMD and has thus far been limited largely to mutational studies and the use of ion channel inhibitors such as amantadine and hexamethylene amiloride.
More recently, purified full-length MERS-CoV E has also demonstrated limited ion-channelling properties and would benefit from a more comprehensive characterisation to establish whether it has ion-channelling properties similar to that of the other CoVs [ ]. It should be cautioned that the charge on the lipid head group of membranes used can modulate the ion-selectivity of the viroporin. Neutral lipids appear to negate the selectivity of the viroporin as the channels formed did not seem to differentiate cations from anions.
In contrast, negatively charged lipids were more cation-selective than neutral lipids, being more permeable to cations [ 76 ]. This suggests that the lipid head group of the membranes in use should be taken into consideration when interpreting the results as it might skew the results and inaccurate conclusions may be drawn. At times, the ion channels were only marginally more selective of cations, bringing into question the ion-selectivity of the CoV E viroporin for one cation over another.
In fact, an ion channel is only considered ion-specific when its permeability is nearly exclusive to one ion while extremely low to others [ ]. Recent efforts have been directed toward understanding how mutant CoV E viruses carrying ion channel-inactivating mutations revert to their original pathogenic state.
Mutant N15A reverted by incorporating a single mutation that led to an amino acid change at the same position A15D , creating a more stable mutant. Intriguingly, the V25F mutants appeared as early as 2 days after mice were infected where revertant mutant T30I surpassed the growth of the original virus by day two.
This suggests that while some of these mutations appear to merely restore the loss of ion channel activity, it is not entirely inconceivable that revertant viruses would acquire gain of function mutations that can render it more virulent [ 77 ].
Some viroporins have been implicated in the release of viruses, but it is not yet known whether the release is mediated by the ion channel activity of the proteins [ , , , , ]. However, this increase in pH was found only in cells expressing a monomeric form of IBV E and not the oligomeric form as required for viroporin formation.
The authors proposed that the change in pH could be attributed to an interaction between the monomeric form of E and a host protein. Although possible, only a very small number of host proteins have been shown to interact with CoV E.
The oligomeric form, however, was the dominant form in infected cells [ 90 ]. This suggests that other viral proteins might affect or modulate the oligomerisation of IBV E. It is interesting to note that the M2 protein amphipathic helix motif was required for release of influenza A virus IAV particles, perhaps indicating that this motif might be required for the processes budding, scission, and for viroporin activity [ ].
It might be worth investigating whether ion-channel inhibitors, such as amantadine, or proton pump inhibitors specifically are able to inhibit this increase in Golgi pH. For now, though, it still remains to be seen whether CoV release is mediated by viroporin ion channel activity or through PPIs with host proteins of the secretory pathway. The ER can sustain a high load of protein content without being overwhelmed [ ]. If, however, the UPR is prolonged and irreversible, apoptosis will be initiated [ ].
By increasing the protein content, folding, and processing of the ER, viral infections can also trigger the UPR and this pathway can be used by the host cell as an antiviral response [ ].
Very few studies have looked at the role of CoV E in the ER stress response and its ability to induce apoptosis. This study demonstrates the risk of interpreting data from overexpression and epitope-tagged studies. Results generated by such studies might offer some insight into the putative functions of viral proteins but should be interpreted with great care as they can be misleading.
Findings can only be more conclusive when supported by results from studies in more biologically relevant systems. The study also shows that CoV E has an anti-apoptotic function in infected cells by suppressing the UPR during infection, likely as a survival mechanism and to continue viral propagation. It would be interesting to see whether E of the other CoVs, as well as the less virulent HCoVs, are also able to contribute to pathogenesis by regulating the host cell stress response. Viruses often encode proteins that interfere with the immune system to either inhibit a response or enhance one as part of their pathogenicity.
Some viral proteins disrupt components of the immune response pathways to disrupt the immune system and promote their viral evasion and pathogenesis [ , , , ]. Alternatively, viral proteins can modulate other cellular factors that could also disrupt the immune response to promote pathogenesis. Coxsackievirus 2B protein promotes the internalisation of major histocompatibility complex class I MHC-I proteins and, in doing so, prevents their transport to the cell surface for immune recognition [ ].
Influenza virus M2 protein triggers activation of the NOD-like receptor family, pyrin domain containing 3 NLRP3 inflammasome by creating ionic imbalances through its ion-channel activity [ ]. Other viruses use viroporins to stimulate an immune response as part of their pathogenicity, including the E protein of PRRSV [ , , ].
Blocking ion channel activity with amantadine significantly inhibited activation of the inflammasome, demonstrating an association between E viroporin activity and inflammation. Interestingly, despite attempts to inhibit ion channel activity in SARS-CoV E, by mutating N15A and V25F, viruses restored ion channel activity by incorporating additional mutations after several passages.
The authors concluded that this ion-channelling function confers a selective advantage to the virus [ 77 ]. The reduction of inflammatory cytokines in the absence of CoV E ion channel activity suggests that inhibition of the CoV E viroporin limits CoV pathogenicity and could be of therapeutic value to CoV infections. There are currently no effective, licensed therapies for HCoV infections and existing treatment strategies are generally limited to symptomatic treatment and supportive care [ 26 , 27 , 28 , ].
While an extensive amount of research has gone into identifying potential treatment options, most have only shown promise in vitro and will likely not progress further as they often have one or more limitations. Anti-viral candidates either exhibit only a narrow spectrum of activity, are only effective at unusually high therapeutic dosages or cause serious side effects or immune suppression [ ].
Vaccinated animal models developed robust immune responses, both cellular and humoral, and were protected against infective challenges. This shows that CoV vaccines with mutated or deficient in E can potentially be used for prophylactic treatment, but the duration of immunity does not seem to have been established yet.
This dependence on PPIs offers the unique opportunity to target both viral-host and intraviral PPIs and, thereby, stop viral replication and propagation. Therapies that use small-molecule drugs have the advantage of small size, which allows the drugs to cross cell membranes efficiently, but it also severely limits the selectivity and targeting capabilities of the drug, which often leads to undesired side-effects [ ]. Interactions between proteins take place over large, flat surface areas that feature shallow interaction sites.
Small-molecule drugs, however, tend to bind to deep grooves or hydrophobic pockets not always found on the surface of target proteins, making it difficult for such drugs to disrupt PPIs Fig. Larger, protein-based therapies, on the other hand, make use of insulin, growth factors, and engineered antibodies, that form many more, and much stronger, interactions, making these therapies more potent and selective for their targets.
Such properties result in fewer side-effects but the size of these agents also restricts their ability to cross the membranes of target cells [ ]. This calls for therapeutic agents that can bridge the gap between molecules that are large enough to be specific and potent for their targets but still small enough to be able to cross target cell membranes efficiently and can also be manufactured easily.
Mechanisms of interaction between small molecules and proteins, and protein-protein interactions. Left: The binding of biotin to avidin occurs in a deep groove, while the interaction between the human growth hormone hGH and the hGH receptor hGHR occurs over a larger, flatter area [ ]. Stapled peptides fulfil these criteria to a large extent and have been applied to various human diseases and fields such as cancer, infections, metabolism, neurology, and endocrinology [ , , , , ].
The company has already completed the first-in-human trail with ALRN for the treatment of rare endocrine diseases, such as adult growth hormone deficiency. Granted, the therapeutic application of stapled peptides, particularly regarding viral infections, is still relatively new, but their numerous advantages give them tremendous potential as antiviral agents.
As more viral PPIs for CoV E are identified, the repertoire of stapled peptide targets also expands making it easier to limit viral replication, propagation, and even pathogenesis. Stapled peptides have the potential to be used as antiviral agents that can work effectively at multiple levels. Autophagy is a cellular process that recycles excess or damaged cellular material to maintain the energy levels of the cell and ensure its survival.
The material is removed from the cytoplasm by forming enclosed DMVs known as autophagosomes and then fused with lysosomes to be degraded [ , ]. Recent studies have increasingly pointed to the involvement of autophagy components in viral infections [ ]. Some suggest that it might have an antiviral function by inhibiting viral replication [ , , ].
Others reported inhibition or subversion of autophagy as a defence mechanism to promote viral propagation [ , , ]. Others still, notably RNA viruses, appear to exploit autophagy for the purpose of viral propagation [ , ].
Interestingly, PRRSV activates autophagy machinery, possibly to enhance viral replication as certain components of autophagy are required for MHV replication [ , ]. These studies suggest the possibility of CoVs exploiting autophagy for replicative purposes. It has even been proposed that the DMVs formed in CoV-infected cells might be the result of autophagy and derived from the rough ER [ ]. The rotavirus non-structural protein 4 NSP4 reportedly induces autophagy by a similar mechanism [ ].
However, experimental evidence would be required to support the possibility of such a mechanism in CoVs. From studies, it appears that some viral proteins do not have unique, definitive functions. Despite the deletion of some viral genes, the viral life cycle continues, suggesting that other viral genes can compensate for this loss. It was recently shown to be the case for the vaccinia virus [ ].
This is also evident in the varied requirements of the E protein for different CoVs and the reason s for this is not understood. Certain CoV accessory proteins appear to be able to complement, or sometimes even compensate for, the absence of E in processes such as assembly, release, and the pathogenesis of some CoVs [ 30 ].
It is particularly noteworthy that SARS-CoV encodes two accessory proteins, 3a and 8a, that might exhibit relative compensatory functions in the absence of E [ , ]. In terms of viral replication in vivo and in vitro, 3a could partially compensate for the loss of E. Moreover, 3a also contains a PBM and might be able to compensate for the loss of E to an extent but utilises different signalling pathways [ ]. Although the study demonstrated that even the accessory proteins demonstrate some measure of dispensability, the virus still encodes these additional proteins with overlapping functions.
The dynamics between these proteins, however, are not quite clear yet and warrants further investigation. What is clear, though, is that viroporin proteins, case in point IAV M2, can exhibit a multitude of different functions independent of their ion-channel properties [ , ]. The studies in this review have shown that CoV E could be involved in multiple aspects of the viral replication cycle: from assembly and induction of membrane curvature to scission or budding and release to apoptosis, inflammation and even autophagy.
Although a lot of progress has been made on CoV E, there is still much to be discovered about this small, enigmatic protein. Virus taxonomy: Classification and nomenclature of viruses Seventh report of the International Committee on Taxonomy of Viruses. San Diego: Academic Press; ISBN Coronavirus infection in equines: A review.
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