This mini-review provides a brief overview as to how the virus is able to invade host cells, replicate itself, and exit the host cell. Influenza A belongs to the family of Orthomyxoviridae. It is an enveloped virus with a genome made up of negative sense, single-stranded, segmented RNA. The influenza virus virions are known to display a number of shapes, with the most abundant one being roughly spherical.
The viral envelope is made up of a lipid bilayer that contains three of the viral transmembrane proteins: HA, NA, and M2. HA is the most abundant envelope protein at approximately 80 percent, followed by NA, which makes up around 17 percent of the viral envelope proteins. M2 is a very minor component of the envelope, with only 16 to 20 molecules per virion. HA and NA are exclusively associated with the lipid rafts in the viral lipid membrane, whereas M2 is not [ 4 , 5 ].
Sitting just underneath the viral lipid membrane is M1, which forms a matrix holding the viral ribonucleoproteins vRNPs. The influenza virus life cycle can be divided into the following stages: entry into the host cell; entry of vRNPs into the nucleus; transcription and replication of the viral genome; export of the vRNPs from the nucleus; and assembly and budding at the host cell plasma membrane.
In this review, each stage of the viral life cycle will briefly be described. HA is a homotrimer that forms spikes on the viral lipid membrane. These subunits are linked by disulphide bonds [ 8 ]. These are extremely important for the specificity of the HA molecules in binding to cell surface sialic acid receptors found in different species. Those from swine recognize both [ 7 ]. This explains the importance of swine being a good mixing vessel for avian and human influenza viruses, hence producing dangerous pathogenic viruses.
The endosome has a low pH of around 5 to 6, which triggers the fusion of the viral and endosomal membranes. The low pH induces a conformational change in HA0, leading to maintenance of the HA1 receptor-binding domain but exposing the HA2 fusion peptide.
This fusion peptide inserts itself into the endosomal membrane, bringing both the viral and endosomal membranes into contact with each other. Several crystal structures of HA in its various conformations, i. The acidic environment of the endosome is not only important for inducing the conformation in HA0 and, thus, fusion of the viral and endosomal membranes but also opens up the M2 ion channel. M2 is a type III transmembrane protein that forms tetramers, whose transmembrane domains form a channel that acts as a proton-selective ion channel [ 9 , 10 ].
Opening the M2 ion channels acidifies the viral core. Influenza viral transcription and replication occurs in the nucleus; therefore, after being released into the cytoplasm, the vRNP must enter the nucleus. All of these proteins have known nuclear localization signals NLSs that can bind to the cellular nuclear import machinery and, thus, enter the nucleus. The different NLSs present in each of these viral proteins are reviewed in [ 12 ]. The influenza viral genome is made up of negative sense strands of RNA.
In order for the genome to be transcribed, it first must be converted into a positive sense RNA to serve as a template for the production of viral RNAs.
It appears that a great number of di-nucleotide base pairs form, although the full mechanism of viral genome replication is still yet to be understood [ 13 - 16 ]. PB2 has endonuclease activity. During transcription initiation, serine 5 on the C-terminal repeat domain CTD of Pol II is phosphorylated, leading to the activation of cellular cap synthesis complex.
Six but two of the viral segments encode for one protein. Segments 7 and 8 encode for two proteins each due to splicing. NS1 binds to U6 small nuclear RNAs snRNAs [ 31 , 32 ] and other splicing components, causing them to re-localize to the nucleus of infected cells [ 33 ].
In this way, influenza is able to inhibit splicing of cellular mRNAs. It also has been shown to bind to a novel protein called NS1 binding protein NS1-BP , causing it to re-localize to the nucleus in infected cells. The function of NS1-BP is unknown, although it is predicted to be involved in splicing given its co-localization with SC35, a spliceosome assembly factor [ 34 ].
The mechanism of polyadenylation of viral mRNAs is very unusual. Therefore, polyadenylation of the viral mRNAs occurs due to a stuttering mechanism, whereby the RdRp moves back and forth over this stretch of U residues, leading to the formation of a poly A tail [ 39 , 40 ]. Interestingly, NS1 inhibits the nuclear export of cellular mRNAs by preventing cellular mRNAs from being cleaved at the polyadenylation cleavage site [ 41 ].
It is known that only negative sense vRNPs are exported from the nucleus [ 44 ]. M1 is known to interact directly with the vRNPs through the C-terminal end of the protein. Recently, live imaging has been employed to visualize the movement of vRNPs during the influenza life cycle.
It has been shown that NP preferentially localizes to the apical side of infected nuclei, indicating polarized exit of the viral genome [ 47 , 48 ]. After the vRNPs have left the nucleus, all that is left for the virus to do is form viral particles and leave the cell. In this state, the fusion peptides are buried inside the viral fusion proteins. Various triggers, such as acidic pH and receptor binding, induce conformational rearrangements, resulting in the anchoring of the fusion peptide in the juxtaposing cellular membrane.
Anchoring leads to concurrent formation of a complementary amphipathic domain in the prehairpin extended intermediates. These newly exposed domains are unstable and refold to form more energetically favorable structure. The inner leaflet of the lipid bilayers then come into contact and begin mixing, opening a pore fusion pore between viral and cellular membranes as the trimeric structures refold into a highly stable postfusion conformation.
The fusion peptide yellow is buried inside the fusion protein, which is in an energetically unfavorable metastable prefusion state A. The conformational change induced by triggers eg, acidic pH and receptor binding results in anchoring the fusion peptide in the cell membrane B , forcing the viral membrane and cell membrane into a hemifusion state C.
Subsequently refolding of the fusion protein into a highly stable postfusion conformation leads to a fusion pore formation D. For simplicity, only dimers are represented, but the fusion proteins are always trimeric: HA of influenza virus and F fusion protein of paramyxovirus. It is worth noting some features of membrane fusion. First, only one viral factor ie, the fusion protein drives membrane fusion, but no cellular factors are involved in membrane fusion.
This feature contrasts with that of budding, which also involves membrane fusion. Specifically, numerous cellular factors of the MVBs pathway are involved in budding see Box 3. Secondly, membrane fusion, which is essentially the mixing of two lipid bilayers, is thermodynamically driven.
In other words, membrane fusion is accompanied with the conformational changes of the fusion protein that is poised to change from a metastable prefusion state to a highly stable postfusion state.
It was believed that viruses could infect neighboring cells only by being released extracellularly from the infected cells. In contrast to this belief, a novel mechanism has been described, in which a virus could infect the neighboring cell without being released. This new mode of infection is termed cell—cell transmission or cell-to-cell spread.
Four distinct modes of cell—cell transmission mechanisms have been described. First, cell—cell transmission is mediated by plasma membrane fusion between two cells. The viral capsids are transmitted from an infected cell to uninfected cells without being enveloped. This mode of cell—cell transmission is described in retrovirus and herpesvirus.
Second, cell—cell transmission occurs across a tight junction. Using viral entry receptors on the target cell, virions enter the uninfected target cells. This mode of cell—cell transmission is described in herpesvirus and HCV. Third, cell-to-cell spread occurs across a neural synapse. Virions, either mature or incomplete naked core , assemble in either the postsynaptic or presynaptic cell depending on the virus, and either bud through the membrane into the synaptic space or are released from synaptic vesicles into the cleft.
Virions then either fuse directly with the opposing synaptic cells or are endocytosed. Rhabdovirus, herpes viruses, and paramyxoviruses move across neural synapses.
Fourth, cell—cell transmission occurs across a virological synapse. Immune cells can be polarized via cell contact, which is termed an immunological synapse. A Via plasma membrane fusion. B Across tight junction. C Across a neural synapse. D Across a virological synapse. What is the advantage of cell—cell transmission? It facilitates the viral spread from infected cell to uninfected neighboring cells via direct contact without diffusion.
More importantly, the viruses associated with cells are physically protected from neutralizing antibodies. In fact, cell—cell transmission was uncovered by an experiment characterizing the neutralizing antibodies-resistant viral transmission. Notably, cell—cell transmission was found only in enveloped viruses, but not in naked viruses. Perhaps, cell—cell transmission is useless for naked viruses, where a bulk of virion is abruptly released upon cell lysis.
As stated above, most viruses enter the cell via receptor-mediated endocytosis. What would be the advantages of receptor-mediated endocytosis, as opposed to direct fusion? Unlike direct fusion, evidently, receptor-mediated endocytosis bypasses the actin cortex or the meshwork of microfilaments in the cortex that presents an obstacle for the penetration see Fig.
Moreover, by being taken up by endocytosis, animal viruses can avoid leaving the viral envelope glycoprotein on the plasma membrane, thus likely causing a delay in detection by immune system.
Typically, receptor-mediated endocytosis proceeds via a clathrin-dependent manner Fig. Receptor-mediated endocytosis is the mechanism intrinsic to the cells, which is utilized to take extracellular molecules into the cells. Clathrin -mediated 6 endocytosis, which is also the pathway utilized for uptake of LDL, is employed by many viruses, such as influenza virus and adenovirus.
Upon the binding of the virus particle with the receptor, a clathrin-coated pit is formed, as clathrins are recruited near the plasma membrane. Following the formation of an endocytic vesicle, the vesicles are fused with early endosomes. The virus particles are now located inside the early endosomes. Upon the binding of virus particles to the receptor, clathrins are recruited to form the clathrin-coated pit via its interaction with AP-2 adapter.
Clathrin-coated pits are pinched off by dynamins. After the vesicle coat is shed, the uncoated endocytic vesicle fuses with the early endosome. The capsids are released from the endosome by membrane fusion between viral envelope and endosome that is triggered by low pH inside the endosome.
In addition to receptor-mediated endocytosis, a few other endocytic mechanisms are utilized by animal viruses Fig. For instance, caveolin -mediated 7 endocytosis is used for the entry of polyomaviruses, such as SV40 see Fig.
In this case, caveolin, instead of clathrin, serves as a coat protein; otherwise it is similar to clathrin-mediated endocytosis. Macropinocytosis 8 is utilized for the entry of particles with a larger size, such as vaccinia virus and herpes viruses.
The virus particle first activates the signaling pathways that trigger actin-mediated membrane ruffling and blebbing. The formation of large vacuoles macropinosomes at the plasma membrane is followed by the internalization of virus particles and penetration into the cytosol by the viruses or their capsids. Clathrin-mediated endocytosis. This pathway is the most commonly observed uptake pathway for viruses.
The viruses are transported via the early endosome to the late endosome and eventually to the lysosome. The caveola pathway brings viruses to caveosomes. By the second vesicle transport step, viruses are transported to Golgi, and then to ER. Macropinocytosis is utilized for the entry of particles with larger size, such as vaccinia viruses and herpes viruses. Following successful penetration inside cells, the virus particles need to get to an appropriate site in the cell for genome replication.
This process is termed intracellular trafficking. In fact, the biological importance of the cytoplasmic trafficking was not realized until the invention of live cell imaging technology. For viruses that replicate in the cytoplasm, the viral nucleocapsids need to be routed to the site for replication. In fact, microtubule-mediated transport coupled with receptor-mediated endocytosis is the mechanism for the transport Fig. In addition, for viruses that replicate in the nucleus, the viral nucleocapsids need to enter the nucleus.
For many DNA viruses, the viral nucleocapsids are routed to the perinuclear area via microtubule-mediated transport. In this process, a dynein motor powers the movement of virus particles. As an analogy, the viral nucleocapsids can be envisioned as a train in a railroad. Two distinct viruses are used to explain how the entry is linked to cytoplasmic trafficking: A adenovirus naked and B herpes virus enveloped. Incoming viruses can enter cells by endocytosis A or direct fusion B.
Following penetration into cytoplasm, either endocytic vesicles or viral capsids exploit dynein motors to traffic toward the minus ends of microtubules. Either the endocytic vesicles A or the capsids B interact directly with the microtubules.
The virus can also lyse the endocytic membrane, releasing the capsid into the cytosol A. As the virus particles approach to the site of replication, from the cell periphery to the perinuclear space, the viral genome becomes exposed to cellular machinery for viral gene expression, a process termed uncoating. Uncoating is often linked with the endocytic route or cytoplasmic trafficking see Fig.
For viruses that replicate in the nucleus, the viral genome needs to enter the nucleus via a nuclear pore. Multiple distinct strategies are utilized, largely depending on their genome size Fig. For the virus with a smaller genome, such as polyomavirus, the viral capsid itself enters the nucleus. For viruses with a larger genome, the docking of nucleocapsids to a nuclear pore complex causes a partial disruption of the capsid eg, adenovirus or induces a minimal change in the viral capsid eg, herpes virus , allowing the transit of DNA genome into the nucleus.
A Polyomavirus capsids are small enough to enter the nucleus directly via the nuclear pore complex without disassembly. Uncoating of the polyomavirus genome takes place in the nucleus. B The adenovirus capsids are partially disrupted upon binding to the nuclear pore complex, allowing the transit of the DNA genome into the nucleus.
C For herpesvirus, the nucleocapsids are minimally disassembled to allow transit of the DNA genome into the nucleus. The viral genome replication strategies are distinct from each other among the virus families. In fact, the genome replication mechanism is the one that defines the identity of each virus family. Furthermore, the extent to which each virus family relies on host machinery is also diverse, ranging from one that entirely depends on host machinery to one that is quite independent.
However, all viruses, without exception, entirely rely on host translation machinery, ribosomes, for their protein synthesis. Exit can be divided into three steps: capsid assembly, release, and maturation. The capsid assembly follows as the viral genome as well as the viral proteins abundantly accumulates.
The capsid assembly can be divided into two processes: capsid assembly and genome packaging. Depending on viruses, these two processes can occur sequentially or simultaneously in a coupled manner. Picornavirus is an example of the former, while adenovirus is an example of the latter Fig. In the case of picornavirus, the capsids ie, immature capsid or procapsid are assembled first without the RNA genome.
Subsequently, the RNA genome is packaged or inserted via a pore formed in the procapsid structure. By contrast, in the case of adenovirus, the capsid assembly is coupled with the DNA genome packaging.
Then, a question that arises is how does the virus selectively package the viral genome? A packaging signal , 9 a cis -acting element present in the viral genome, is specifically recognized by the viral capsid proteins, which selectively package either RNA or DNA.
A Sequential mechanism. For picornavirus, the procapsid, a precursor of the capsids, is preassembled without RNA genome. Subsequently, the RNA genome penetrates into the procapsid via a pore.
B Coupled mechanism. For adenovirus, the DNA genome is packaged into the capsid during capsid assembly. For naked viruses, the virus particles are released via cell lysis of the infected cells. Thus, no specific exit mechanism is necessary, because the cell membrane that traps the assembled virus particles are dismantled.
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