Viral and Envelopes: Secondary article Structure and Function Article Contents . Introduction William Lucas, Harvard Medical School, Boston, Massachusetts, USA . Viral Capsids David M Knipe, Harvard Medical School, Boston, Massachusetts, USA . Viral Envelopes . and Envelope Function: Viral Entry into Host Cells particles contain the viral genome packaged in a protein coat, called a capsid, and sometimes a lipid coat called the envelope. These structures play many roles in viral infection, including virus entry into cells and spread from one cell to another.

Introduction and proteins necessary for a stable, infectious virus are infectious agents that are obligate intracellular particle. This particle must exit the cell and survive in the parasites because they must replicate inside a host cell, extracellular environment until it encounters a suitable utilizing its macromolecular machinery and energy sup- host cell. The virion must then bind to and enter a new host plies for their replication process. The infectious form of a cell for replication. Thus, the virus particle must be stable virus, the virus particle or virion, replicates itself by extracellularly but readily disassembled upon entry into a entering a host cell, disassembling itself and copying its new host cell. Some of the best-understood examples of components, which are then assembled into progeny virus these structure–function relationships will be reviewed in particles. These progeny virus particles can then infect this article. additional cells. Survival of the virus requires transport of the genetic material from an infected cell to an uninfected cell in either the same or a new host organism. To Viral Capsids accomplish this, viruses have evolved mechanisms of packaging their genomic nucleic acids, ribonucleic acid Helical capsids (RNA) or deoxyribonucleic acid (DNA), along with any other components necessary for replication, within protein Probably the best-studied example of a nonenveloped coats comprised of repeating protein subunits. The protein helical capsid is tobacco mosaic virus (TMV). TMV is a coat is called the capsid, and the complex of the genome plant virus with a single-stranded RNA genome of 6390 plus capsid is called the nucleocapsid. Capsids can be nucleotides (nt). The capsid of TMV is comprised of 2130 classified into three general classes based on the symmetry copies of a single protein. The overall structure of TMV is a of the protein arrangement within the capsid. The first hollow tube with the genomic RNA attached to the form of symmetry is helical, where the subunits are wound internal face of the tube, 3 nt held in the cleft of each capsid around a central axis (Figure 1a). The second is icosahedral, 1 subunit. The capsid contains 163 subunits per helical resulting in a spherical particle with 2-, 3- and 5-fold axes of rotation. This results in a final structure that is a rigid rod symmetry (Figure 1b). The third general class contains more approximately 300 nm in length and 18 nm in diameter. complex virion structures, such as those of poxviruses. In Because the capsid protein units assemble on to the RNA some viruses this complex is surrounded by a lipid molecule, the size of the TMV particle is defined by the size membrane and associated proteins, a structure called the of the genome. The direct relationship between genome . Thus, we can broadly divide viruses into five size and capsid size is an important advantage for helical classes based on structure: helical nonenveloped virions viruses. If additional genetic material is inserted into the (e.g. tobacco mosaic virus), helical enveloped virions (e.g. genome of a helical virus, the capsid size can expand to rabies virus: Figure 1a), icosahedral non-enveloped virions allow incorporation. Icosahedral viruses have a rigidly (e.g. adenovirus), icosahedral enveloped virions (e.g. defined amount of internal space to package nucleic acid virus), and other more complex structures and thus their genomes have a predetermined maximum (e.g. pox viruses such as smallpox and virus) size. (Sander et al., 2002). Many examples of enveloped viruses with helical Despite the fact that these viral structures are made from nucleocapsids also exist. One example of such viruses is only a few different proteins (in some cases only one), they vesicular stomatitis virus (VSV), a rhabdovirus (structure must be able to perform a wide variety of functions. The similar to rabies virus, Figure 1a (Sander et al., 2002). VSV is virus must successfully package all of the viral nucleic acids approximately 180 nm long and 75 nm wide. The nucleo-

ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net 1 Viral Capsids and Envelopes: Structure and Function

2-fold symmetry 3-fold symmetry Envelope (membrane) Ribonucleoprotein

Matrix 5-fold protein symmetry

(a) (b) f = 1 f = 2 f = 3

Figure 1 Helical and icosahedral symmetry. (a) The structure of rabies virus, an example of a virus containing a helical nucleocapsid, labelled here as ribonucleoprotein. From http://www.cdc.gov/ncidod/dvrd/rabies/the_virus/virus.htm (b) Icosahedral symmetry, with axes of 2-, 3-, and 5-fold symmetry indicated. From http://www-micro.msb.le.ac.uk/335/335Structure.html with permission of Dr Shaun Heaphy.

capsid has a bullet-shaped morphology characteristic of 60 subunits, the particles contain pentameric and hexame- rhabdoviruses, consisting of 35 helical turns of the ric assemblies. Because the same groups of proteins are ribonucleoprotein complex. Closely associated with the used to build both pentamers and hexamers, the bonding N protein is the , which bridges the between proteins and the angles of joining are not exactly membrane and nucleocapsid. This close association equivalent. This concept of quasiequivalence of subunit between the nucleocapsid and the membrane results in a packing in virus capsids was first described by Caspar and very uniform bullet-shaped structure for the viral particles. Klug (1962). This can be contrasted with the overall structure of X-ray crystallography is used to define the atomic influenza A virus, another helical enveloped virus. While structure of virus capsids. The first crystal structure for an the nucleocapsid of influenza has an ordered helical icosahedral virus was for tomato bushy stunt virus (TBSV) structure, the association of membrane and matrix protein solved by Stephen Harrison and his colleagues (Harrison is not uniform. This results in particles that can appear in et al., 1978). The T 5 3 structures like TBSV and any form from roughly sphere-shaped blobs to highly poliovirus are often built up of wedge-shaped b-barrel pleomorphic rod-shaped particles. subunits, sometimes linked together by arm-like extensions from the individual subunits.

Icosahedral capsids Capsid function: packaging of nucleic acids The second form of symmetry used in capsids is the icosahedral or spherical symmetry. An icosahedron is a 20- The viral capsid performs a variety of specialized faced structure made up of triangular faces, each of which functions, which are directed toward the goal of dissemi- is built from three subunits (Figure 1b). Thus, the smallest nating the viral genes to suitable hosts. In this section we number of protein subunits found in icosahedral virions is will discuss the mechanisms of packaging of nucleic acids 60 (triangulation number or T 5 1), with larger viruses into capsids, a process often called encapsidation. For built from multiples of 60 subunits (T 4 1). In a 60-subunit viruses without envelopes, this would result in a complete virus, each protein subunit will have identical shape and virion particle. Additional assembly processes are involved bonding to the other subunits surrounding it. This in the final assembly of enveloped virions. Capsid– structure has symmetry around 2-fold, 3-fold and 5-fold envelope interactions will be discussed in a later section. axes (Figure 1b). An example of a 60-subunit capsid is the In infected cells, viruses produce many copies of their parvoviruses, which package a relatively small genome of genomes for assembly into new virions. The capsid approximately 5.3 kb of single-stranded DNA (ssDNA). proteins must be able to recognize the viral genome and In fact, only a few viruses are able to fit their genetic efficiently package it into the virion particle at the correct material in a 60-subunit capsid. Because most viruses time after infection. It is important that this packaging require more space inside the capsid structure than is reaction does not occur too early in infection, because this afforded by a 60-subunit icosahedron, a slight modification would deplete the pool of genomes that serve as templates of the structure is necessary. In viruses that use multiples of for replication. Many viruses avoid this potential problem

2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net Viral Capsids and Envelopes: Structure and Function by temporally regulating gene expression such that the would predict that these particles would begin forming capsid proteins are expressed only after the proteins needed with RNA inside the particle. The nearly completed for replication have been made. This results in a ready- particle would then lose the RNA shortly before the final made pool of genomes available for packaging as soon as penton attaches to the rest of the shell, resulting in an the capsid proteins are produced. In general, viral genomes empty particle. However, it has been shown that empty have packaging signals in their genome to which capsid capsids can dissociate into pentamers and that these proteins bind to initiate encapsidation, followed by the pentamers can reform into empty capsids without the need progressive assembly of the capsid around the nucleic acid for genomic RNA. The formation of these higher order or the insertion of the nucleic acid into the capsid. structures in the absence of RNA allow for the possibility Encapsidation of viral genomes into helical nucleocapsids that nearly complete capsids form and only then does the is generally thought to begin by attachment of one or more genome enter the particle. of the nucleocapsid proteins to a specific recognition site on Certain bacteriophages and animal DNA viruses do the viral genome. Following this initial attachment, other form preformed shells of capsid proteins into what is called single nucleocapsid proteins or preassembled complexes of an empty capsid or procapsid. These particles contain an nucleocapsid proteins polymerize away from the first internal protein network called the scaffolding. Viral DNA complex. The sequential addition of nucleocapsid proteins binds to a portal complex at one vertex of the procapsid, continues until the nucleic acid is fully encased. This is and the DNA is drawn into the capsid concomitant with illustrated well by the packaging of TMV RNA. This virus the expulsion of the scaffolding protein. The capsid shell has an assembly signal sequence at nucleotides 5444–5518 expands during this process to form the final nucleocapsid (of 6390) that serves as the site to which a small preformed structure. disc of capsid protein attaches. During the association of An even more complicated task is performed by viruses RNA and capsid protein a conformational change occurs that package multisegmented genomes. An infectious in the capsid–protein complex, resulting in a helical influenza A virus must contain at least one copy of each nucleocapsid structure. Complexes of capsid protein of of eight different RNA molecules, and a mammalian various sizes then attach and extend the helical nucleo- reovirus must package 10 double-stranded RNA (dsRNA) capsid structure until the genome is completely encased. segments. The reovirus particle has icosahedral symmetry For icosahedral viruses, the exact mechanism of packa- with an internal cavity predicted to be large enough to hold ging nucleic acid into the capsid is still a topic of debate. not many more than the 10 dsRNA genomic segments. Two general models have emerged. In the first model the Clearly there must be a selection process to package one viral nucleic acid associates with single capsid proteins or copy of each segment without duplication. As the capsid small preformed capsid subunits. The capsid then builds subunits are repeating units of the same proteins, it is itself by polymerization around the nucleic acid. The unlikely that the capsid alone selects the genome segments. second model requires assembly of nearly complete One proposed mechanism that solves this problem is a particles, which then draw the genome inside through a chain-like selection method in which one segment (A) pore or a gap in the particle. A final structural rearrange- attaches to the capsid. Segment A is also able to associate ment is then required to yield a structurally sound virus with only one other genome segment (B). Segment B is particle. Both of these mechanisms have been invoked for involved in selecting segment C and so on, until a chain the assembly of poliovirus. Poliovirus has a 60-subunit containing only one of each genome segment is selected for icosahedral shell, each subunit being comprised of four packaging. While this model has also been suggested for proteins known as VP1–VP4. Prior to final maturation of influenza A virus packaging, the helical nucleocapsid the capsid, VP2 and VP4 exist as a single protein called structure allows enough flexibility in genome packaging VP0. Early in capsid formation VP0, VP1 and VP3 join size to permit another theory. By packaging a number of together to form a single subunit, five of which join genome segments larger than the number needed for a together to form a free pentamer. A favoured model of complete genome, the virus can remove the need for poliovirus assembly has the RNA genome first associating selection during packaging. It has been estimated that less with one pentamer, followed by the stepwise addition of 11 than one in 10 influenza particles is actually infectious. This more pentamers to the structure. This results in a level of infectivity could be achieved by random packaging completed provirion, which then autocatalyses the pro- of approximately 12–13 segments in the virion. While it has teolytic cleavage of VP0 to VP2 and VP4. This final step been demonstrated that influenza particles can contain at results in the production of an infectious poliovirus least nine segments, proof for this, as well as other particle. However, there are also data to suggest that the packaging theories, is still lacking. order of assembly of poliovirus may be different. Like Unenveloped virions may be infectious once the capsid other icosahedral viruses, poliovirus produces many has assembled around the viral genome. For these viruses, particles that are ‘empty’, i.e. they do not have a viral surface proteins play roles in entry of these viruses into host genome packaged inside the particle. The first model cells, as described below in the section on viral entry. involving nucleation around an RNA–pentamer complex

ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net 3 Viral Capsids and Envelopes: Structure and Function

Viral Envelopes proteins, E1 and E2, are regularly arrayed in the viral envelope. There are 80 of these trimers, and each is Many types of virus particles exist not as naked nucleo- postulated to interact with capsid proteins at a three-fold capsids but as nucleocapsids surrounded by lipid mem- axis. However, this relationship between icosahedron and branes. These membranes contain various viral encoded envelope protein disappears in more complex viruses. proteins and perform some subset of the functions that are Herpes simplex virus, for example, is a large enveloped required for successful viral spread. We refer to these icosahedral virus that has at least nine different envelope structures comprised of lipid bilayer and associated proteins. Additionally, the capsid is physically separated proteins as the viral envelopes, and many examples exist from the envelope membrane by a layer of proteins known of both helical and icosahedral viruses that have envelopes. as the tegument. Thus, other methods for envelope protein selection must exist, such as attachment to matrix proteins that bridge the nucleocapsid to membrane. Envelope structure The major component of viral envelopes is one or more Assembly of enveloped viruses lipid bilayers. Nearly all enveloped viruses have one lipid bilayer, but one form of poxvirus virion has two membrane As previously mentioned, viral envelopes perform some of layers. The lipid bilayers in virions are generally derived the functions that would otherwise need to be performed from pre-existing membranes of the host cell; therefore, the by the viral capsid proteins. However, the addition of a lipid components are taken from the cellular membrane. In membrane to the viral capsid also offers some distinct many cases the acquisition of an envelope occurs as the advantages. We will explore these functions and advan- nucleocapsid buds out from the cytoplasm to the extra- tages using influenza A virus as a model system. Influenza cellular milieu. Other membranes that may contribute to A viruses have a negative-sense, segmented single-stranded viral envelopes include the nuclear envelope, the Golgi RNA genome surrounded by a nucleocapsid protein (NP) apparatus and the endoplasmic reticulum. The site of virus that results in a helical virus structure. The virus envelope budding is determined, at least in part, by the sites of contains three proteins. The haemagglutinin protein (HA) localization of the envelope . In addition to is the protein used to bind to sialylated proteins that serve targeting to specific organelles, viral glycoproteins may as receptors on the target cells. The influenza HA protein target to specific membrane sites within an organelle, such was the first transmembrane protein and viral envelope as lipid rafts or glycosphingolipid-enriched microdomains protein whose crystal structure was solved by the late Don within the membrane. Thus, viral envelope lipids may Wiley and his colleagues (Wilson et al., 1981). To be reflect the composition of local regions within a membrane infectious, the HA must be proteolytically cleaved into or organelle. parts HA1 and HA2. The protein (NA) is While the lipid portion of viral membranes is comprised able to remove sialic acid from proteins, and thus can of cellular products, viruses have developed ways to select destroy the viral receptors. This receptor-destroying their own outer membrane proteins for inclusion in the enzyme function is thought to help prevent the virus from envelope. Viral outer membrane proteins are usually sticking to cells during egress as well as preventing the transmembrane proteins and therefore consist of three clumping of virions. The third membrane protein is the major functional domains. There is an extracellular viral M2 protein, which forms a channel in the membrane domain, often glycosylated, that may perform various that allows the transmission of protons across the viral functions including receptor binding, receptor destruction, envelope. membrane fusion, or binding to and anchoring other viral During infection these three proteins are targeted to the proteins to the membrane. There is usually one or more plasma membrane of the infected cell (Figure 2, right half). transmembrane domains, which are needed to hold the The proteins are assembled in patches on the cell surface protein in the viral envelope. The third domain is internal from which host proteins have been largely excluded. to the viral membrane and may be used to select the protein Organization of these patches of viral proteins is thought to for inclusion into the viral envelope. Incorporation of these occur by interaction of the cytoplasmic tails of the proteins into budding virus particles occurs through membrane proteins with the viral matrix (M1) protein. specific interactions with other viral proteins. Icosahedral The can also interact with viral nucleocapsids. viruses have highly ordered structures with a fixed number The process of viral budding is thought to occur by the of contact sites on the capsid. Based on this structure, one movement of nucleocapsids to the ‘patched’ areas of the prediction would be that the outer membrane proteins cellular membrane. The nucleocapsids are then sur- would attach to capsid proteins, resulting in a fixed number rounded by matrix protein. Because the matrix proteins of outer membrane proteins that are held in a regular array. are attached to the envelope proteins, wrapping of M1 Indeed, this structure is seen with some simple viruses such around the nucleocapsids results in a bulging of the cellular as Sindbis virus. Trimers of the Sindbis virus envelope membrane. As the M1 completely surrounds the nucleo-

4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net Viral Capsids and Envelopes: Structure and Function

task to be performed is entry into new host cells. Entry a involves the attachment to a receptor molecule on the Respiratory surface of the host cell, crossing the plasma membrane to tract gain entry into the host cell, and uncoating of the genomic nucleic acid within the host cell. Icosahedral viruses often virus have one of two different structures that are used for attachment to host cells. The first is a cleft on the surface of Matrix Neuroaminidase k the subunits that can recognize the receptor. Again we shall Haemagglutinin use poliovirus as a model for this type of receptor. Each of the 60 external faces of the poliovirus capsid is comprised RNA M2 Protein of VP1, VP2 and VP3 (with VP4 buried below). These three j Neuraminidase external proteins sit at the vertices of the triangular-shaped b and polymerases Endosome Viral subunits. In the centre of this triangle is a cleft or ‘canyon’, c messenger RNA i which binds to the cellular receptor. It has been proposed Virus that having the receptor-binding site buried in a canyon d h Viral e g offers an advantage to the virus. Because the canyon is too Sialic Viral RNA proteins narrow to allow antibodies access to the amino acid acid Endosome f Ribosome residues that contact the receptor, the residues that bind to Haemagglutinin from cell Infected Viral RNA the receptor are protected from immune attack. The cell copies second method of icosahedral virus attachment utilizes a single specialized receptor-binding protein that is exposed Figure 2 The replication cycle of influenza virus, showing entry (left) and on the outer surface. Often these proteins are attached to budding (right). Redrawn after http://www.sciam.com/1999/0199issue/ 0199laverbox4.html with permission of Dr Robert Webster. the capsid at the vertices of the five-fold axes of symmetry. Examples of this type of receptor-binding protein arrange- ment can be found with the adenovirus fibre protein or the capsid, the membrane pinches off to form a complete viral reovirus s1 protein. In the case of reovirus, a region on the envelope. The virus is now free from the cell and able to stalk of the s1 protein binds to sialylated glycoproteins, infect cells of this or other host organisms. which are very common viral receptors. A second region of Following assembly of a complete infectious virus the s1 protein more distal to the virus, in the globular head particle, the particles exit the cell, either through cell lysis of the structure, is thought to bind to a protein receptor and or budding from the cell. With naked capsid virions, capsid give some neuronal specificity to certain strains of the proteins play an important role in protecting the virus from virus. Thus, in the case of reovirus, a single protein can damaging chemical or physical conditions until a suitable provide the means for the virus to attach to two different host cell is located. Successful completion of this task classes of receptor protein. The multiple receptor functions requires a high degree of stability from the capsid structure. for adenovirus require two receptor proteins on both the Genetic mapping has identified proteins that protect virus and cell. Adenovirus attachment is thought to begin viruses from hazards such as drying, heat and chemical with binding of the fibre protein to a cellular receptor. disinfectants, such as ethanol. Indeed, stable capsid However, adenovirus attachment through the fibre protein properties are greatly desired by manufacturers of live- is not sufficient to ensure entry into the cells. Further virus vaccines so that these vaccines can be used in research has revealed that a second interaction between the locations of the world where refrigeration is unreliable. penton base proteins of the capsid and a family of proteins Enveloped virions are often less stable in the environment on the cell surface, known as integrins, is required for because they are often susceptible to drying and other efficient infection of the cells. environmental conditions; therefore, they are usually Attachment to the cellular surface can be considered the spread by direct contact between host organisms. Envel- first step in viral entry. The virus is now in close proximity oped virions are highly efficient in entering a host cell, if to the cellular membrane and can interact with this they come into contact with a new host cell within the membrane at the cell surface or after the virus has been appropriate time. endocytosed to form a virus-containing intracellular compartment. This interaction with cellular membranes requires structural alterations in the viral capsid that result in delivery of the viral payload of nucleic acids and/or Capsid and Envelope Function: Viral proteins into the cytoplasm. Note that the ability to uncoat Entry into Host Cells and discharge the contents of the virion is in direct opposition with the requirement that capsids provide Assuming that the capsid and envelope are successful in protection and stability to the virus. Viruses have solved protecting the virus from the environment, the next major this problem by requiring that a specific signal must be

ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net 5 Viral Capsids and Envelopes: Structure and Function

HIV-1 gp120 is that a lipid–protein structure is generally far less stable in variable loops the environment than is a protein shell. Many enveloped viruses can exist for only minutes or hours in the environment. This instability is balanced by the advan- Core tages of having an envelope to shield the virion from antibody neutralization and to enhance entry into cells by fusion. The proteins found in viral envelopes are often CD4 gp120 glycoproteins. The carbohydrate structures attached to these proteins can help prevent the binding of antibodies to CXCR4 the proteins, protecting the virus from the immune system. CCR5 The presence of a lipid envelope also helps to shield the Cell internal proteins from detection by the immune system. For influenza virus, protective immunity can only be achieved if antibodies are generated to the HA and NA Figure 3 The stages of entry of human immunodeficiency virus (HIV). gp, glycoprotein. Redrawn after http://www.brown.edu/Courses/Bio_160/ proteins. Antibodies to the internal proteins have little or Projects1999/hiv/infect.html with the permission of Dr Joseph Sodroski. no effect on the course of disease, presumably because the internal proteins are protected by the viral envelope. From a biochemical point of view it should be easy to accommodate additional proteins in the envelope. Proteins delivered by the cell to the virus to start uncoating, only need the intracellular recognition sequence on their essentially informing the virus that it has successfully cytoplasmic domain. The same modification would very reached its final destination. Most often this signal is difficult for nonenveloped viruses, as major structural delivered by either contact with the receptor protein or rearrangements of the capsid would be necessary. acidification of the environment inside of the virus- Entry of enveloped viruses into cells is also easier to containing endosome. This is illustrated by the current envision. The virus need only bring its envelope into close model for HIV entry into its host cell, the CD4+T contact with the cellular membrane and provide a catalyst lymphocyte (Figure 3). The virus attaches to the cell by for fusion. In addition to fusion at the cell surface, binding of the virion glycoprotein gp120 to the CD4 membrane fusion between the viral envelope and cell protein on the cell surface. This binding causes a membrane may also occur in internal vesicles. For conformational change in gp120 that allows it to bind to example, the entry process for influenza virus begins with a cellular coreceptor molecule, a CXCR4 or CCR5 the attachment of the HA protein to receptors on the cell chemokine receptor. This brings the gp41 to the cellular membrane (Figure 2, lower left). The virus is then plasma membrane and allows it to insert and promote internalized in an endosome, which is acidified by the cell. fusion between the viral envelope and the cellular plasma This acidification causes the HA to change shape and a membrane, releasing the nucleocapsid into the cytoplasm. hydrophobic portion of HA2 interacts with the vesicle For poliovirus, binding to the cellular receptor initiates a membrane. This interaction is thought to lead to fusion of sequence of events that results in delivery of the RNA the viral envelope and the vesicle membrane. Acidification genome into the cytoplasm. This sequence is thought to of the vesicle also leads to acidification of the internal begin with a structural rearrangement of the capsid that components of the virus, as protons can pass freely through results in the loss of the most internal of the four capsid the M2 channel in the viral envelope. This acidification proteins, VP4. This alteration also changes the structure of dissociates the from the matrix protein, so the VP1 protein such that the N-terminal portion of VP1 is that upon membrane fusion the nucleocapsid structures repositioned to interact with the cellular membrane. can release from the other viral components and move to Although not proven, it is believed that the RNA then the nucleus. The viral replication cycle can then begin. enters the cell through a pore made from the VP1 and In summary, the viral capsid and envelope are highly possibly VP4 proteins. For many viruses, this step marks specific structures that promote the transmission of the the final capsid function. In others, the capsid or a viral genomic material from one host cell to another. subassembly of the capsid may have additional functions. Antiviral strategies are beginning to target the molecules in For example, the capsid may provide the function of these structures and the processes they mediate to block transport of the viral genome to the nucleus. More viral infection and prevent or treat viral disease. One complicated functions may also be performed by some example of such an antiviral drug is amantidine, which capsids. For example, a form of the reovirus capsid blocks the M2 ion channel protein of influenza virus and functions as the viral transcriptase/replicase. blocks uncoating and infection by influenza virus. A During the extracellular journey from one cell to second example is the class of drugs called fusion another, the advantages and disadvantages of having a inhibitors, which are being tested against human immuno- viral envelope become apparent. The major disadvantage deficiency virus (HIV). We can hope that further study of

6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net Viral Capsids and Envelopes: Structure and Function the biochemistry of viruses will lead to drugs specific for all Further Reading classes of viruses. Flint J, Enquist LW, Krug RM, Racaniello VR and Skalka AM (2000) Principles of Virology, Washington, DC: ASM Press. References Harrison SC (2001) Principles of virus structure. In: Fields BN, Knipe DM, Howley PM et al. (eds) Fields Virology, 4th edn, pp. 53–85. Caspar D and Klug A (1962) Physical principles in the construction of Philadelphia: Lippincott Williams and Wilkins. regular viruses. Cold Spring Harbor Symposium on Quantitative Hunter E (2001) Virus assembly. In: Fields BN, Knipe DM, Howley PM Biology 27: 1–24. et al. (eds) Fields Virology, 4th edn, pp. 171–197. Philadelphia: Harrison SC, Olson A, Schutt CE et al. (1978) Tomato bushy stunt virus Lippincott Williams and Wilkins. at 2.9 Angstrom resolution. Nature (London) 276: 368–373. Laver WG, Bischofberger N and Webster RG (1999) Disarming flu Sander DM (2002) The Big Picture Book of Viruses. http://www.Vir- viruses. Scientific American 280: 78–87. ology.net/Big_Virology Young JAT (2001) Virus entry and uncoating. In: Fields BN, Knipe DM, Wilson IA, Skehel JJ and Wiley DC (1981) Structure of the Howley PM et al. (eds) Fields Virology, 4th edn, pp. 87–103. haemagglutinin membrane glycoprotein of influenza virus at 3- Philadelphia: Lippincott Williams and Wilkins. Angstrom resolution. Nature (London) 289: 366–373.

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