Budding influenza virus

Influenza virus HA and NA associate with lipid rafts, and influenza viruses bud from lipid rafts. The presence of specific peptides in a specific conformation often facilitates association with lipid rafts and may increase the order of lipids in the lipid raft. For example, the helicity of the HA TMD peptide increased in lipid bilayers composed of acidic lipids and in turn, the presence of the peptide also increased the acyl chain order of the lipid bilayer.

This process may aid in targeting HA and NA transmembrane proteins to ordered lipid rafts and organizing ordered lipid rafts around them Tatulian and Tamm, Furthermore, raft-dependent protein—protein interactions may facilitate bringing proteins that are present in less-ordered membrane to lipid rafts by interaction with raft-associated proteins. Interaction between influenza virus M1 and HA brings M1, a non-raft-associated protein, into lipid rafts Ali et al. Also, raft-ordered membrane domains may be formed de novo around transmembrane proteins on the plasma membrane such as the engaged immune receptors for review, see Cheng et al.

The affinity of l o domains can be increased by organization, acylation, coupling to raft-associated molecules or by conformational changes Harder et al. Although viruses can bud and form particles VLPs in the absence of glycoproteins and although the Gag protein of HIV and the matrix proteins of many negative strand viruses can bud and acquire envelope, the lipid composition of such VLPs is not known.

Whether these VLPs contain lipid rafts in their envelope or whether glycoproteins are required for acquiring lipid rafts in their envelope remains to be determined. The lipid composition of a VLP's envelope may indicate whether virus budding occurs from the plasma membrane outside lipid raft microdomains or whether budding requires the presence of lipid raft microdomains.

Finally, involvement of lipid rafts in virus replication may provide a novel antiviral approach. In addition to lipids, a number of host proteins, including microfilaments, G proteins, and some protein kinases, have been shown to be involved in the budding of many enveloped viruses for review, see Ludwig et al. In addition, the family of proteins of the vacuolar protein sorting pathway have been shown to interact with the L domains of the Gag and matrix proteins of a number of viruses.

However, for influenza viruses, host protein s that interact with M1 and specifically affect virus budding have not yet been identified. Furthermore, inhibitors of proteasomes involving ubiquitination were found to inhibit budding of a number of enveloped viruses for review, see Vogt, although the specific role of ubiquitination in virus budding remains unclear.

However, inhibitors of ubiquitination did not affect influenza virus budding Hui and Nayak, Cytoskeletal elements, particularly microfilaments, have been proposed to be involved in the maturation of influenza virus including bud formation and bud completion.

In abortively influenza virus-infected HeLa cells, virus particles could be released using microfilament-disrupting agents Gujuluva et al. Also, the budding of filamentous influenza virus particles was converted to spherical particles by inhibitors of actin polymerization such as cytochalasin B cytoB , cytochalasin D cytoD , jasplakinolide, and latrunculin A Roberts and Compans, , Simpson-Holley et al. Furthermore, actin was found in many enveloped virus particles for review, see Cudmore et al.

Also, actin and actin-binding protein ezrin-radixin-moesin ERM have been found in influenza virus particles Sagara et al. The presence of actin-associated proteins in virions suggests specific functions of the actin filament during assembly and budding.

Influenza virus budding was shown to be an active, energy-dependent process requiring ATP hydrolysis Hui and Nayak, Energy is required for biomembrane bending and shape transition during bud formation Sackmann, ATP may play a multifunctional role during influenza virus budding by maintaining a lipid raft membrane structure favorable for virus budding, by providing the energy for membrane shape transition or actin polymerization, and by functioning as a molecule for protein kinase signaling during virus budding.

Among the kinases, casein kinase 2 CK2 is involved in influenza virus budding since a CK2 inhibitor disrupted virus budding, and increased CK2 activity correlated with the replication cycle of influenza virus Hui and Nayak, Moreover, CK2 was found in influenza virus particles Tucker et al. Furthermore, although the M1 protein is a phosphoprotein and both phosphorylated M1 and NP have been found in virus particles Gregoriades et al.

Subsequent to bud formation, buds are released by a mechanism of fusion of the apposing membranes and fission of the bud from the cell membrane Fig. These processes determine the size and shape of the particles. The mechanism of bud completion is yet unclear and a number of factors both viral and host may affect this process. For some viruses, such as Semliki Forest virus, the icosahedral nucleocapsids determine the spherical shape of the released virus particles.

Similarly, the length of the helical VSV nucleocapsid is critical in determining the bullet shape and the length of the virus particles. Defective interfering VSV particles contain smaller nucleocapsids, which are responsible for producing small virus particles. Therefore, with these viruses, separation of virus buds from host membranes depends on the cargo nucleocapsid and occurs immediately after the enclosure of the nucleocapsid.

However, many viruses such as influenza are flexible and pleomorphic and can produce spherical or filamentous particles. With these viruses, a number of factors may play critical roles in causing the fusion and fission processes and determining the size and shape of the released virus particles. As mentioned earlier, among the viral components, matrix proteins as well as glycoproteins have been shown to affect virus shape and size.

In addition, mutation in the CT of NA was shown to generate spherical to filamentous form not dependent on lipid raft association Barman et al. Also, as mentioned earlier, influenza virus M1 possesses L domain activity that affects fission of virus buds Hui et al.

In addition to viral factors, a number of host proteins as indicated earlier Section 5. All of these host proteins in some way facilitated the fusion and fission processes in bud release so that any defect in the interaction of these virus and host components led to defective or incomplete virus release, often forming multiple VLPs joined together.

However, how these host proteins or their interactions with viral late domains facilitate the process of fusion and fission remains unclear.

These defective particles were not completely filamentous or tubular but exhibited clover leaf-like or tethered structures Garrus et al. Similar structures representing defective budding by joining of multiple particles due to incomplete fusion and fission were found in mutant influenza viruses Hui et al.

It will be interesting to determine if these particles represent a state similar to hemifusion in which only the inner leaflet undergoes fusion and therefore cannot undergo complete fission and release from the host membrane and separation from each other Fig.

In addition, as indicated earlier, cytoskeletal components, particularly actin microfilaments, have been shown to contribute to filamentous forms of influenza virus particles Roberts and Compans, Microfilaments that bind to the vRNP may provide outward pushing force in bud formation. However, if actin is involved in the budding process, the fusion of membrane at the stalk of the bud and fission of buds will require disassembly of actin filaments at the last stage of the budding process.

Enhanced release of virus particles from influenza virus-infected HeLa cells with actin disrupting agents Gujuluva et al. Finally, lipid rafts can affect both bud formation and fusion and fission processes at multiple steps. As indicated earlier, asymmetry in the lipid bilayer can cause membrane curvature leading to the formation of buds Holopainen et al. Assembly of lipid rafts at the budding site will affect physical properties of the membrane including lipid heterogeneity, lipid—protein interaction, increased viscosity and rigidity, slow diffusion, etc.

The presence of lipid heterogeneity could cause increased fission and release of buds. However, a specific role of lipid rafts in bud completion remains undefined. Lastly, after their budding from the host cell, viruses must be released into the surrounding medium to infect other cells.

With influenza viruses, bud formation and bud closure causing pinching off of the virus particle may not be sufficient to release the virus into the external environment since the released particles may still be attached to the infected host cell via sialic acid. The data from ts viruses at restrictive temperature, deletion or mutations of NA gene leading to the loss of NA enzyme activity as well as inhibitors of NA clearly demonstrate that NA activity is involved in virus release Barman et al.

The NA removes sialic acid, the receptor for influenza virus, from the membrane glycolipids and glycoproteins of both the virus particles and virus-infected cells and thus prevents self-aggregation of virus particles and reattachment to the virus-infected cell. However, as indicated earlier, NA is not critically required for the infectious cycle in cultured cells provided sialidase is present in the medium Liu et al. In a natural setting of viral infection, either the human or animal host is infected at a very low MOI with relatively few virus particles.

Therefore, multiple cycles of replication leading to release of new progeny viruses and infection of new host cells by the progeny viruses must be repeated many times and are critically required not only for the survival of the virus and cell-to-cell spread but also for producing the disease syndrome in the infected host. In most cases, viruses must kill, destroy or alter the function of a large number of cells of a specific organ or tissue before the specific functional abnormality in the form of a disease syndrome such as pneumonia, hepatitis, or acquired immune deficiency syndrome AIDS , etc.

The site and the nature of budding can be an important contributory factor in viral pathogenesis particularly for respiratory viruses like influenza viruses. Influenza viruses bud from the apical surface of polarized epithelial cells e. However, some influenza viruses like fowl plague H5 or H7 as well as WSN H1N1 viruses H1, H5, H7 indicate the HA subtype specificity of type A influenza viruses are not restricted to lungs and produce viremia infecting other internal organs pantropism and cause severe mortality in infected animals Mori et al.

In humans, most influenza viruses are pneumotropic and do not spread to other internal organs. Why the Spanish flu virus of caused such a devastating pandemic, killing 20—40 million people world-wide and affecting young healthy adults, remains unclear.

In addition to pneumonia, some people died due to massive pulmonary hemorrhage and edema. The Spanish flu virus, like fowl plague viruses, may have been pantropic causing viremia and infecting other organs. Why some influenza viruses are pneumotropic while others are pantropic and highly virulent is not fully understood.

The severity of viral pathogenesis depends on both viral factors and host factors including host defense and immunity. Determinants for virulence of influenza viruses are complex and multigenic. Normally, influenza virus is restricted in lungs because its HA can be cleaved by tryptase Clara , a serine protease restricted to the lungs Kido et al. However, HAs of H5 and H7 pantropic avian virus subtypes contain multiple basic amino acids at the junction of HA1 and HA2 and can be cleaved by furin and subtilisin-type enzymes Horimoto and Kawaoka, , which are present ubiquitously.

Such viruses can therefore grow in other organs. Therefore, WSN virus lacking multiple basic residues in its HA can grow and multiply in tissues other than lungs. The specific function of M and NS genes in pantropism and neurovirulence remains unknown. The NS1 protein, an interferon antagonist, can contribute to virulence in a species-specific manner Krug et al. As indicated earlier, the M gene, encoding M1 and M2 proteins, can affect virus replication at multiple stages of the infectious cycle and has a profound effect on virus virulence.

However, the role of the M gene in the virulence of specific virus strains like the influenza virus is unknown. Recent studies with M1 mutants have shown that the M1 gene can have a profound effect on virulence of WSN virus in mice but no effect on virus replication and growth in MDCK cells in culture Hui, Smee and Nayak, unpublished data.

In Sendai virus, the M gene was shown to cause enhanced basolateral budding and increased virulence. Therefore, altered budding could be an important contributing factor in the dissemination of virus into blood, invasion of internal organs, pantropism and consequently, higher virulence of a specific influenza virus strain. Influenza viruses bud from the plasma membrane, more specifically from the apical domain of the plasma membrane in polarized epithelial cells both in vivo and in tissue culture.

Assembly and morphogenesis of influenza viruses require the transport of the viral components to the assembly site and interaction among the viral components. Furthermore, influenza viruses bud from the apical plasma membrane and from specific membrane microdomains called lipid rafts present on the plasma membrane.

Virus morphogenesis also requires an outward membrane curvature at the assembly site leading to bud formation, eventual fusion of the apposing membranes, fission of buds and separation of virus particles from cellular membranes, and virus release to the outside environment. These budding processes are active and energy-dependent, and are affected by physical factors such as membrane fluidity and viscosity at the budding site. Elucidation of the processes involved in the assembly and morphogenesis of virus particles is critical to understanding virus growth and multiplication is therefore crucial in defining viral infectivity, transmission, virulence, tissue tropism, host specificity and pathogenesis, and will contribute to an overall understanding of the disease process and progression of disease including morbidity and mortality of infected hosts.

In addition, the site of budding can also affect virus virulence and pathogenesis. In this review, we have discussed the critical steps required for the assembly and morphogenesis of influenza viruses, i. However, virus budding is among the least understood processes in virus biology and requires concerted action by a number of viral and host factors. Little is known about the host factors involved in influenza virus budding. A better understanding of viral replication and morphogenesis will facilitate the development of novel therapeutic agents capable of interfering with these critical steps in viral multiplication, pathogenesis and disease progression.

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This article has been cited by other articles in PMC. Introduction Assembly and budding of virus particles are the last but critically important steps in the virus life cycle for both the survival of the virus as well as its disease-producing ability in the host.

Steps involved in the assembly and morphogenesis of influenza virus Morphogenesis of influenza virus is a complex multi-step process, which involves not only nucleocapsid vRNP formation but also envelopment of the nucleocapsid and release of viral particles into the external environment.

Transport of viral components to the assembly site Since influenza viruses assemble and bud from the plasma membrane, complete influenza virus particles are not found inside infected cells. Exit of vRNP from the nucleus of infected cells Since vRNPs are synthesized in the nucleus, they must be exported from the nucleus into the cytoplasm and to the assembly site on the plasma membrane for envelopment and budding.

Transport of viral envelope proteins to the apical cell surface Among the viral components, most information is available about the transport, sorting and targeting of viral envelope proteins HA, NA, and M2 to the virus assembly site.

Transport of M1 and vRNP to the assembly site M1, the most abundant viral protein in the virus particle, plays a critical role in the processes of virion assembly and budding. Interaction among the viral components 2. Interaction of M1 with envelope proteins As mentioned earlier, the position of M1 in the viral structure implies that M1 forms a bridge between the envelope proteins and vRNP and that M1 interacts with the envelope proteins, namely HA, NA, and M2, on the outer side.

Selection of the budding site It is generally believed that viral glycoproteins determine the site of virus assembly and budding.

Bud formation and completion Budding requires the selection of an assembly site where viral components are transported and assembled leading to the initiation of the budding process, growth of the bud and finally, completion of the bud with the release of the virus particles. Role of M1 in virus budding M1 is the most abundant protein in the influenza virion and plays critical roles in many aspects of the virus life cycle including virus budding for review, see Nayak, , Nayak and Hui, Open in a separate window.

Role of lipid rafts in virus budding Viral morphogenesis is a complex phenomenon requiring concerted actions of many viral and host components for review, see Cadd et al. Role of host proteins in virus budding In addition to lipids, a number of host proteins, including microfilaments, G proteins, and some protein kinases, have been shown to be involved in the budding of many enveloped viruses for review, see Ludwig et al.

Bud completion Subsequent to bud formation, buds are released by a mechanism of fusion of the apposing membranes and fission of the bud from the cell membrane Fig. Release of virus particles Lastly, after their budding from the host cell, viruses must be released into the surrounding medium to infect other cells. Role of virus budding in pathogenesis In a natural setting of viral infection, either the human or animal host is infected at a very low MOI with relatively few virus particles.

Conclusion Influenza viruses bud from the plasma membrane, more specifically from the apical domain of the plasma membrane in polarized epithelial cells both in vivo and in tissue culture.

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When virus-infected cells were incubated in the presence of ferritin, such aggregates were found to be labeled with ferritin, indicating that they are derived from uptake at the cell surface. Furthermore, the recruitment of M2 to sites of budding, by M1, puts M2 in a cholesterol-rich environment, where M2 stabilizes the site of budding instead of causing membrane scission Fig.

This would allow for proper assembly of the budding virion before M2 is localized to the neck of the budding virion, placing it at the boundary between the lipid raft-enriched virion and the bulk plasma membrane phases Fig. At the budding neck, M2 may exert its own positive membrane curvature by inserting its amphipathic helix into the membrane and modifying the line tension between the two lipid phases.

This further alteration of membrane curvature may provide the final force needed to mediate membrane scission and the release of the budding virion Fig. Following the completion of membrane scission, the virion may still be tethered to the cell membrane due to the interaction of virion-associated HA and cell-surface sialic acid moieties. NA is then able to play the final role in virus budding, cleaving sialic acid off the cell surface, preventing the HA-receptor interaction and freeing the budded virion.

Interestingly, recent cryo-electron tomography experiments have shown that NA is concentrated at one location on budded virions, which may reflect the role of NA in mediating the final release of virions from the cell surface Calder et al.

Influenza virus budding requires a tightly organized assembly of multiple different viral proteins, with many proteins providing a level of redundancy, helping to ensure successful budding. The activities of HA, NA, M1 and M2 may serve to sequentially modify membrane curvature, with each protein furthering the process of virus assembly and budding.

Thus, for influenza virus, budding is not a solo performance, but a carefully orchestrated symphony with each component functioning at precisely defined points in space and time. By better understanding this orchestration it may be possible to alter these relationships, causing a failure of budding and inhibiting the replication of influenza viruses. We thank Andrew S. Pekosz for useful discussions.

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National Center for Biotechnology Information , U. Author manuscript; available in PMC Sep Jeremy S. Rossman 1, 2 and Robert A. Robert A. Author information Copyright and License information Disclaimer. Telephone: ; Fax: ; ude. Copyright notice. The publisher's final edited version of this article is available at Virology. See other articles in PMC that cite the published article. Abstract Influenza A virus causes seasonal epidemics, sporadic pandemics and is a significant global heath burden.

Introduction Influenza is a major cause of morbidity and mortality around the world. HA, Lipid Rafts and the Initiation of Virus Budding Influenza virus, both spherical as well as filamentous forms, utilize lipid raft domains in the plasma membrane of infected cells as sites of virus assembly and budding Chen et al.

M1 and Virus Assembly If HA is able to initiate, but not complete, virus budding then it is possible that M1 mediates both the restriction on HA budding as well as the recruitment of viral proteins necessary to complete budding. Model of Influenza Virus Budding The mechanism of influenza virus budding and assembly has been investigated for many years.

Open in a separate window. Figure 1. Acknowledgments We thank Andrew S. Footnotes Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. Biological and physical properties of the Ryan strain of filamentous influenza virus.

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