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Expert Reviews in Molecular Medicine: http://www.expertreviews.org/
Accession information: (01)00244-7h.htm (shortcode: txt001gwn); 8 February 2001
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Intracellular trafficking of influenza virus: clinical implications for molecular medicine
Gary R. Whittaker
The
trafficking and processing steps that occur in cells that are infected with
influenza virus play a crucial role in the outcome of infection. These steps
are targets for new and future anti-viral drugs, and can affect the relative
virulence of the virus and its ability to cause disease. The virus first binds
to its host cell via specific sialic acid residues, which can control the species
tropism of the virus. The internalisation of the virus, into the nucleus of
the cell, is dependent on a low pH, and this process is therapeutically targeted
by the drug amantadine. Following replication, the newly formed viral genomes
leave the nucleus and assemble into infectious particles at the plasma membrane.
The targeting and processing of the various viral components at this late stage
of the infectious cycle can have a major effect on the ability of the virus
to spread and cause disease in its host. Finally, the release of viruses is
dependent on the enzyme neuraminidase (NA), and this function has recently been
targeted by the NA inhibitors, a new generation of drugs against influenza virus.
Expert
Reviews in Molecular Medicine © Cambridge University Press ISSN 1462-3994
Like all viruses, influenza has an intimate relationship with its host cell and, during the course of replication, it undergoes many important trafficking steps. A study of such intracellular trafficking has revealed many facets of the virus life cycle, and how the life cycle relates to the pathogenic properties of the virus. Some of these trafficking steps can be targeted by anti-viral drugs, which are used to treat influenza virus infections. The trafficking of influenza virus within its host cell, and how these events are related both to the pathogenic properties of the virus and to therapeutic treatments for viral infection have been discussed in this review. Strategies for vaccination have not been covered; instead, readers are referred to Subbarao (Ref. 1) for more information on this topic.
Aetiology and pathogenesis of influenza virusesInfluenza virus is a member of the Orthomyxoviridae family of RNA viruses, and is an enveloped virus (Fig. 1; fig001gwn). Its genome consists of individual segments (or genes) of negative-sense RNA. There are three types of influenza viruses: A, B and C. Influenza A viruses are the most widespread and infect many animal species. Influenza B and C viruses were originally thought to cause disease only in humans; however, influenza B virus infection has recently been discovered in seals (Ref. 5). It is currently unclear whether this is a single transmission event or whether it implies a wider distribution of the virus.
Influenza virus subtypes are designated by a nomenclature that is based on their surface glycoproteins, namely haemagglutinin (HA or H) and neuraminidase (NA or N; also known as sialidase). The first human influenza viruses to be isolated during the 1930s were subsequently designated H1N1, based on their serological reaction. This group includes the viruses that are now known to have been present in the pandemic 1918 strain. In 1958, an antigenic shift resulted in the emergence of human H2N2 viruses and, in 1968, a shift to H3N2 viruses occurred in human populations. H3N2 viruses have remained the most prevalent in recent years (Ref. 6), but the re-emergence of H1N1 strains during the 1970s, most probably from a laboratory source, has resulted in co-circulating influenza H1N1 viruses. Influenza B viruses have not been given the same H and N designation and, in recent years, have represented a minor population of circulating viruses in humans. Influenza C viruses generally result in only mild respiratory illness and are much less studied.
The emergence of new influenza strains in the human population occurs via transmission from other animal species, most notably birds. Transmission to humans is most commonly thought to occur through an intermediate such as swine (Ref. 3). Typically, human and avian influenza viruses are quite different and are not infectious for both species. However, pigs can become infected with both types of viruses, and it has been proposed that they act as a ‘mixing vessel’ for the transmission of avian influenza viruses to humans. Occasionally, direct avian–human transmission can occur with deadly results, as demonstrated by the emergence of the recent H5 ‘Hong Kong avian flu’ during 1997–1998 (Ref. 7). Several instances of the transmission of this virus from domestic chickens to humans proved fatal, but no proven cases of human to human transmission occurred.
Structure of influenza virusesInfluenza A viruses produce ten proteins from eight RNA segments (Refs 10, 11). The eight negative-sense RNAs are associated with many copies of a nucleoprotein (NP) and a heterotrimeric polymerase, which form the viral ribonucleoproteins (vRNPs). Inside the virus, the vRNPs are surrounded by a shell of the matrix protein (M1). M1 links the vRNPs to the virus envelope, which contains the viral glycoproteins as well as the tetrameric M2 ion channel. Host-cell proteins are typically excluded from the mature virus particles. All influenza viruses have similar internal components, but the constituents of their envelopes can differ markedly (see Fig. 2; fig002gwn). Influenza B viruses have an alternative ion channel (NB) that is produced as an overlapping reading frame by alternative initiation from the gene encoding NA. Influenza C viruses have a single glycoprotein (the haemagglutinin-esterase-fusion, or HEF, glycoprotein) that functionally replaces both HA and NA. Influenza C viruses also differ in having an alternative ion channel (CM2) and a genome that consists of only seven segments of RNA, rather than eight. Influenza viruses also synthesise two proteins (NS1 and NS2) that were originally considered to be non-structural. However, NS2 is now believed to be part of the virus particle. During virus replication, the genes that encode M and NS are both spliced, accounting for the synthesis of two additional polypeptides.
Cell and tissue tropism of influenza viruses
Virus binding, internalisation, trafficking and export
A single cycle
of influenza virus infection in a typical cell is depicted in Figure 3 (fig003gwn).
Briefly, the virus initially binds to its cell-surface receptor and is internalised
into endosomes (cytoplasmic vesicles), where the low pH of the environment triggers
virus fusion and uncoating. The uncoated vRNPs then enter the nucleus of the
host cell for virus replication. Following virus replication, the vRNPs leave
the nucleus and move to the plasma membrane, where they associate with viral
glycoproteins before final budding and release. Each of these transport events
is considered below, in relationship to our current understanding of influenza
virus pathogenesis and treatment.
Virus
binding
It is well established that human influenza viruses bind to moieties that contain
5-N-acetyl neuraminic acid (sialic acid) on the surface of host cells;
however, in the pig and horse, N-glycolyl neuraminic acids can be used.
Binding to sialic acid occurs via a shallow depression near the membrane-distal
tip of the HA glycoprotein. It is also well established that some viruses bind
preferentially to terminal sialic acids containing a-(2,6)
linkages, whereas others favour binding to a-(2,3)-linked
sialic acid (Ref. 15). This receptor-binding specificity correlates
with a specific amino acid at position 226 of HA. HAs that have leucine at position
226 selectively bind to a-(2,6) sialic acid and occur
preferentially in human strains. However, HAs that have glutamine at position
226 are specific for a-(2,3) linkages, and occur
mostly in avian and equine strains of the virus. Both a-(2,3)-
and a-(2,6)-linked sialic acid occur in the trachea
of swine – accounting for the ability of pigs to become infected with both
avian and human strains. Thus, receptor binding is one of the initial determinants
of pathogenicity, such that the specificity of receptor binding accounts for
much of influenza’s species tropism (i.e. the predilection of the virus
to infect certain animal species and not others).
The cell-surface receptor for influenza viruses can apparently take the form of sialic acid linked to either glycoprotein or glycolipid. In vitro, viruses can bind to, and fuse with, synthetic lipid vesicles that contain only glycolipid (Ref. 16), suggesting that entry does not require a specific cellular protein as a receptor. However, the infection of desialylated cells has been reported recently, suggesting either the presence of sialic-acid-independent receptors or a multi-stage process (Ref. 17). In vivo, other factors may well be important for virus entry. In macrophages, recent evidence suggests that the viruses undergo an additional lectin-like interaction with the mannose receptors of the macrophages, following the initial interaction with sialic acid (Ref. 18). Whether other ‘co-receptor-like’ activities occur in other cell types remains to be determined.
Following the interaction of the virus with a receptor at the cell surface, it is rapidly internalised into clathrin-coated pits – a process that is dependent on dynamin, a cellular GTPase (GTP phosphohydrolase; Ref. 19). Viruses are trafficked through the endocytic pathway and ultimately reach a low-pH compartment (where the pH is approximately 5.5; Refs 20, 21). At this pH, the viral fusion machinery is triggered. HA undergoes a conformational change, forming a ‘coiled-coil’ of a helices and exposing the previously buried hydrophobic fusion peptide, which then inserts into the endosomal membrane (Refs 22, 23). This initiates the fusion event and releases the interior components of the virus (i.e. M1 and vRNPs) into the cytoplasm.
Uncoating
and nuclear import
In addition to
triggering fusion, endosome acidification has one other crucial function in
virus entry. The presence of the M2 ion channel in the envelope of the virus
means that the components inside the virus (i.e. M1 and the vRNPs) become exposed
to the low pH of the endosome. Exposure to a low pH is necessary both in vitro
and in vivo to disrupt M1–vRNP interactions and uncoat the virus (Refs
24, 25). Although the acidification of vRNPs
is not required for nuclear import per se (Ref. 26), it is
required to uncoat completely the M1–vRNP complexes, which are otherwise
too big to pass through the size-restricted channel of the nuclear-pore complex.
The import of vRNPs occurs through nuclear pores and is mediated by nuclear
localisation signals on NPs (Refs 27, 28,
29).
It is now known that two closely related anti-viral drugs, namely amantadine (Symmetrel®) and rimantadine (Flumadine®), target the pH-dependent uncoating event. At micromolar concentrations, amantadine inhibits the nuclear import of vRNPs in cell culture (Ref. 30). The target of amantadine is the M2 ion channel (Refs 31, 32). Amantadine blocks the M2 channel and prevents the acidification of the virus interior. Thus, endosome acidification and virus fusion are not compromised, but M1–vRNP dissociation and ultimately nuclear import are prevented. Amantadine therefore inhibits M2-dependent virus uncoating and is specific for influenza A viruses. At micromolar concentrations, it has no effect on either influenza B or C viruses, which have different ion channels. At higher concentrations (e.g. millimolar), amantadine has additional non-specific effects and can act as a weak base, neutralising the acidic pH in both the endosome and the Golgi apparatus of the cell (Refs 31, 33). As discussed below, the Golgi apparatus affects the HA trafficking of certain influenza viruses through the secretory pathway during the later stages of infection.
Although amantadine and rimantadine are useful for certain at-risk populations, they tend not to be heavily prescribed, mainly owing to the rapid emergence of drug-resistant strains (Ref. 34), and their neurological side effects. Drug resistance is caused by mutations occurring in the nucleotides that encode the amino acids lining the interior of the M2 tetramer. Both amantadine and rimantadine appear to act by the same mechanism, although rimantadine is more commonly used because it has fewer side effects.
Virus
replication and transcription
Influenza
viruses are one of the few RNA viruses to undergo replication and transcription
in the nucleus of their host cells (Ref. 35). In the nucleus,
the vRNPs serve as templates for the production of two forms of positive-sense
RNA: viral messenger RNA (mRNA) and complementary RNA (cRNA; Ref. 36).
The synthesis of mRNA is catalysed by the viral RNA-dependent RNA polymerase
(comprising the three subunits PA, PB1 and PB2), which is part of the incoming
vRNP complex. Viral mRNAs are processed in an analogous fashion to other eukaryotic
mRNAs; that is, they are capped (i.e. contain a methylated 5' guanosine residue)
and are polyadenylated (i.e. contain a sequence of polyadenylic acid at their
3' end), and are exported from the nucleus for translation by cytoplasmic ribosomes.
The nuclear export of viral mRNA utilises the ‘machinery’ of the host
cell, but is selective; export is controlled by the viral non-structural protein
NS1 (Ref. 37). Many viral proteins (NP, M1, NS2 and the polymerases)
are then imported into the nucleus for the final stages of replication and for
vRNP assembly. The viral cRNA is neither capped nor polyadenylated, and remains
in the nucleus, where it serves as a template for the production of negative-sense
genomic RNA (vRNA).
In birds, the situation can be quite different. Whereas most non-virulent or low pathogenicity avian influenza viruses also have a monobasic cleavage site (e.g. HA1-PEKQTR–GL-HA2), highly pathogenic strains have a polybasic cleavage site (e.g. HA1-KKREKR–GL-HA2). Thus, they can be cleaved by ubiquitous proteases, such as furin, which is present in the Golgi apparatus of all cells. These HAs also have a high pH optimum of fusion and the M2 ion channel acts to keep the pH of the Golgi above the threshold for fusion. Following the addition of high concentrations of amantadine to these cells, M2 function is blocked and HA undergoes premature pH-mediated activation, and thus infectious progeny viruses are not produced (Ref. 33). Avian influenza subtypes that have polybasic cleavage sites (e.g. fowl plague virus) are not restricted to particular tissues and can cause fatal systemic infections.
One other factor that enhances pathogenicity is bacterial superinfection (Ref. 46). In humans, influenza viruses are normally confined to the upper respiratory tract; however, influenza viruses can invade a patient’s lower respiratory tract if it is colonised by bacteria (e.g. in patients suffering from chronic bronchitis or emphysema). Bacteria such as Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae and various Gram-negative bacilli often produce extracellular proteases that can cleave monobasic cleavage sites on HA, enhancing virus spread. In addition, some bacterial products (e.g. lipopolysaccharide) can activate serum plasminogen, as well as inflammatory host proteases such as kallikrein and factor Xa. These host-derived proteases can cleave certain HAs, facilitating the activation of progeny influenza viruses in the lung and the development of deadly influenza pneumonia.
Complementary
role of NA
HA cleavage can
clearly be a major factor in influenza virus pathogenesis, but the overall process
is complex and is affected by both viral and host factors. Importantly, the
1918 pandemic strain was highly virulent, yet contained an unremarkable monobasic
HA cleavage site (Ref. 48). However, the recent H5 ‘Hong
Kong avian flu’ that infected humans did contain a polybasic cleavage site
(Refs 7, 48). A study of the WSN strain of
influenza virus has given rise to some clues about the controlling factors for
HA-mediated pathogenesis. WSN is an H1N1 virus that was originally isolated
from humans in 1933 and has been adapted to, and is neurovirulent in, mice (Ref.
49). It has been known for many years that WSN has a wider
than usual cell tropism in the laboratory, and undergoes multi-cycle growth
in other cell types besides the canine cell line MDCK, including Madin-Darby
bovine kidney (MDBK) cells (Ref. 50). The NA in WSN viruses
has a key C-terminal lysine residue (lys 453) and can bind plasminogen and sequester
it close to the infected cell surface. Plasmin, the cleaved, active product
of plasminogen, can then cleave and activate HA, allowing influenza virus spread
(Ref. 51). However, a C-terminal lysine is present in all
influenza N1 strains (including the 1918 strain; Ref. 52),
and the functional relevance of plasminogen binding is uncertain outside of
the laboratory setting.
Virus
assembly at the plasma membrane
For virus assembly at the plasma membrane, it is essential that all of the
viral components (i.e. HA, NA, M2, M1 and the vRNPs) are trafficked to the correct
physical location in the cell and are correctly processed. M1 is central to
this interaction. M1 molecules bind to vRNPs, the plasma membrane (possibly
via the cytoplasmic tails of the glycoproteins) and also other M1 molecules
to form a shell beneath the virus envelope (Fig. 5b; fig005gwn).
Originally, M1 was thought to bind to membranes via a large, buried hydrophobic
surface (Ref. 53), but has recently been shown to act as a
peripheral membrane protein and to interact via surface electrostatic interactions
in vitro (Ref. 54). It is possible that the binding of M1
to membranes in vivo relies on a combination of both hydrophobic and electrostatic
interactions, as well as specific protein interactions with the envelope proteins
(Ref. 55). In polarised epithelia, budding of virus particles
occurs exclusively from the apical surface (Ref. 56). All
of the envelope proteins are localised to the apical surface of polarised cells
when expressed individually in heterologous systems, and thus are independently
transported to the site of assembly.
Virus
budding and release
For the final budding
step, it has recently been shown that the viral components coalesce into specific
regions of the plasma membrane, which are known as detergent-insoluble glycolipid-enriched
domains (DIGs), or lipid rafts. It is likely that these DIGs are specialised
sub-compartments of the membrane from which the viruses bud (Refs 57,
58). The formation of viruses at these sites appears to rely
on the presence of the cytoplasmic tails of both HA and NA. These glycoproteins,
along with M1, M2 and host-cell factors (the actin cytoskeleton and the polarised
nature of the cell), appear to control virus morphology, and thus determine
the spherical or filamentous nature of the resultant particles (Refs 9,
59, 60). An overall model for virus assembly
might involve the initial interaction of M1 with membranes, followed by more-specific
interactions of the HA and NA cytoplasmic tails in specialised DIGs.
The final release of viruses from the cell surface relies on the action of the viral NA. NA (sialidase) acts as a receptor-destroying enzyme, by removing sialic acid (the viral receptor) from the surface of host cells (Ref. 61). Without this step, the newly forming virus particles immediately re-bind to their receptor and are not released into the extracellular space. Instead, they remain attached to the cell in large clumps. NA is therefore important for the efficient release of viruses. Indeed, the establishment of a productive infection is dependent on both NA and HA. The carbohydrate residues surrounding the receptor-binding site of HA are known to modulate the affinity of interaction with sialic acid (Ref. 62). Thus, although an increase in the affinity of HA for sialic acid might increase infection, it might counteract the receptor-destroying activity of NA, thereby reducing virus release from the cell surface. Virus release and spread therefore requires a delicate balance between the function of the two glycoproteins.
Recently, the crucial role of NA in the life cycle of the virus has been exploited to great effect for the development of anti-viral drugs. Following the determination of the NA crystal structure (Ref. 63), a concerted effort was made to find small molecules that would bind to, and block, the highly conserved sialic-acid-binding site of NA (Ref. 64). Two analogues of sialic acid, namely Zanamivir (Relenza®) and Oseltmavir (Tamiflu®), have recently been approved for the treatment of influenza (Ref. 65), and other related compounds are currently in development (Ref. 66). These drugs are effective against both influenza A and B viruses. The new inhibitors of influenza NA are significant because they act as anti-viral compounds in a previously unexplored manner – by preventing virus release and spreading from cell to cell. The development of these drugs is a direct consequence of the information provided by X-ray crystallography; thus, along with HIV-1 protease inhibitors, they can be classed as one of the major successes of rational structure-based drug design.
ConclusionsAcknowledgements
and funding
I
thank Elizabeth Wills (Cornell University, Ithaca, NY, USA) and Melanie Ebersold
(Yale University, New Haven, CT, USA) for the electron micrographs, and Melissa
Grabowski and Ruth Collins (Cornell University, Ithaca, NY, USA) for helpful
discussions during the preparation of this manuscript. I also thank Dr Wendy
Barclay (Department of Microbiology, University of Reading, UK) and Dr Colin
Parrish (James A. Baker Institute for Animal Research, Cornell University, Ithaca,
NY, USA) for critically reviewing this manuscript before publication. Work in
my laboratory is sponsored by the United States Department of Agriculture, the
American Heart Association and the American Lung Association.
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Further reading, resources and contacts Nicholson, K.G., Webster, R.G. and Hay, A.J. (1998) Textbook of Influenza, Blackwell Science, Oxford, UK Flint, S.J. et al. (2000) Principles of Virology, ASM Press, Washington DC, USA The Influenza Sequence Database is a curated database of nucleotide and amino acid sequences, produced by the Los Alamos National Library. It is intended to provide the research community with easy sequence deposit and retrieval capabilities, together with tools tailored, in particular, to the analysis of haemagglutinin and neuraminidase sequences. The website also provides many links to other sites, including Genbank, Medline and the Protein Databank (for retrieval of structural records). The Influenza Prevention and Control website, produced by the US Centers for Disease Control and Prevention, Atlanta, GA, is a useful information source. All the Virology on the WWW seeks to be the best single site for virology information on the Internet that will be of interest to both the professional virologist and the general public. The Virology at Cornell website has been created by the Departments of Plant Pathology and Microbiology and Immunology at Cornell University, NY, USA (produced by Dr Sondra Lazarowitz). It emphasises molecular aspects of virology, focusing on fundamental principles of virus structure, replication, genetics and virus–host interactions that lead to disease development. |
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Features associated with this article Figures Figure 2. Structure
and genome organisation of influenza viruses Figure 3. Replication
cycle of an influenza virus Figure 4. Processing
of influenza haemagglutinin (HA) Figure 5. Budding of influenza viruses |
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