Structure and Classification of Viruses
Hans R. Gelderblom
General Concepts
Structure and Function
Viruses are small
obligate intracellular parasites, which by definition contain either a RNA or
DNA genome surrounded by a protective, virus-coded protein coat. Viruses may be viewed as mobile genetic
elements, most probably of cellular origin and characterized by a long
co-evolution of virus and host. For propagation viruses depend on specialized
host cells supplying the complex metabolic and biosynthetic machinery of
eukaryotic or prokaryotic cells.
·
A complete virus particle is called a virion.
·
The main function of the virion is to
deliver its DNA or RNA genome into the host cell so that the genome can be
expressed (transcribed and translated) by the host cell.
·
The viral genome, often with associated
basic proteins, is packaged inside a
symmetric protein capsid.
·
The nucleic acid-associated
protein, called nucleoprotein, together with the genome, forms the nucleocapsid. In
enveloped viruses, the nucleocapsid is surrounded by a lipid bilayer derived
from the modified host cell membrane and studded 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 pleomorphic viruses. Helical nucleocapsids consist of a helical
array of capsid proteins (protomers) wrapped around a helical filament of
nucleic acid. Icosahedral morphology
is characteristic of the nucleocapsids of many
"spherical" viruses. The
number and arrangement of the capsomeres
(morphologic subunits of the icosahedron) are useful in identification and
classification. Many viruses also have an outer
envelope.
Chemical Composition and Mode of Replication: The genome
of a virus may 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 acid molecule
(monopartite genome) or several nucleic acid segments
(multipartite genome). The different
types of genome necessitate different replication
strategies.
Nomenclature
Aside from physical data, genome structure and mode of replication are criteria
applied in the classification and nomenclature of viruses, including the
chemical composition and configuration of the nucleic acid, whether the genome
is monopartite or multipartite. The genomic
RNA strand of single-stranded RNA viruses is called sense
(positive sense, plus sense) in orientation if it can serve as mRNA, and antisense (negative sense, minus sense) if a
complementary strand synthesized by
a viral RNA transcriptase serves as mRNA. Also considered in viral
classification is the site of capsid assembly and, in enveloped viruses, the
site of envelopment.
STRUCTURE AND FUNCTION
Viruses are inert outside the host cell. Small viruses, e.g., polio and tobacco mosaic
virus, can even be crystallized. Viruses are unable to generate energy.
As obligate intracellular parasites, during replication, they fully depend on
the complicated biochemical machinery of eukaryotic or prokaryotic cells. The main purpose of a virus is to deliver its genome into the
host cell to allow its expression (transcription and translation) by the host
cell.
A fully assembled infectious virus is called a virion. The simplest virions consist of two basic components:
·
nucleic acid (single- or double-stranded RNA or DNA)
·
and a protein
coat, the capsid, which
functions as a shell to protect the viral genome from
nucleases and which during infection attaches the virion to specific receptors
exposed on the prospective host cell. Capsid proteins are coded for by the virus genome. Because of its
limited size (Table 41-1) the genome codes for only a
few structural proteins
(besides non-structural
regulatory proteins involved in virus replication).
Capsids are formed as single or double protein shells and consist
of only one or a few structural protein species. Therefore, multiple protein copies must self assemble to form the
continuous three-dimensional capsid structure. Self assembly of virus capsids
follows two basic patterns:
·
helical symmetry, in which the
protein subunits and the nucleic acid are arranged in a helix, and
·
icosahedral symmetry, in which the
protein subunits assemble into a symmetric shell that covers the nucleic
acid-containing core.
Some virus families have an additional
covering, called the envelope,
which is usually derived in part from modified host
cell membranes.
Viral envelopes consist
of a lipid bilayer that
closely surrounds a shell of virus-encoded membrane-associated proteins. The exterior of the bilayer is studded with virus-coded,
glycosylated (trans-) membrane proteins. Therefore, enveloped
viruses often exhibit a fringe of glycoprotein spikes or knobs, also called peplomers. In viruses that
acquire their envelope by budding
through the plasma or another intracellular cell membrane, the lipid composition of the viral envelope closely reflects
that of the particular host membrane.
The outer capsid and
the envelope proteins of viruses are glycosylated
and important in determining the host range and
antigenic composition of the virion. In addition to virus-specified
envelope proteins, budding viruses
carry also certain host cell proteins as integral
constituents of the viral envelope. Virus envelopes can be considered an additional
protective coat. Larger viruses
often have a complex architecture consisting of both
helical and isometric symmetries confined to different structural
components. Small viruses, e.g.,
hepatitis B virus or the members of the picornavirus or parvovirus family, 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 of replication. The viruses that infect humans are currently
grouped into 21 families, reflecting only a small part of the spectrum of
the multitude of different viruses whose host ranges extend from vertebrates to
protozoa and from plants and fungi to bacteria.
Morphology
Helical Symmetry
In the replication of viruses with helical symmetry, identical
protein subunits (protomers) self-assemble into a
helical array surrounding the nucleic acid, which follows a similar spiral path.
Such nucleocapsids form
·
rigid,
·
highly elongated rods
·
or flexible filaments; in either
case, details of the capsid structure are often discernible by electron
microscopy. In addition to classification as flexible or rigid and as naked or
enveloped,
·
helical nucleocapsids are
characterized by length, width, pitch of the helix, and
number of protomers per helical turn. The most extensively studied
helical virus is tobacco mosaic virus
(Fig. 41-1). Many important structural features of this plant virus have been
detected by x-ray diffraction studies. Figure
41-2 shows Sendai virus, an
enveloped virus with helical nucleocapsid symmetry, a member of the
paramyxovirus family (see Ch. 30).
FIGURE 41-1 The helical structure of the
rigid tobacco mosaic virus rod. About 5 percent of the length of the virion
is depicted. Individual 17,400-Da protein subunits (protomers) assemble in a
helix with an axial repeat of 6.9 nm (49 subunits per three turns). Each turn
contains a nonintegral number of subunits (16-1/3), producing a pitch of 2.3
nm. The RNA (2x1O6 Da) is sandwiched internally between adjacent turns of
capsid protein, forming a RNA helix of the same pitch, 8 nm in diameter, that
extends the length of virus, with three nucleotide bases in contact with each
subunit. Some 2,130 protomers per virion cover and protect the RNA. The
complete virus is 300 nm long and 18 nm in diameter with a hollow cylindrical
core 4 nm in diameter. (From Mattern CFT: Symmetry in virus architecture. In
Nayak DP (ed): Molecular Biology of Animal Viruses. Marcel Dekker, New York,
1977, as modified from Caspar DLD: Adv Protein Chem, 18:37,1963, with
permission.) 
FIGURE 41-2 Fragments of flexible helical nucleocapsids
(NC) of Sendai virus, a paramyxovirus, are seen either within the protective
envelope (E) or free, after rupture of the envelope.
The intact nucleocapsid is about 1,000 nm long and 17 nm in diameter; its pitch
(helical period) is about 5 nm. (x200,000) (courtesy of A. Kalica, National
Institutes of Health.)
Icosahedral Symmetry
An icosahedron is a polyhedron
having 20 equilateral triangular faces and 12 vertices (Fig. 41-3). Lines
through opposite vertices define axes of fivefold
rotational symmetry: all structural features of the polyhedron repeat
five times within each 360° of rotation about any of the fivefold axes. Lines
through the centers of opposite triangular faces form axes of threefold
rotational symmetry; twofold rotational symmetry axes are formed by lines
through midpoints of opposite edges. An icosaheron (polyhedral or spherical)
with fivefold, threefold, and twofold axes of rotational symmetry (Fig. 41-3)
is defined as having 532 symmetry (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 pass through
the centers of each figure. Both polyhedral (upper) and
spherical (lower) forms are represented by different virus families.
Viruses were first found to have 532 symmetry by x-ray diffraction studies and subsequently by electron
microscopy with negative-staining techniques. In most icosahedral
viruses, the protomers, i.e. the
structural polypeptide chains, are arranged in oligomeric clusters called capsomeres, which
are readily delineated by negative staining electron microscopy and form the closed capsid shell (Fig. 41-4 a/b). The
arrangement of capsomeres into an icosahedral shell (compare Fig. 41-4 with the
upper right model in Fig. 41-3) permits the
classification of such viruses by capsomere number and pattern. This
requires the identification of the nearest pair of vertex capsomeres (called penton:
those through which the fivefold symmetry axes pass) and the distribution of
capsomeres between them.
FIGURE 41-4a Adenovirus after negative stain electron
microscopy. The capsid reveals the typical isometric
shell made up from 20 equilateral triangular faces. The 252 capsomeres, 12
pentons and the 240 hollow hexon capsomeres are arranged in a T = 25 symmetry
pattern vetite (x 400,000).
FIGURE 41-4b Adenovirus model.
Capsomeres are depicted as circles surrounded by an electron dense stain. The
inclined axes, h and k, are indicated. The second vertex has indices h = 5, k =
0. The total number of capsomeres C
= 10(h2 + hk + k2) + 2 = 252.
Capsomere organization is also expressed by the triangulation number, T, the
number of unit triangles on each of the 20 faces of the icosahedron. A unit
triangle is formed by lines joining the centers of three adjacent capsomeres. T
= (h2 + hk + k2) = 25 for adenoviruses, and C = 1OT + 2. The 12 vertex
capsomeres are surrounded by 5 other capsomeres each, therefore called penton and show 5-fold rotational
symmetry. The penton base consists of 5 identical 85 kD polypeptide chains and
extrudes a long antenna-like fiber protein. The 240 hexon capsomeres are
trimers of the 120 kD hexon protomere polypeptide (for details see Ch. 67).
In the adenovirus model in Figure 41-4, one of the penton
capsomeres is arbitrarily assigned the indices h = 0, k = 0 (origin), where h
and k are the indicated axes of the inclined (60°) net of capsomeres. The net
axes are formed by lines of the closest-packed neighboring capsomeres. In adenoviruses,
the h and k axes also coincide with the edges of the triangular 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 k indices
and the equation: C = 10(h2 +hk + k2) + 2. This symmetry and number of
capsomeres is typical of all members of the adenovirus family.
Virus Core Structure
Except in helical nucleocapsids, little is known about the
packaging or organization of the viral genome within the core. Small virions are simple nucleocapsids containing 1 to 2 protein species.
The larger viruses contain in a core the nucleic acid genome complexed with
basic protein(s) and protected by a single- or double layered capsid
(consisting of more than one species 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 for the
structural components in a 2-letter code and with the molecular weights of the
virus structural (glyco-) proteins. SU
stands for outer surface glycoprotein, TM for transmembrane gp, MA for membrane associated
or matrix protein, LI for core-envelope-link,
CA for major capsid, NC for nucleocapsid protein, respectively.
PR, RT and IN represent
the virus-coded enzymes protease, reverse transcriptase and integrase
that are functional during the life cycle of a retrovirus (from Gelderblom, HR,
AIDS 5, 1991).
Chemical Composition and Mode of Replication
RNA Virus Genomes
RNA viruses, comprising 70% of all viruses, vary
remarkably in genome structure (Fig. 41-6). Because of the error rate of
the enzymes involved in RNA replication, these viruses
usually show much higher mutation rates than do the DNA viruses.
Mutation rates of 10-4 lead to the continuous generation of virus variants
which show great adaptability to new hosts. The viral
RNA may be single-stranded (ss) or double-stranded (ds), and the genome
may occupy a single RNA segment or
be distributed on two or more separate segments (segmented genomes). In addition, the RNA strand of a single-stranded genome may be either a sense strand (plus strand), which can function as messenger
RNA (mRNA), or an antisense strand
(minus strand), which is
complementary to the sense strand and cannot function as mRNA protein
translation (see Ch. 42). Sense viral RNA alone can
replicate if injected into cells, since it can function as mRNA and initiate
translation of virus-encoded proteins. Antisense RNA, on the other hand, has no translational function and
cannot per se produce viral components.
DsRNA viruses, e.g., members of the reovirus family, contain 10, 11 or 12
separate genome segments coding for 3 enzymes involved in RNA replication,
3 major capsid proteins and a number of smaller structural proteins. Each segment consists of a complementary
sense and antisense strand that is hydrogen bonded into a linear ds
molecule. The replication of
these viruses is complex; only the sense
RNA strands are released from the infecting virion 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 a short terminal region.
Retroviruses contain 2 envelope proteins
encoded by the env-gene,
4-6 nonglycosylated core proteins and 3
non-structural functional proteins
(reverse transcriptase, integrase, protease: RT, IN, PR) specified by the gag-gene (Fig. 41-5).
·
The RT transcribes the viral ssRNA into double-stranded, circular
proviral DNA.
·
This DNA, mediated by the viral
integrase, becomes covalently bonded
into the DNA of the host cell to make possible the subsequent transcription of
the sense strands that eventually give rise to retrovirus progeny.
·
After assembly and budding, retroviruses show structural and functional
maturation. In immature virions the structural
proteins of the core are present as a large precursor protein shell. After proteolytic processing by the
viral protease the proteins of the
mature virion are rearranged and form the dense isometric or cone-shaped
core typical of the mature virion, and the particle becomes infectious.
DNA Virus Genomes
Most DNA viruses (Fig. 41-6) contain a single
genome of linear dsDNA. The papovaviruses, comprising
the polyoma- and papillomaviruses, however, have circular DNA genomes, about 5.1 and 7.8 kb pairs in size. DsDNA serves as a template both for mRNA
and for self-transcription. Three or 2 structural proteins make up the
papovavirus capsid: in addition, 5-6 nonstructural proteins are encoded that
are functional in virus transcription, DNA replication and cell transformation.
FIGURE 41-6 Schemes of 21 virus families infecting humans
showing a number 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 of capsomeres or holes, where known; nm, dimensions of capsid, or
envelope when present; the hexagon designates the presence of an isometric or
icosahedral outline.
Single-stranded linear
DNA, 4-6 kb in size, is found with the members of the Parvovirus family that comprises the parvo-, the erythro-
and the dependoviruses. The virion contains 2-4 structural protein species
which are differently derived from the same gene product (see Ch. 64). The adeno-associated virus (AAV, a dependovirus)
is incapable of producing progeny virions except in the presence of helper
viruses (adenovirus or herpesvirus). It is therefore said to be replication defective.
Circular
single-stranded DNA of only 1.7 to 2.3 kb is found in
members of the Circovirus family which comprise
the smallest autonomously propagated viruses.
The isometric capsid measures 17 nm and is composed of 2 protein species only.
Virus Classification
On the basis of shared properties viruses are grouped at different hierarchical levels of order, family,
subfamily, genus and species. More than 30,000 different virus isolates are known today
and grouped in more than 3,600 species, in 164 genera and 71 families. Viral morphology provides the basis for
grouping viruses into families. A
virus family may consist of members that replicate only in vertebrates, only in
invertebrates, only in plants, or only in bacteria. Certain families contain
viruses that replicate in more than one of these hosts. This section concerns
only the 21 families and genera of medical importance.
Besides physical
properties, several factors pertaining to the mode of replication play 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 or is segmented, and
·
whether the strand of ss RNA is sense or antisense.
·
Also considered in classification
is the site of viral capsid assembly
and,
·
in enveloped viruses, the site of nucleocapsid envelopment. Table
41-1 lists the major chemical and morphologic properties of the families of
viruses that cause disease in humans.
The use of Latinized names ending in -viridae for virus
families and ending
in -virus
for viral genera has gained wide acceptance. The
names of subfamilies
end in -virinae. Vernacular names continue to be used to
describe the viruses within a genus. In this text, Latinized endings for
families and subfamilies usually are not used. Table 41-2 shows the current
classification of medically significant viruses.
In the early
days of virology, viruses were named according to common pathogenic
properties, e.g. organ tropism and/or modes of transmission, and often also
after their discoverers. From the early 1950s until the
mid-1960s, when many new viruses were being discovered, it was popular to
compose virus names by using sigla (abbreviations
derived from a few or initial letters). Thus the name Picornaviridae is derived from pico (small) and RNA; the name Reoviridae is derived from respiratory, enteric, and orphan
viruses because the agents were found in both respiratory
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; Hepadnaviridae is from the
replication of the virus in hepatocytes and their DNA genomes, as seen in hepatitis B
virus. Hepatitis A virus
is classified now in the family
Picornaviridae, genus Hepatovirus. Although the current rules for
nomenclature do not prohibit the introduction of new sigla, they require that
the siglum be meaningful to workers in the field and be recognized by
international study groups.
The names of the other families that contain viruses
pathogenic for humans are derived as follows: Adenoviridae (adeno,
"gland"; refers to the adenoid tissue from which the viruses were
first isolated); Astroviridae
(astron means star); Arenaviridae (arena "sand") describes the
sandy appearance of the virion. Bunyaviridae (from Bunyamwera,
the place in Africa where the 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 the peplomers protruding from the viral surface; Filoviridae (from the
Latin filum, "thread" or
"filament") describes the morphology of these viruses. Herpesviridae (herpes, "creeping") describes
the nature of the lesions; Orthomyxoviridae
(ortho, "true," plus myxo "mucus," a substance for
which 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
difficult or impossible to propagate in standard laboratory host systems and
thus cannot be obtained in sufficient quantity to permit more precise
characterization. Hepatitis E virus,
the Norwalk virus and similar agents
(see Ch. 65) that cause nonbacterial gastroenteritis in humans are now assigned
to the calicivirus family.
The fatal transmissible
dementias in humans and other animals (scrapie in sheep and goat; bovine spongiform
encephalopathy in cattle, transmissible mink encephalopathy; Kuru, Creutzfeldt-Jakob
disease, and Gerstmann-Straussler-Scheinker syndrome in humans) (see Ch.
71 ) are caused by the accumulation of non-soluble amyloid fibrils in the
central nervous systems. The agents causing transmissible subacute spongiform encephalopathies have been
linked to viroids or virinos (i.e. plant pathogens
consisting of naked, but very stable circular RNA molecules of about 3-400
bases in size, or infectious genomes enwrapped into a host cell coat) because
of their resistance to chemical and physical agents. According to an
alternative theory, the term "prion" has
been coined to point to an
essential nonviral infectious cause for these fatal encephalopathiesprion
standing for self-replicating proteinaceous agent devoid of demonstrable
nucleic acid. Some of the transmissible
amyloidoses show a familial pattern and can be explained by defined
mutations which render a primary soluble glycoprotein insoluble, which in turn
leads to the pathognomonic accumulation
of amyloid fibers and plaques. The pathogenesis of the sporadic
amyloidoses, however, is still a matter of highly ambitious research.
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Gajdusek DC: Unconventional viruses and the origin and
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Gelderblom HR: Assembly and morphology of HIV: potential
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Mattern CFT: Symmetry in virus architecture. In Nayak DP (ed):
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