General Concepts
Structure and Function
Viruses are small obligate intracellular parasites, which by definition containeither a RNA or DNA genome surrounded by a protective, virus-coded protein coat.Viruses may be viewed as mobile genetic elements, most probably of cellularorigin and characterized by a long co-evolution of virus and host. Forpropagation viruses depend on specialized host cells supplying the complexmetabolic and biosynthetic machinery of eukaryotic or prokaryotic cells. Acomplete virus particle is called a virion. The main function of the virion isto deliver its DNA or RNA genome into the host cell so that the genome can beexpressed (transcribed and translated) by the host cell. The viral genome, oftenwith associated basic proteins, is packaged inside a symmetric protein capsid.The nucleic acid-associated protein, called nucleoprotein, together with thegenome, forms the nucleocapsid. In enveloped viruses, the nucleocapsid issurrounded by a lipid bilayer derived from the modified host cell membrane andstudded with an outer layer of virus envelope glycoproteins.
Classification of Viruses
Morphology: Viruses are grouped on the basis of size and shape,chemical composition and structure of the genome, and mode of replication.Helical morphology is seen in nucleocapsids of many filamentous and pleomorphicviruses. Helical nucleocapsids consist of a helical array of capsid proteins(protomers) wrapped around a helical filament of nucleic acid. Icosahedralmorphology is characteristic of the nucleocapsids of many“spherical” viruses. The number and arrangement of thecapsomeres (morphologic subunits of the icosahedron) are useful inidentification and classification. Many viruses also have an outer envelope.
Chemical Composition and Mode of Replication: The genome of a virusmay consist of DNA or RNA, which may be single stranded (ss) or double stranded(ds), linear or circular. The entire genome may occupy either one nucleic acidmolecule (monopartite genome) or several nucleic acid segments (multipartitegenome). The different types of genome necessitate different replicationstrategies.
Nomenclature
Aside from physical data, genome structure and mode of replication are criteriaapplied in the classification and nomenclature of viruses, including thechemical composition and configuration of the nucleic acid, whether the genomeis monopartite or multipartite. The genomic RNA strand of single-stranded RNAviruses is called sense (positive sense, plus sense) in orientation if it canserve as mRNA, and antisense (negative sense, minus sense) if a complementarystrand synthesized by a viral RNA transcriptase serves as mRNA. Also consideredin viral classification is the site of capsid assembly and, in envelopedviruses, the site of envelopment.
Structure and Function
Viruses are inert outside the host cell. Small viruses, e.g., polio and tobaccomosaic virus, can even be crystallized. Viruses are unable to generate energy. Asobligate intracellular parasites, during replication, they fully depend on thecomplicated biochemical machinery of eukaryotic or prokaryotic cells. The mainpurpose of a virus is to deliver its genome into the host cell to allow itsexpression (transcription and translation) by the host cell.
A fully assembled infectious virus is called a virion. The simplest virions consistof two basic components: nucleic acid (single- or double-stranded RNA or DNA) and aprotein coat, the capsid, which functions as a shell to protect the viral genomefrom nucleases and which during infection attaches the virion to specific receptorsexposed on the prospective host cell. Capsid proteins are coded for by the virusgenome. Because of its limited size (Table41-1) the genome codes for only a few structural proteins (besidesnon-structural regulatory proteins involved in virus replication). Capsids areformed as single or double protein shells and consist of only one or a fewstructural protein species. Therefore, multiple protein copies must self assemble toform the continuous three-dimensional capsid structure. Self assembly of viruscapsids follows two basic patterns: helical symmetry, in which the protein subunitsand the nucleic acid are arranged in a helix, and icosahedral symmetry, in which theprotein subunits assemble into a symmetric shell that covers the nucleicacid-containing core.
Table 41-1
Chemical and Morphologic Properties of Animal Virus Families Relevant toHuman Disease.
Some virus families have an additional covering, called the envelope, which isusually derived in part from modified host cell membranes. Viral envelopes consistof a lipid bilayer that closely surrounds a shell of virus-encodedmembrane-associated proteins. The exterior of the bilayer is studded withvirus-coded, glycosylated (trans-) membrane proteins. Therefore, enveloped virusesoften exhibit a fringe of glycoprotein spikes or knobs, also called peplomers. Inviruses that acquire their envelope by budding through the plasma or anotherintracellular cell membrane, the lipid composition of the viral envelope closelyreflects that of the particular host membrane. The outer capsid and the envelopeproteins of viruses are glycosylated and important in determining the host range andantigenic composition of the virion. In addition to virus-specified envelopeproteins, budding viruses carry also certain host cell proteins as integralconstituents of the viral envelope. Virus envelopes can be considered an additionalprotective coat. Larger viruses often have a complex architecture consisting of bothhelical and isometric symmetries confined to different structural components. Smallviruses, e.g., hepatitis B virus or the members of the picornavirus or parvovirusfamily, are orders of magnitude more resistant than are the larger complex viruses,e.g. members of the herpes or retrovirus families.
Classification of Viruses
Viruses are classified on the basis of morphology, chemical composition, and mode ofreplication. The viruses that infect humans are currently grouped into 21 families,reflecting only a small part of the spectrum of the multitude of different viruseswhose host ranges extend from vertebrates to protozoa and from plants and fungi tobacteria.
Morphology
Helical Symmetry
In the replication of viruses with helical symmetry, identical proteinsubunits (protomers) self-assemble into a helical array surrounding thenucleic acid, which follows a similar spiral path. Such nucleocapsids formrigid, highly elongated rods or flexible filaments; in either case, detailsof the capsid structure are often discernible by electron microscopy. Inaddition to classification as flexible or rigid and as naked or enveloped,helical nucleocapsids are characterized by length, width, pitch of thehelix, and number of protomers per helical turn. The most extensivelystudied helical virus is tobacco mosaic virus (Fig. 41-1). Many important structural features ofthis plant virus have been detected by x-ray diffraction studies. Figure 41-2 shows Sendai virus, anenveloped virus with helical nucleocapsid symmetry, a member of theparamyxovirus family (see Ch.30).
Figure 41-1
The helical structure of the rigid tobacco mosaic virusrod. About 5 percent of the length of the virion is depicted.Individual 17,400-Da protein subunits (protomers) assemble in ahelix with an axial repeat of 6.9 nm (49 subunits per threeturns). Each (more...)
Figure 41-2
Fragments of flexible helical nucleocapsids (NC) of Sendaivirus, a paramyxovirus, are seen either within the protectiveenvelope (E) or free, after rupture of the envelope. The intact nucleocapsid is about 1,000 nm long and 17 nm indiameter; its pitch (more...)
Icosahedral Symmetry
An icosahedron is a polyhedron having 20 equilateral triangular faces and 12vertices (Fig. 41-3). Lines throughopposite vertices define axes of fivefold rotational symmetry: allstructural features of the polyhedron repeat five times within each360° of rotation about any of the fivefold axes. Lines through thecenters of opposite triangular faces form axes of threefold rotationalsymmetry; twofold rotational symmetry axes are formed by lines throughmidpoints of opposite edges. An icosaheron (polyhedral or spherical) withfivefold, threefold, and twofold axes of rotational symmetry (Fig. 41-3) is defined as having 532symmetry (read as 5,3,2).
Figure 41-3
Icosahedral models seen, left to right, on fivefold,threefold, and twofold axes of rotational symmetry. These axes are perpendicular to the plane of the page and passthrough the centers of each figure. Both polyhedral (upper) andspherical (lower) forms (more...)
Viruses were first found to have 532 symmetry by x-ray diffraction studiesand subsequently by electron microscopy with negative-staining techniques.In most icosahedral viruses, the protomers, i.e. the structural polypeptidechains, are arranged in oligomeric clusters called capsomeres, which arereadily delineated by negative staining electron microscopy and form theclosed capsid shell (Fig. 41-4 a/b). The arrangement of capsomeres into an icosahedral shell (compare Fig. 41-4 with the upper right modelin Fig. 41-3) permits theclassification of such viruses by capsomere number and pattern. Thisrequires the identification of the nearest pair of vertex capsomeres (calledpenton: those through which the fivefold symmetry axes pass) and thedistribution of capsomeres between them.
Figure 41-4
Adenovirus after negative stain electron microscopy. (A) The capsid reveals the typical isometric shell made up from20 equilateral triangular faces. The 252 capsomeres, 12 pentonsand the 240 hollow hexon capsomeres are arranged in a T= 25 symmetry (more...)
In the adenovirus model in Figure41-4, one of the penton capsomeres is arbitrarily assigned theindices h = 0, k = 0 (origin), where h and k are theindicated axes of the inclined (60°) net of capsomeres. The net axesare formed by lines of the closest-packed neighboring capsomeres. Inadenoviruses, the h and k axes also coincide with the edges of thetriangular faces. Any second neighboring vertex capsomere has indices h= 5, k = 0 (or h = 0, k = 5).The capsomere number (C) can be determined to be 252 from the h and kindices and the equation: C = 10(h2 +hk+ k2) + 2. This symmetry and number ofcapsomeres is typical of all members of the adenovirus family.
Virus Core Structure
Except in helical nucleocapsids, little is known about the packaging ororganization of the viral genome within the core. Small virions are simplenucleocapsids containing 1 to 2 protein species. The larger viruses containin a core the nucleic acid genome complexed with basic protein(s) andprotected by a single- or double layered capsid (consisting of more than onespecies of protein) or by an envelope (Fig.41-5).
Figure 41-5
Two-dimensional diagram of HIV-1 correlating (immuno-)electron microscopic findings with the recent nomenclature forthe structural components in a 2-letter code and with themolecular weights of the virus structural (glyco-)proteins. SU stands for (more...)
Chemical Composition and Mode of Replication
RNA Virus Genomes
RNA viruses, comprising 70% of all viruses, vary remarkably in genomestructure (Fig. 41-6). Because ofthe error rate of the enzymes involved in RNA replication, these virusesusually show much higher mutation rates than do the DNA viruses. Mutationrates of 10-4 lead to the continuous generation of virus variantswhich show great adaptability to new hosts. The viral RNA may besingle-stranded (ss) or double-stranded (ds), and the genome may occupy asingle RNA segment or be distributed on two or more separate segments(segmented genomes). In addition, the RNA strand of a single-stranded genomemay be either a sense strand (plus strand), which can function as messengerRNA (mRNA), or an antisense strand (minus strand), which is complementary tothe sense strand and cannot function as mRNA protein translation (see Ch. 42). Sense viral RNA alonecan replicate if injected into cells, since it can function as mRNA andinitiate translation of virus-encoded proteins. Antisense RNA, on the otherhand, has no translational function and cannot per se produce viralcomponents.
Figure 41-6
Schemes of 21 virus families infecting humans showing anumber of distinctive criteria: presence of an envelope or(double-) capsid and internal nucleic acid genome. +, Sense strand; -, antisense strand; ±,dsRNA or DNA; 0, circular DNA; C, number (more...)
DsRNA viruses, e.g., members of the reovirus family, contain 10, 11 or 12separate genome segments coding for 3 enzymes involved in RNA replication, 3major capsid proteins and a number of smaller structural proteins. Eachsegment consists of a complementary sense and antisense strand that ishydrogen bonded into a linear ds molecule. The replication of these virusesis complex; only the sense RNA strands are released from the infectingvirion to initiate replication.
The retrovirus genome comprises two identical, plus-sense ssRNA molecules,each monomer 7–11 kb in size, that are noncovalently linked over ashort terminal region. Retroviruses contain 2 envelope proteins encoded bythe env-gene, 4–6 nonglycosylated core proteins and 3non-structural functional proteins (reverse transcriptase, integrase,protease: RT, IN, PR) specified by the gag-gene (Fig. 41-5). The RT transcribes the viral ssRNA intodouble-stranded, circular proviral DNA. This DNA, mediated by the viralintegrase, becomes covalently bonded into the DNA of the host cell to makepossible the subsequent transcription of the sense strands that eventuallygive rise to retrovirus progeny. After assembly and budding, retrovirusesshow structural and functional maturation. In immature virions thestructural proteins of the core are present as a large precursor proteinshell. After proteolytic processing by the viral protease the proteins ofthe mature virion are rearranged and form the dense isometric or cone-shapedcore typical of the mature virion, and the particle becomes infectious.
DNA Virus Genomes
Most DNA viruses (Fig. 41-6) containa single genome of linear dsDNA. The papovaviruses, comprising the polyoma-and papillomaviruses, however, have circular DNA genomes, about 5.1 and 7.8kb pairs in size. DsDNA serves as a template both for mRNA and forself-transcription. Three or 2 structural proteins make up the papovaviruscapsid: in addition, 5-6 nonstructural proteins are encoded that arefunctional in virus transcription, DNA replication and celltransformation.
Single-stranded linear DNA, 4–6 kb in size, is found with themembers of the Parvovirus family that comprises the parvo-, the erythro- andthe dependoviruses. The virion contains 2–4 structural proteinspecies which are differently derived from the same gene product (see Ch. 64). The adeno-associatedvirus (AAV, a dependovirus) is incapable of producing progeny virions exceptin the presence of helper viruses (adenovirus or herpesvirus). It istherefore said to be replication defective.
Circular single-stranded DNA of only 1.7 to 2.3 kb is found in members of theCircovirus family which comprise the smallest autonomously propagatedviruses. The isometric capsid measures 17 nm and is composed of 2 proteinspecies only.
Virus Classification
On the basis of shared properties viruses are grouped at different hierarchicallevels of order, family, subfamily, genus and species. More than 30,000 differentvirus isolates are known today and grouped in more than 3,600 species, in 164 generaand 71 families. Viral morphology provides the basis for grouping viruses intofamilies. A virus family may consist of members that replicate only in vertebrates,only in invertebrates, only in plants, or only in bacteria. Certain families containviruses that replicate in more than one of these hosts. This section concerns onlythe 21 families and genera of medical importance.
Besides physical properties, several factors pertaining to the mode of replicationplay a role in classification: the configuration of the nucleic acid (ss or ds,linear or circular), whether the genome consists of one molecule of nucleic acid oris segmented, and whether the strand of ss RNA is sense or antisense. Alsoconsidered in classification is the site of viral capsid assembly and, in envelopedviruses, the site of nucleocapsid envelopment.Table 41-1 lists the major chemical and morphologic properties of thefamilies of viruses that cause disease in humans.
The use of Latinized names ending in -viridae for virus families and ending in -virusfor viral genera has gained wide acceptance. The names of subfamilies end in-virinae. Vernacular names continue to be used to describe the viruses within agenus. In this text, Latinized endings for families and subfamilies usually are notused. Table 41-2 shows the currentclassification of medically significant viruses.
Table
Current Classification of Major Groups Of viruses of MedicalSignificance.
In the early days of virology, viruses were named according to common pathogenicproperties, e.g. organ tropism and/or modes of transmission, and often also aftertheir discoverers. From the early 1950s until the mid-1960s, when many new viruseswere being discovered, it was popular to compose virus names by using sigla(abbreviations derived from a few or initial letters). Thus the name Picornaviridaeis derived from pico (small) and RNA; the name Reoviridae is derived fromrespiratory, enteric, and orphan viruses because the agents were found in bothrespiratory and enteric specimens and were not related to other classified viruses;Papovaviridae is from papilloma, polyoma, and vacuolating agent (simian virus 40[SV40]); retrovirus is from reverse transcriptase; Hepadnaviridaeis from the replication of the virus in hepatocytes and their DNA genomes, as seenin hepatitis B virus. Hepatitis A virus is classified now in the familyPicornaviridae, genus Hepatovirus. Although the current rules for nomenclature donot prohibit the introduction of new sigla, they require that the siglum bemeaningful to workers in the field and be recognized by international studygroups.
The names of the other families that contain viruses pathogenic for humans arederived as follows: Adenoviridae (adeno, “gland”; refers to theadenoid tissue from which the viruses were first isolated); Astroviridae (astronmeans star); Arenaviridae (arena “sand”) describes the sandyappearance of the virion. Bunyaviridae (from Bunyamwera, the place in Africa wherethe type strain was isolated); Calicivirus (calix, “cup” or“goblet” from the cup-shaped depressions on the viral surfaces);Coronaviridae (corona, “crown”) describes the appearance of thepeplomers protruding from the viral surface; Filoviridae (from the Latin filum,“thread” or “filament”) describes themorphology of these viruses. Herpesviridae (herpes, “creeping”)describes the nature of the lesions; Orthomyxoviridae (ortho,“true,” plus myxo “mucus,” a substance forwhich the viruses have an affinity; Paramyxoviridae derived from para,“closely resembling” and myxo; Parvoviridae (parvus means,“small”); Poxviridae (pock means,“pustule”); Rhabdoviridae (rhabdo, “rod”describes the shape of the viruses and Togaviridae (toga,“cloak”) refers to the tight viral envelope.
Several viruses of medical importance still remain unclassified. Some are difficultor impossible to propagate in standard laboratory host systems and thus cannot beobtained in sufficient quantity to permit more precise characterization. Hepatitis Evirus, the Norwalk virus and similar agents (see Ch. 65) that cause nonbacterial gastroenteritis in humansare now assigned to the calicivirus family.
The fatal transmissible dementias in humans and other animals (scrapie in sheep andgoat; bovine spongiform encephalopathy in cattle, transmissible mink encephalopathy;Kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome inhumans) (see Ch. 71) are caused by theaccumulation of non-soluble amyloid fibrils in the central nervous systems. Theagents causing transmissible subacute spongiform encephalopathies have been linkedto viroids or virinos (i.e. plant pathogens consisting of naked, but very stablecircular RNA molecules of about 3-400 bases in size, or infectious genomes enwrappedinto a host cell coat) because of their resistance to chemical and physical agents.According to an alternative theory, the term “prion” has beencoined to point to an essential nonviral infectious cause for these fatalencephalopathies—prion standing for self-replicating proteinaceous agentdevoid of demonstrable nucleic acid. Some of the transmissible amyloidoses show afamilial pattern and can be explained by defined mutations which render a primarysoluble glycoprotein insoluble, which in turn leads to the pathognomonicaccumulation of amyloid fibers and plaques. The pathogenesis of the sporadicamyloidoses, however, is still a matter of highly ambitious research.
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