Adenoviruses
S Jane Flint, Princeton University, Princeton, New Jersey, USA
Adenoviruses are nonenveloped viruses with double-stranded DNA genomes that are
generally associated with relatively mild, self-limiting diseases in humans. They rely on
cellular systems for expression of viral genetic information during reproduction in
permissive cells and can transform normal cells in culture; some are tumorigenic in rodents.
Introduction
Adenoviruses, which appear to be restricted to warm-
blooded animals, are defined by their linear, double-
stranded deoxyribonucleic acid (DNA) genomes and the
characteristic size and structure of virions. Human
members of this family are important causes of respiratory
disease and gastroenteritis in children and of conjunctivitis
in children and adults, but in general they are not highly
pathogenic. Nevertheless, adenoviruses have received
considerable attention, in part because this family includes
the first human viruses shown to be tumorigenic in
experimental animals. Most adenoviruses can convert
normal, nontumorigenic rodent cells in culture to trans-
formed cells with tumorigenic potential. Investigation of
the molecular basis of adenovirus transformation spurred
development of a general paradigm for transformation by
small DNA tumour viruses such as the Simian virus 40
(SV40) and polyoma papovaviruses. More importantly
perhaps, such studies led to much improved understanding
of both the mechanisms of action of the products of cellular
tumour suppressor genes and the circuits that govern
orderly progression of normal cells through the cell cycle,
and hence their growth and proliferation.
Like all viruses, adenoviruses are molecular parasites
that exploit cellular biosynthetic systems for their replica-
tion. In permissive host cells, adenoviruses direct synthesis
of viral proteins that replicate the viral DNA genome, but
rely on cellular transcription, pre-mRNA (messenger
ribonucleic acid) processing and translation systems for
expression of viral genetic information. Consequently,
much fundamental information about mechanisms that
mediate and regulate cellular gene expression has come
from investigation of adenoviral reproduction, including
the splicing of pre-mRNA that is a characteristic feature of
eukaryotic cells (Berget et al., 1977; Chow et al., 1977).
Adenoviruses are not, however, merely passive competi-
tors for access to these cellular systems, for the adenoviral
genome encodes a number of regulatory proteins that
ensure orderly and efficient expression of viral coding
sequences. The strictly defined sequence in which viral
genes are expressed is determined primarily by regulation
of transcription, while posttranscriptional mechanisms
induce inhibition of cellular mRNA production and
protein synthesis as the infectious cycle progresses. The
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Secondary article
Article Contents
. Introduction
. Classification
. Structure
. Replication
. Epidemiology
. Clinical Features
. Viral Oncogenesis
end result of infection is the production of large quantities
of the viral genome and protein components of virions for
assembly of progeny virions and death of the host cell.
The processes necessary for successful adenovirus
reproduction, from initial attachment to maturation and
release of progeny virions, can be outlined in some detail.
Nevertheless, many questions remain about the molecular
mechanisms underlying important regulatory circuits
established by viral proteins and the production of progeny
virions. Within the past decade, there has been great
resurgence of interest in adenoviruses, because of their
experimental use as vectors in gene therapy or in anticancer
therapies. Broad cell tropism, ability to infect highly
differentiated cells, and the ease with which the viral
genome can be manipulated are some of the properties that
make these viruses attractive as vectors for therapeutic
purposes. Many specific protocols are now being tested,
and much effort is being devoted to the development of
adenoviral vectors with optimal features. One dividend has
been the greatly improved understanding of crucial
reactions in the infectious cycle, notably the mechanisms
of adenovirus attachment and entry into host cells.
Classification
Adenoviruses were named in recognition of the isolation of
the prototype strain, Human adenovirus 2 (Ad2), from
young children’s adenoids placed in culture (Rowe et al.,
1953). Their definitive properties include linear, double-
stranded DNA genomes of 30 000–45 000 bp and none-
nveloped particles, 80–110 nm in diameter, which exhibit a
striking icosahedral appearance and carry one or two fibres
projecting from each vertex (Figure 1a). Many viruses with
these properties have been isolated from humans, other
primates, domesticated mammals, rodents, marsupials
and birds. In 1976, the International Committee on
Taxonomy of Viruses recognized this group of viruses as
the family Adenoviridae, comprising the genera Mastade-
novirus and Aviadenovirus.
These genera were defined originally on the basis of the
taxonomic class of the virus host (Mammalia and Aves,
1
 Adenoviruses

Figure 1 Structure of adenovirus particles. (a) Surface view of the Ad2 virion obtained by cryoelectron microscopy and image reconstruction. The fibres
project some 33 nm, but only the portions proximal to the virion surface are seen, because these structures are bent. This view, which is orientated
along an icosahedral axis of 3-fold rotational symmetry, has a nominal resolution of 30 Å. From Stewart PL et al. (1991) Cell 67: 145–154, with
permission. (b) Schematic section through the virion, illustrating the locations of the virion proteins and DNA genome. The organization of the capsid
proteins shown is based on biochemical and structural studies. However, protein VIII has not been localized, even though it is known to be internal, and is
shown associated with hexons because it is believed to stabilize the capsid. In the core, the viral DNA is shown associated with protein VII (dashed lines), the
major DNA-binding protein of the virion. There have been reports of organization of the DNA into spherical domains, but in the absence of more detailed
structural information, no specific structure is shown for the core. Adapted from Flint SJ et al. (2000) Principles of Virology: Molecular Biology, Pathogenesis
and Control, ASM Press, Washington, DC, with permission.

respectively), and the presence of group-specific antigens in
the hexon, the major structural protein of the virion;
however, mammalian and avian adenoviruses can also be
distinguished by the sizes, sequences and organization of
their genomes. Those of the former are significantly smaller
than those of the latter, 35 937 bp for Ad2 and 43 804 bp for
Chicken embryo lethal orphan (CELO) virus, respectively.
Moreover, the CELO virus genome lacks certain coding
sequences found in all mastadenoviral DNAs examined
and includes long sequences at either end with no
counterparts in the genomes of Mastadenovirus.
More than 120 adenovirus serotypes have been distin-
guished largely by immunological tests. Individual ser-
otypes can be distinguished by genomic differences, now
often detected by DNA sequencing. Such molecular
approaches also permit the identification of variants of
individual serotypes, often called genome types. Most
attention has been paid to human adenoviruses and their
classification into subgroups (subgenera). Currently, the
Adenoviridae includes 49 human serotypes (Ad1–Ad49).
These viruses have been classified into subgroups using
biological properties, structural or biochemical features,
and the relatedness of their genomes (Table 1). There is
remarkably good agreement among these disparate
criteria. The six human adenovirus subgroups, A–F, were
defined by the degrees of genome relatedness, but all
members of each subgroup also share biological, structural
and biochemical properties. More recent phylogenetic
analyses of specific coding or control sequences of
mastadenoviral genomes have confirmed this classification
scheme (Bailey and Mautner, 1994).
Structure
Electron microscopy of negatively stained adenovirus
particles established that the capsid is built from 252
structural units, 12 pentons located at the axes of 5-fold
rotational symmetry (vertices) of the icosahedral virion
and 240 hexons that form the remainder of the protein shell
(Figure 1). These structural units are formed from three viral
proteins (II, III and IV), but virions contain nine additional
proteins that have been ascribed specific structural or
functional roles (Table 2). The current model of these
complex and large particles (some 150
106 Da in the case
of Ad2) (Figure 1b) is based on biochemical studies and
cryoelectron microscopy and image reconstruction of
subgroup C human adenoviruses.
Most Mastadenovirus species carry a single fibre, with a
fixed, serotype-specific length (Table 1), projecting from the
penton at each vertex of the virion (Figure 1); however, some
carry both long and short fibres (one at each vertex)
(subgroup F in Table 1), while two fibres project from each
penton base of all but one avian adenoviruses. Adenoviral

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 Table 1 Some properties of human adenoviruses
Fibre % Relatedness Oncogenicity in
Subgroup Serotypes lengths a (nm) of DNAb newborn rodents Haemagglutination Most common disease syndromes
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

A 12, 18, 31 28–31 48–69 High Little or none (type IV) Diarrhoea; most frequently
(8–20) isolated from stool specimens
B 3, 7, 11, 14, 16, 9–11 89–94 Moderate Complete agglutination of Upper and lower respiratory
21, 34, 35 (9–20) monkey erythrocyctes infections, e.g. bronchitis,
(type I) pneumonia (especially Ad7);
acute respiratory disease;
pharyngoconjunctival fever
C 1, 2, 5, 6 23–31 99-100 None Partial agglutination of rat Upper and lower respiratory
(10–16) erythrocytes (type III) infections in young children;
endemic
D 8–10, 13, 15, 17, 12–13 95–99 Nonec Complete agglutination of Epidemic keratoconjunctivis
19, 20, 22–30, 32, (4–17) rat erythrocytes (type II) (Ad8, 19 and 37); conjunctivitis
33, 36–39, 42–49
E 4 17 NA None Type III Acute respiratory disease;
(4–23) pharyngoconjunctival fever
F 40, 41 33 62–69 None Type III Gastroenteritis
22 (15–22)
NA, not applicable.
a
Values for the length of the fibre projecting beyond the penton base estimated from electron micrography of purified virions or pentons. For subgroup F (Ad40), the total lengths of the two
fibres including the portion within the penton base were measured. The values listed were calculated by subtracting the length of the latter portion (~4 nm) from the reported values.
b
The values shown were obtained by liquid hybridization between pairs of the viral DNA genomes listed in column 2. Those in parentheses are from hybridization between the DNAs of a
serotype within the subgroup and one belonging to a different subgroup.
c
With the exception of Ad9, which induces oestrogen-dependent mammary tumours in female rats of a certain strain.

Adenoviruses
3
 Adenoviruses

Table 2 Adenovirus type 2 virion proteins

Molecular mass
Proteina (kDa) b Number per virionc Location and function(s)
II 110 720 Hexons (trimers of II); major structural unit of the capsid
III 63 60 Penton bases (pentamers of III); structural units at axes of
5-fold rotational symmetry; anchor fibres; bind to cell
surface integrins to induce internalization of particles and
penetration of endosomal membrane
IIIa 63 60 Monomers span from exterior to interior of capsid at the
edges between hexon faces; stabilize capsid
IV 62 36 Fibres (trimers of IV) projecting from penton bases; distal
knob carries binding sites for cellular receptor
V 42 157 ± 1 Core, probably on outer surface; contacts protein VI;
packaging of DNA genome
Terminal protein (TP) 38 2 Core, monomer covalently linked to the 5′ end of each
strand of the genome; protease cleavage product of the
protein primer for viral DNA synthesis
L3 protease 23 ~20 Cleaves precursors to proteins IIIa, VI, VII, VIII, µ and TP
following assembly to convert immature to infectious
virions; required for uncoating
VI 22 34.2 ± 4 Hexamers associated with peripentonal hexons; stabilizes
capsid; contacts components of the core
VII 19 833 ± 19 Core, bound to viral DNA; major DNA packaging protein
VIII 15 127 ± 3 Internal surface of capsid shell; stabilization of capsid?
IX 14 240 Trimers on exterior surface of the capsid, with monomers
extending along hexon–hexon interfaces in the centre of
each face of the icosahedral particle; stabilizes capsid
µ 2 125–160 Core; packaging of the genome
a
Virion proteins were originally named with Roman numerals on the basis of their separation by electrophoresis in SDS-polyacrylamide gels. In
addition to those listed, virions contain a number of small polypeptides produced when structural protein precursors are processed by the L3
protease.
b
Calculated from predicted amino acid sequence, and rounded to the nearest kilodalton.
c
Absolute numbers per virion are from the current model of Ad2 particles obtained by three-dimensional reconstruction of images collected by
cryoelectron microscopy. All others were determined by biochemical methods.

fibres are responsible for the initial attachment of particles
to host cells, and fibre length may be an important
determinant of attachment and internalization mechan-
isms. All fibres examined exhibit a conserved organization:
a capsid-distal, globular knob is separated from a ‘tail’
domain by a long, thin shaft formed from the central
domains of the three protein IV monomers (Table 2). In
each monomer, this central segment contains multiple
copies of a pseudorepeat of 15 amino acids, defined by the
presence of conserved amino acids at specific positions,
which form a triple spiral structure in the trimer. The highly
conserved tail domain and the knob are responsible for
binding of the fibre to the penton base and to the cellular
receptor for attachment, respectively. Most human ser-
otypes bind to the same cellular protein, the coxsackievirus
B–adenovirus receptor (CAR). In the high-resolution
crystal structure, the Ad5 fibre knob resembles a three-
bladed propeller, one blade contributed by each monomer.
The location of the structural features necessary for CAR
binding suggests that the fibre carries three binding sites for
the viral receptor.
The penton base anchors the fibre to the particle, must
bind stably to the five surrounding hexons (Figure 1) and is
required for internalization of virions. In side view, it
appears as a hollow bucket with a central hole into which
the tail of the fibre is inserted. On its outer surface, each of
the protein III subunits (Table 2) possesses a groove that
could accommodate a b-barrel motif of the hexon subunits
(see below). During adenovirus entry, the penton base
binds to specific integrins on the host cell surface, an
interaction that requires the sequence Arg-Gly-Asp, which
is conserved within an otherwise variable region of protein

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 Adenoviruses

IX VA RNAs E3
E1A E1B ML

L1 L2 L2 L4 L5
289R 55kDa gp19k10.4k14.5k
TP
A 243R 19kDa IX 52/55k IIIa III pVII V pµ pVI II Protease 100k 33k pVIII 11.6k 14.7k IV
A’
Ori Ori
IVa2 Pol pTP DBP ORF6 ORF4 ORF1
TP ORF6/7 ORF3 ORF2

E2 E4
IVa2

Figure 2 Organization of the human adenovirus 2 (Ad2) genome. The linear double-stranded DNA genome is represented by the pair of solid horizontal
lines in the centre of the figure. The terminal protein (TP) that is covalently linked to the 5’ end of each strand and the adjacent sequence required for
initiation of viral DNA synthesis (Ori) are indicated. The origins are included within an inverted terminal repeat sequence of 202 bp present at the ends
of the genome, designated A and A’. The locations of the eight RNA polymerase II transcription units are represented by barbed arrows drawn in the
direction of transcription, with the immediate early, early and late transcription (ML) units shown in pink, blue and red, respectively. Viral proteins encoded
within each transcription unit are listed above or below the genome, using the unsystematic nomenclature adopted in the field (see Tables 2 and 3). Several
virion proteins are synthesized as precursors that are proteolytically processed by the viral protease only following virion assembly. Such proteins are
indicated by the prefix p. The five families, L1 to L5, of ML proteins, which are defined by the locations of the 3’ ends of the mRNAs that specify them (see
Figure 5), are indicated. The coding sequences for proteins that perform related functions are often organized together in the viral genome. Thus, all viral
replication proteins, including the DNA polymerase (Po1), the protein primer and precursor to the TP (pTP) and the single-stranded DNA-binding
protein (DBP), are encoded in the E2 transcription unit, while coding sequence for the core proteins or their precursors, pVII, V and pm, lie within the L2
segment of the ML transcription unit. The positions of the virus-associated (VA) RNA genes transcribed by RNA polymerase III are indicated by the solid red
arrowheads.

III in many human serotypes. These Arg-Gly-Asp
sequences are located in five projections, one per subunit,
that extend some 20 Å from the top surface of the penton
base. Each penton base can bind five integrin molecules,
and can therefore presumably induce clustering of
integrins in the plasma membrane to trigger internalization
of virus particles by endocytosis.
The major structural features of the hexon monomer
(Table 2), determined by X-ray crystallography of the Ad2
hexon (Athappilly et al., 1994), are two copies of an eight-
stranded b-sheet motif termed a b barrel. This motif is
found in the major capsid proteins of a number of other
DNA and RNA viruses. In the hexon trimer, the b barrels
form a pseudohexagonal base that is well suited to the close
packing of each hexon with its six identical neighbours.
This hollow base supports three towers projecting outward
from the surface of the capsid (Figure 1a). Extensive
intertwining of loops from each monomer in the tower
make the hexon a very stable structure.
The other four proteins of the capsid (IIIa, VI, IX and
VIII; Table 2) are believed to stabilize this structure. Such a
function is clearly established for protein IX, for particles
that lack this protein are more thermolabile than their
wild-type counterparts. On the outer surface of the capsid,
protein IX molecules lie along the entire length of the
interfaces among the hexons in the centre of each of the 20
faces of the icosahedral particle, as mortar between hexon
bricks (Figure 1b). Protein IIIa contacts hexons at the 30
edges of the icosahedron, where it extends from the exterior
to the interior of the capsid shell, like a protein rivet that
fastens the edges between the faces of the capsid. Protein
VI, like protein VIII, is entirely internal and located at the
vertices of the particle, where it anchors the ring of
peripentonal hexons. It is also likely to contact the inner
nucleoprotein core.
In addition to the DNA genome, the inner cavity
contains the basic core proteins, V, VII and m, two copies of
the terminal protein (TP; Figure 2), and the viral protease
(Table 2 and Figure 1b). Multimers (of unknown stoichio-
metry) of protein VII are tightly associated with the viral
DNA, while protein V occupies a more external location in
the core. The high arginine content and strong double-
stranded DNA binding activity of protein m suggest that it
plays an important role in condensing viral DNA for
packaging into virions. Although protein VII is the major
DNA packaging protein, very little is known about how it
binds to and organizes the viral genome. Indeed, no details
of the structure of the core are presently available, for the
viral nucleoprotein is not stable once released from virions,
and appears disordered in images of virions reconstructed
from cryoelectron micrographs.
Replication
Most studies of adenovirus replication have employed
human tumour cells in culture synchronously infected by
Ad2 or Ad5, with approximately 104 virions produced per
cell within 2 days. Such efficient virus reproduction is
achieved by redirection of the cellular systems responsible
for synthesis and translation of mRNAs. The viral genome
contains coding sequences for at least 40 proteins, but only
eight transcription units for cellular RNA polymerase II
(Figure 2). All but one (IX) of the viral transcription units is
polycistronic, encoding from several to nearly 20 proteins.

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 Adenoviruses

This organization minimizes the viral genetic information
devoted to transcriptional control signals, but requires
alternative processing of primary transcripts to produce
mRNAs for translation into the individual viral proteins.
During the infectious cycle, viral proteins are made in a
strict temporal sequence. By convention, early genes are
defined as those expressed before viral DNA synthesis
begins. The early phase is devoted to synthesis of viral
proteins needed for efficient expression of viral genes and
viral DNA synthesis, or that optimize the environment for
virus reproduction. By contrast, structural proteins are
made only once the genome has replicated, during the late
phase of infection.
Attachment, entry and uncoating
The binding of the virion fibres to the integral membrane
protein CAR mediates the initial attachment of most
human adenoviruses to susceptible cells. Detailed char-
acterization of fibre protein–CAR interactions has im-
plications for construction of peptide-based inhibitors of
adenovirus infection (Kirby et al., 2000). The concentra-
tion and location of this receptor on cell surfaces is one
parameter that influences the tissue tropism of these viruses
and their utility as recombinant vectors for therapy
(Shayakhmetov et al., 2000; Wickham, 2000). Initial
attachment via the fibre facilitates binding of penton bases
to av-integrins, interactions that induce clustering of
integrin-bound virions into coated pits and subsequent
internalization by receptor-mediated endocytosis. Some
80–85% of the adenovirus particles that initially bind to a
cell enter endosomes. Their escape from these organelles
into the cytoplasm via disruption of the endosomal
membrane is mediated by the penton base, by a mechanism
that has not been elucidated.
During entry, the virus particle is sequentially disas-
sembled, or uncoated. Within endosomes, the pentons and
proteins IIIa and VIII first dissociate. Once particles
lacking these proteins enter the cytoplasm, protein VI is
degraded by the virion protease, a cysteine protease whose
activity appears to be regulated by redox potential. The
remaining stabilizing protein, protein IX, then dissociates,
allowing release of the core nucleoprotein into the
cytoplasm for transport to the nucleus, the site of viral
gene expression, replication and assembly. Adenoviral
nucleoproteins traverse nuclear pore complexes, presum-
ably via the cellular nuclear protein import pathway.
Within the nucleus, the viral genome, which remains
associated with protein VII, localizes to a limited number
of specific sites, termed replication centres. These sites
correspond to preexisting nuclear niches that are used by a
number of other viruses with DNA genomes.
Early phase of infection
The first biosynthetic reaction in the infectious cycle is
synthesis of E1A pre-mRNA by RNA polymerase II under
the direction of E1A control sequences that allow efficient
transcription in a variety of cell types. Alternative splicing
produces mRNAs for two E1A proteins (Figure 3a).

13S Inactive
289R E2f + Rb Ad2 E2 early
Dp1
CR1 CR2 CR3 E2f site Cdk2
Cyclin E
12S Thymidine kinase
E1A Active
243R
CR1 CR2 E2f
Rb
p300
Rb E1A
(a) (b)

Figure 3 Structure and function of human adenovirus 2 (Ad2) E1A proteins. (a) Organization of E1A proteins. Alternative splicing of E1A pre-mRNA, in
which introns are indicated by the caret symbols, in the infected cell nucleus produces the abundant 13S and 12S E1A mRNAs. Because splicing
does not change the translational reading frame, the 289R and 243R E1A proteins translated from these mRNAs differ only in the internal sequence
of 46 amino acids unique to the 289R protein. This unique sequence contains most of one of the three highly conserved regions (CR1 to 3) identified by
comparison of E1A sequences of human adenoviruses. The regions of the E1A proteins necessary for binding to the cellular proteins Rb and p300 are
indicated. (b) Model for countermanding Rb protein-mediated regulation of transcription by E1A proteins. The E2f proteins are sequence-specific
transcriptional activators first identified by virtue of their binding to the adenoviral E2 early promoter. As indicated, these are heterodimeric proteins,
comprising one member of the E2f family, which contains six known members, and a Dp protein, such as Dp1. In actively growing mammalian cells, E2f
proteins are bound to hypophosphorylated Rb protein for most of the cell cycle, but free from mid-G1 through S phase, when Rb becomes heavily
phosphorylated. The Rb-E2f complexes retain DNA-binding activity and bind to E2f recognition sites in specific promoters. However, the Rb protein
actively represses transcription, as indicated by the red bar (top right). The adenoviral E1A proteins made in infected (or transformed) cells bind to the Rb
protein by means of a CR2 sequence and, via CR1 sequences, actively dismantle Rb-E2f complexes. Thus, the E1A protein-Rb interaction releases E2f
that can then stimulate transcription (green arrow, bottom right). This mechanism would make E2f available for transcription from the viral E2
promoter and from those of cellular genes normally expressed in the late G1 and S phases of the cell cycle. Such genes include those whose products
ensure progression through the cell cycle (e.g. cyclin-dependent kinase (Cdk) 2 and cyclins E and A), carry out replication of the cellular genome or produce
substrates for DNA synthesis, such as thymidine kinase and dihydrofolate reductase. Adenoviruses supply viral replication proteins, but depend on host cells
for the latter enzymes. The ability of E1A proteins to abrogate the negative regulatory function of the Rb protein is required for their transforming activity.
Adapted from Flint SJ et al. (2000) Principles of Virology: Molecular Biology, Pathogenesis and Control, ASM Press, Washington, DC, with permission.

6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net


Mutations that impair production of the larger (289R)
E1A protein prevent efficient transcription of all other viral
genes. Thus, E1A expression defines an immediate early
phase of infection. The 289R E1A protein is the prototype
for viral transcriptional activators that stimulate RNA
polymerase II transcription, but do not bind specifically to
DNA sequences in the template. It has therefore been
studied extensively in simplified experimental systems, in
which it stimulates transcription from an enormous variety
of viral, cellular and synthetic promoters. It can bind to
several of the general initiation proteins required for
specific transcription by RNA polymerase II and can
operate by means of many cellular transcriptional reg-
ulators that bind to specific promoter sequences. The 289R
E1A protein may therefore function as a coactivator of
broad specificity, facilitating interactions among cellular
transcriptional components and assembly of active RNA
polymerase II initiation complexes.
Both E1A proteins also regulate transcription by
binding to, and counteracting, the repression of transcrip-
tion of specific genes by the cellular retinoblastoma protein
(Rb protein), the product of a tumour suppressor gene
(Figure 3b). This activity of E1A proteins is presumed to
coordinate viral DNA synthesis with production of the
necessary substrates. The E2f transcriptional activators to
which Rb binds (Figure 3b) are required for efficient
transcription of both the viral E2 transcription unit, which
encodes the viral replication proteins (Figure 2), and the
cellular genes for enzymes that synthesize substrates for
DNA synthesis, upon which adenoviruses depend. Tran-
scription of these cellular genes normally begins shortly
before S phase, but in Ad2 infected cells would be induced
in parallel with viral E2 transcription once E1A proteins
were available to remove Rb from Rb-E2f complexes
(Figure 3b).
Transcripts of the early E1B, E3 and E4 transcription
units, like E2 pre-mRNAs, are processed by alternative
pathways to mRNAs specifying two or more proteins
(Figure 2). These early proteins facilitate efficient viral
replication in various ways (Table 3): some stimulate viral
gene expression later in the infectious cycle; some block
E1A protein-induced apoptosis (programmed cell death);
and yet others protect the infected cell against immune
defences mounted by the host organism (Table 3). The early
phase of infection is also marked by production of a viral
countermeasure to a host defence that operates intracellu-
larly. The small virus-associated (VA) RNA I, one of two
very abundant viral RNAs synthesized by cellular RNA
polymerase III (Figure 2), prevents inactivation of an
essential component of the translation initiation machin-
ery (eIF2) by a general antiviral defence mechanism
(Table 3). Thus, VA RNA I is necessary for efficient
synthesis of viral late proteins (Thimmappaya et al., 1982).
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Adenoviruses
Viral DNA synthesis
The adenoviral genome is replicated by continuous
synthesis of both new strands of the DNA from a protein
primer (Challberg et al., 1980) (Figure 4). A complex of the
viral DNA polymerase and preterminal protein (pTP)
binds specifically to the terminal origins of replication
(Figure 2) and the polymerase then catalyses covalent
linkage of deoxycytidine monophosphate (dCMP) to the
pTP to provide the 3’-OH primer universally required for
template-directed DNA synthesis (Figure 4). The parental
strand initially displaced is replicated in the same way
(Figure 4). The viral DNA-binding protein (DBP) (Table 3)
unwinds the double-stranded DNA template and acts as a
processivity factor, allowing the DNA polymerase to move
long distances along the template. Viral proteins carry out
all the synthetic reactions needed for replication of the
adenoviral genome, but cellular transcriptional activators
(Figure 4), topoisomerases and enzymes that make the
deoxyribonucleotide triphosphate substrates are also
required. The rate of accumulation of viral replication
proteins and the availability of these cellular proteins are
governed by the viral E1A proteins. Viral DNA synthesis
begins 6–8 h after infection and continues exponentially as
the products of one replication cycle serve as templates for
the next. The concentration of viral DNA molecules and
replication proteins at specific intranuclear sites must
facilitate efficient replication. Multiple factors may con-
tribute to the cessation of viral DNA synthesis by about
24 h after infection, including encapsidation of an increas-
ing fraction of newly synthesized DNA genomes as virion
proteins are made, exhaustion of the cellular substrate pool
and inhibition of synthesis of proteins needed for replica-
tion late in the infectious cycle.
Late phase of infection
Viral DNA replication leads to synthesis of the structural
proteins, most of which are encoded within the major late
(ML) transcription unit (Figure 2). During the early phase
of infection, ML transcription ceases near the middle of the
genome, rather than at the end of the transcription unit, the
pattern observed during the late phase. The mechanism
responsible for this unusual transcriptional change has not
been established. The rate of ML transcription by RNA
polymerase II increases between 20- and 30-fold in the late
phase of infection. Such stimulation requires two infected
cell-specific proteins that bind specifically to sequences
within the first ML intron. One is a dimer of the viral IVa2
gene product (Figure 2), while the other comprises the IVa2
protein and at least one other, not yet identified protein.
Thus, synthesis of the IVa2 protein in the infected cell is
essential for efficient ML transcription. However, this
viral, sequence-specific transcriptional activator is itself the
product of a late gene (Figure 2). Temporal regulation of
IVa2 transcription appears to be effected by titration of a
7
 Adenoviruses

Pol
5’
A
pTP Ser C OH A’
3’
3’ 5’
3’OH GpTpApGpT 5’
2 DBP
dNTPs
1 Pol
A
+ Nf1, Oct-1
TP pTP
A A’
5’ A’
5’ 5’
5’

Protease

A A’ A A’
5’ 5’
5’ 5’

5
3
Mutiple rounds
of replication
4 A
5’
5’
A’ A pTP- A’
Pol:
Nf1, Oct-1

Figure 4 Replication of adenoviral DNA. Assembly of a complex of the viral DNA polymerase (Po1) and pTP at the viral origins (step 1) at each end of the
genome, is facilitated by the cellular, sequence-specific transcriptional activators Nf1 and Oct-1, which bind to the origins and to the viral replication
proteins. Pol then catalyses covalent linkage of dCMP to a specific serine residue in pTP to provide the 3’-OH primer needed by all known DNA polymerases
(box, top left). This enzyme synthesizes viral DNA from this primer in the 5’!3’ direction (step 2), in a reaction that requires the viral DNA-binding protein
(DBP) (Table 3), which coats the displaced strand and unwinds the double-stranded template, and a cellular topoisomerase to relieve supercoiling of the
DNA ahead of the replication fork and torsional stress. As the genome carries an identical origin at each end, each parental strand can be replicated by this
continuous mechanism, with displacement of its complement. Such displaced strands carry the complementary, terminal sequences of the inverted
terminal repetition, designated A and A’. Their reannealing forms a short duplex stem identical to the terminus of the parental genome (step 3). Thus,
origins are reformed, allowing protein priming and continuous synthesis of the parental strands initially displaced (steps 4 and 5). From Flint SJ et al. (2000)
Principles of Virology: Molecular Biology, Pathogenesis and Control, ASM Press, Washington, DC, with permission.

cellular transcriptional repressor that binds to the IVa2
promoter with exponential viral DNA synthesis.
Induction of the late pattern of transcription leads to
dramatic alterations in the processing of ML pre-mRNAs,
some of the best understood of several examples of
temporal regulation of viral RNA processing. Utilization
of both the five poly(A)-addition sites and of certain splice
sites in ML pre-mRNAs is altered following entry into the
late phase of infection (Figure 5). All mRNAs processed
from ML pre-mRNAs carry a common, 5’-terminal
sequence formed by splicing of three small exons, the
tripartite leader sequence (TPL). As each ML transcript
contains but a single copy of these exons, only one mRNA
can be made, with the sequences for all the others discarded
during processing. The presence of the TPL must therefore
confer advantage(s) that outweigh the apparent ineffi-
ciency of this baroque mechanism of ML mRNA synthesis.
As viral late mRNAs accumulate, synthesis of cellular
proteins is gradually but inexorably inhibited (Beltz and
Flint, 1979). Two posttranscriptional mechanisms con-
tribute to such selective expression of viral genetic
information. A complex of the E1B-55 kDa and E4
ORF6 proteins (Table 3) induces selective export of viral
late mRNAs from the nucleus, by a mechanism that is not
well understood. Viral late mRNAs are also preferentially
translated. Hypophosphorylation of the cap-binding
component of the translation initiation protein eIF4F
induced by a viral late protein, or proteins, inhibits the
most common mechanism of initiation, scanning of
ribosomes from the 5’ cap of the mRNA to the initiation
codon. Translation of most cellular mRNAs is therefore
inhibited, but the TPL allows an alternative mechanism of
initiation, and thus the translation of ML mRNAs. The
viral L4 100-kDa protein, an RNA-binding protein, is

8 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

 Adenoviruses

Major late promoter

0 16.5 50 100 Map
units

Transcription
I1 I2 I3
Pre-mRNA 5’ C L1 L2 L3 L4 L5 3’

L1 L2 L3 L4 L5

Poly(A) addition at one of the L1 to L5 sites

C
C
C
C
C

Alternative splicing

C L1 An C L1 L2 L3 An
Two possible 3’ 4 possible 3’
splice sites splice sites

Tpl
C L1 An 52/55kDa C L3 An pIV
C L1 An IIIa C An Hexon
L1mRNAs C An Protease
C An
(a)
L3 mRNAs

L1 L2 L3
C Primary transcript
Cstf
3’ splice sites
C
SR

L1
C 52/55kDa mRNA

(b)

Figure 5 Alternative processing of major late (ML) pre-mRNA. The Ad2 genome is represented by the solid horizontal lines at the top of the figure, 0-100
map units, with the site of initiation of ML transcription by RNA polymerase II indicated by the jointed arrow drawn in the direction of transcription.
During the late phase of infection (a), ML transcription proceeds from this initiation site to close to the right-hand end of the genome. The large
(nearly 30 kb) primary transcript shown below the genome, with the 5’ cap designated (C), is processed into over 15 mRNAs by polyadenylation at one of
five possible sites, L1 to L5 (vertical arrows), used at approximately equal frequency. The polyadenylation sites define the L1 to L5 families of 3’ coterminal
mRNAs. The tripartite leader sequence present at the 5’ ends of all ML mRNAs is formed by splicing of three small exons, l1 to l3, and is then ligated to
alternative 3’ splice sites, as illustrated for the L1 and L3 mRNAs. During the early phase of infection (b), ML transcription terminates at multiple sites with a
large region around the middle of the transcription unit, so that no sequences beyond map unit 70 are transcribed. Even though these ML transcripts
contain the L1, L2 and L3 polyadenylation sites, the L1 site is preferentially utilized. As indicated, the splicing of L1 pre-mRNAs is also temporally regulated.
Only the 52/55-kDa mRNA is made during the early phase, but the 3’ splice site for the protein IIIa mRNA is also recognized during the late phase. Changes
in the activities of specific, cellular polyadenylation or splicing proteins induced by viral proteins appear to effect these alterations in ML pre-mRNA
processing. Adapted from Flint SJ et al. (2000) Principles of Virology: Molecular Biology, Pathogenesis and Control, ASM Press, Washington, DC, with
permission.

required for efficient initiation of translation of all viral late
mRNAs. It remains to be determined how the actions of
this protein, the TPL and VA RNA I are integrated to
ensure efficient synthesis of viral proteins in a translation-
ally compromised environment.
Assembly, maturation and release of virus
particles
Viral structural proteins enter the nucleus where hexons
and pentons assemble from their monomeric component
(Table 2) in reactions driven by the high concentrations of
the proteins. Formation of hexons trimers requires the L4

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 Adenoviruses

Table 3 Subgroup C adenovirus early products

Transcription unit Protein a or RNA Functions and properties
E1B 55kDa Promotes selective export of viral late mRNA from the nucleus
during the late phase as a complex with the E4 ORF6 protein;
binds to the cellular p53 protein to block apoptosis
19 kDa Blocks apoptosis
E2 DNA polymerase (Pol) Initiates viral DNA synthesis by catalysing covalent linkage of
dCMP to a serine residue in the pTP protein primer, when bound to
pTP at viral replication origins; completes continuous replication
of both strands of the genome
Preterminal protein (pTP) Protein primer for initiation of viral DNA synthesis; incorporated
into virions and processed to the TP by the virion L3 protease; TP
(and probably pTP) facilitate unwinding of the origin during
replication
Single-stranded DNA-binding Stimulates initiation of viral DNA synthesis and essential for
protein (DBP) elongation; binds single-stranded DNA cooperatively and with
high affinity probably as long protein chains, to promote
unwinding of the DNA template, stimulate activity of Pol up to
100-fold and induce highly processive DNA synthesis by the viral
enzyme; can stimulate transcription from viral early promoters;
required posttranscriptionally for efficient production of viral late
mRNAs in semipermissive simian cells
E3 gp19K Glycoprotein localized to membrane of the endoplasmic reticulum
(ER) where it binds MHC class I proteins and prevents their
transport to the cell surface; can therefore block cell killing by
cytotoxic T cells
RID (receptor internalization Heterodimeric integral membrane protein localized to plasma
and degradation) (10.4 K and membrane, Golgi and ER; induces endocytic internalization and
14.5K) degradation of cellular ‘death domain’ containing receptors that
signal apoptosis when activated, to block this response; can
stimulate internalization of receptor protein tyrosine kinases
ADP (adenovirus death Glycoprotein localized to the nuclear membrane, produced in large
protein) (11.6K) quantities late in infection; required for efficient release of progeny
virions from the nucleus and lysis of the infected cell
12.5K Not known
6.7K Not known
E4 ORF1 Not known
ORF2 Not known
ORF3 Increases stability of unprocessed major late pre-mRNA in the
nucleus; required for proper splicing of these pre-mRNAs; can
promote exon inclusion during splicing; required for maximally
efficient viral DNA synthesis, especially when the E4 ORF6
protein cannot be made; in the absence of both this and the ORF6
protein, abnormal concatameric viral DNA molecules are
produced; induces reorganization of nuclear structures containing
cellular transcription and replication proteins
ORF4 Binds to cellular protein phosphatase 2A (PP2A) to induce
hypophosphorylation of E1A proteins and specific cellular
proteins; negatively regulates E1A and E4 transcription in infected
cells via PP2A
continued

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Table 3 – continued
Transcription unit Protein a or RNA
E4 ORF6
ORF6/7
ML L1 52/55 kDa
VA RNA I VA RNA I
ML, major late; VA, virus-associated.
a
Viral early proteins are listed by the unsystematic names in common use. These names are derived from the protein’s properties or functions
(E2, E3), apparent molecular mass based on electrophoresis in SDS-polyacrylamide gels (E1B, E3, L1) or the position of coding sequences
within the transcription unit (E4).
Refer to Figure 5 for explanation of L1 early products.
100-kDa protein. Virus particles then assemble by either a
sequential or a concerted mechanism (Figure 6). The viral
L1 52/55-kDa, the L4 33-kDa and the IVa2 proteins assist
the complex process of assembly in ways not yet well
understood. The encapsidation of viral DNA is directed by
packaging signals located near the left end of the genome
(Figure 6). The initially assembled immature particles
contain precursors to six virion proteins and are not
infectious. Their maturation to infectious particles requires
the L3 protease, which is incorporated into assembling
particles and cleaves these precursors at specific sites after
assembly.
Adenovirus infection inhibits production of cellular
macromolecules as cellular systems and resources are
redirected for viral replication. Consequently, the infected
cell eventually dies, with release of progeny virions. Specific
viral proteins may actively promote such cell destruction or
lysis. The E3 adenovirus death protein (ADP) can disrupt
the nuclear membrane (Table 3) and the viral protease
cleaves certain proteins of the cytoskeleton. The inability
of the infected cell to maintain its architectural integrity
once cellular protein synthesis has been inhibited may
account for the dependence of release of virions on such
inhibition.
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Adenoviruses
Functions and properties
Like the ORF3 protein, increases nuclear stability of major late
pre-mRNAs and is required for qualitatively and quantitatively
normal viral DNA synthesis; can promote exon exclusion during
pre-mRNA splicing; in complex with the E1B 55-kDa protein,
promotes selective export of viral late mRNAs from the nucleus
during the late phase of infection; contains a nuclear export signal
and can shuttle between the nucleus and the cytoplasm; binds to
the cellular p53 protein and stimulates its degradation
Can stimulate cooperative binding of cellular E2f transcriptional
activators to a pair of inverted binding sites in the early E2
promoter
Required for assembly of virions, encapsidation of the DNA
genome
RNA of 166 bp synthesized by RNA polymerase III that
accumulates to ~108 copies per cell; binds to the cellular
double-stranded RNA-dependent protein kinase (PKR); prevents
activation of PKR and hence phosphorylation and inactivation of
eIF2, which is essential for initiation of translation
Epidemiology
Because adenovirus infections in humans are not easily
identified by purely clinical criteria, the epidemiology of
these viruses has been studied using serological or
molecular methods of virus detection. Our current under-
standing is based on studies in various selected populations
and worldwide data on isolation of adenoviruses, collected
by the World Health Organization.
Adenoviruses are ubiquitous pathogens that infect
humans of all ages and races, with few gender-specific
differences. They are transmitted by direct contact, the
faecal–oral route and, in some cases, in water. Members of
subgroup C, and probably subgroup F, are endemic in all
populations examined, with 80–100% of children infected
within the first 3 years of life. By contrast, other human
adenoviruses are associated with epidemics, for example,
of acute respiratory disease (ARD) among military recruits
(Table 1). Parameters that influence transmission and
incidence of infection include population density, crowd-
ing and stress, socioeconomic status and the time of year.
Individuals with impaired cell-mediated immunity, such as
transplant patients receiving immunosuppressive drugs,
are at higher risk for severe adenovirus infection.
11
 Adenoviruses

Cytoplasm Nucleus L1 52/55-kDa protein

Empty
capsid Assembly
intermediate
L4
100-kDa
protein

Protein II

Hexon trimer

Other virion proteins Newly synthesized pIIIa

pTP
viral DNA pVI
pVII
Young pVIII
virion pµ
B

L3 protease

Protein
III
Protein IIIa
IV TP
Penton VI
VII
Virion VIII
µ

Figure 6 Assembly of adenovirus particles. Virion proteins (Table 2) are synthesized in large quantities in the cytoplasm of infected cells and imported into
the nucleus. The major structural units of the virion, hexons and pentons, then assemble from their monomeric components. Pentons are formed by self-
assembly, but hexons can be assembled only with the assistance of the viral L4 100-kDa protein, which binds to hexon monomers. Two possible pathways
for capsid assembly are depicted. In the sequential assembly pathway (A), hexons, pentons and capsid-stabilizing proteins self-assemble into empty
capsids, which contain the L1 52/55-kDa proteins. These L1 proteins may form a scaffold for capsid assembly, and are required for encapsidation of the
genome. In this mechanism, newly-synthesized viral DNA is inserted into preformed empty capsids upon recognition of a packaging sequence that lies at
the left end of the genome. Core proteins enter the capsid with viral DNA to form noninfectious, immature particles (young virions). Cleavage of the
precursors to the six virion proteins listed at the right by the L3 protease, produces infectious virions. The failure of an Ad5 mutant with a deletion within the
packaging sequence to direct assembly of any capsid-like structures indicates that assembly of the capsid and encapsidation of the genome may be
concerted reactions (pathway B). The incomplete particles shown in pathway A would then represent ‘dead-end’ products that cannot complete assembly,
or artefacts of the methods of extraction of particles from infected cells. Adapted from Flint SJ et al. (2000) Principles of Virology: Molecular Biology,
Pathogenesis and Control, ASM Press, Washington, DC, with permission.

Clinical Features children, especially those who are malnourished or

Adenoviruses rarely cause fatal disease, and as many as
30–50% of infections may be asymptomatic. Nevertheless,
these viruses are important causes of respiratory disease,
conjunctivitis and gastroenteritis (Table 1). The subgroup C
serotypes commonly cause acute upper respiratory disease
in young children, and they and subgroup B members
account for 2–7% of lower respiratory illness in this
population, with such symptoms as bronchitis, pharyngitis
and pneumonia. The latter syndrome, which may be fatal,
is most usually associated with Ad7 infection of very young
suffering from measles. Statistics on death resulting from
viral disease identify Ad7 as the most pathogenic of the
human adenoviruses.
The first syndrome to be associated with adenoviruses
was ARD in military recruits. Ad4 (subgroup E), and less
frequently Ad7 and other members of subgroup B, are the
primary causes, with rates of morbidity as high as 6–17 per
100 per week among recruits in North America and
Europe. Other well-characterized epidemic diseases caused
by specific adenoviruses are pharyngoconjunctival fever
(PCF) and epidemic keratoconjunctivitis (EKC) (Table 1),

12 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net


in which the virus is spread by contact with contaminated
water, such as in contaminated ponds and inadequately
chlorinated swimming pools, or with contaminated
instruments (or hands) in medical and ophthamological
facilities, respectively. The former disease is associated
with both respiratory tract illness and conjunctivitis. In
contrast, EKC is characterized by conjunctivitis, followed
by corneal infiltration, which may impair vision for several
months.
Several adenoviruses can cause diarrhoea (Table 1). The
subgroup F viruses are important causes, second only to
rotaviruses, of acute gastroenteritis in young children
throughout the world. Infected children usually exhibit
clinically moderate disease with diarrhoea, vomiting and
dehydration, but the diarrhoea may last for 1–2 weeks and
fatal infections by Ad40 or Ad41 have been recorded.
Much less commonly, adenovirus infection leads to
severe complications, such as encephalomeningitis, intus-
susception (the prolapse of one section of the intestine into
the neighbouring portion; predominantly with Ad13 and
Ad5) in infants, and fatal neonatal infections with systemic
symptoms and pneumonia.
Viral Oncogenesis
Human adenovirus 12 (Ad12) and Human adenovirus 18
(Ad18) were the first human viruses shown to be oncogenic
(Trentin et al., 1962). There is no evidence that any
adenovirus contributes to tumour development in humans,
but the molecular mechanisms by which viral proteins alter
the function of host cell tumour suppressor proteins are
similar to those of human papillomaviruses causally
associated with cervical cancer in women. The striking
differences in the oncogenicity of subgroup A and C
adenoviruses (Table 1) has allowed investigation of
mechanisms that determine cell growth and proliferation
in vivo. Furthermore, most human adenoviruses transform
rodent cells in culture.
Mechanisms of transformation
The products of the adenoviral E1A and E1B transcription
units transform rodent cells. For example, these viral DNA
sequences can induce full transformation when introduced
into cells in the absence of additional viral genetic
information. In such DNA-mediated transformation
assays, E1A DNA is necessary, and in some cases,
sufficient. Complete transformation generally requires
the adenoviral E1B transcription unit; however, E1B
sequences alone exhibit no transformation activity what-
soever.
Our current understanding of the mechanism of E1A
protein-dependent transformation is based on identifica-
tion of cellular proteins that bind to E1A regions required
ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Adenoviruses
for this activity (Whyte et al., 1988) (Figure 3b). The E1A
protein-induced release of E2f transcriptional activators
from association with Rb (or related) protein is believed to
be primarily responsible for the mitogenic activity of these
viral proteins, and the uncontrolled proliferation of E1A-
transformed cells. Unscheduled DNA synthesis induced in
this way activates control mechanisms that inhibit cell
cycle progression or activate apoptosis via the product of
the cellular p53 gene, which is the most frequently mutated
gene in human tumours. When potentially genotoxic
damage is detected, the normally low concentration of
p53 increases substantially and, by stimulation of tran-
scription of specific genes, p53 induces arrest of the cell
cycle in G1 or apoptosis. The E1A proteins induce
accumulation of the p53 protein by at least two mechan-
isms, and apoptosis. However, both proteins encoded
within the viral E1B transcription unit can block this
response. Thus, the E1B proteins are necessary for
complete transformation because they prevent cells
synthesizing E1A proteins from committing suicide.
This model accounts for the activities exhibited by the
viral E1A and E1B transcription units in transformation
assays, and is based on a large body of biochemical,
molecular and genetic data. Nevertheless, other mechan-
isms may contribute to adenovirus transformation: E1A
sequences encoded within the second exon (Figure 3a) are
required for immortalization of primary cells in culture,
and E1A proteins can bind to other cellular proteins that
negatively regulate cell cycle progression.
Differential oncogenicity of human
adenoviruses for rodents
Adenoviruses that are highly oncogenic or nononcogenic
in rodents (Table 1) do not differ markedly in the
frequencies with which they transform cultured rodent
cells, nor can cells transformed by them be distinguished by
their in vitro properties. However, rat cells transformed by
the subgroup A Ad12 induce tumours in newborn, and
sometimes adult, syngeneic rats, whereas those trans-
formed by the subgroup C Ad2 or Ad5 do not, and are
tumorigenic only in experimentally immunosuppressed
rats or immunodeficient nude mice. Such observations
indicate that the host’s immune response mediated by
cytotoxic T cells (CTLs) eliminates subgroup C adeno-
virus-transformed cells much more effectively than those
transformed by subgroup A members. Indeed, Ad5 and
Ad12 transformants derived from the same parental rat
cells are susceptible and resistant, respectively, to lysis by
appropriate CTLs in vitro. This difference is determined by
the viral E1A proteins. Ad12 E1A proteins may confer
resistance to killing by CTLs by reducing cell surface
concentrations of major histocompatibility complex
(MHC) class I proteins, which present proteasome-
processed viral antigens (peptides) on the exterior of the
13
 Adenoviruses
cell for recognition and subsequent cell killing by CTLs.
The Ad12, but not Ad5, E1A proteins repress transcription
of MHC class I genes. The nature of the E1A protein
epitopes presented to the immune system may also
influence CTL recognition.
Other components of the immune system have been
implicated in the rejection of cells transformed by
subgroup C adenoviruses. The degree of resistance of
adenovirus-transformed cells to natural killer (NK) cells,
important components of the innate, ‘nonspecific’ immune
response, also correlates with tumorigenicity. This differ-
ential response is also conferred by viral E1A proteins.
Specific segments of subgroup C Ad E1A proteins render
transformed cells susceptible to apoptosis induced by NK
cells. Although the mechanism is not fully understood,
binding of the E1A proteins to p300/Cbp (Figure 3a)
appears to be important. A segment of the Ad12 E1A
proteins that is absent from E1A sequences of members of
subgroup C, and which does not modulate resistance of
Ad12-transformed cells to either CTLs or NK cells, has
also been identified as an important determinant of
tumorigenicity. Finally, although the tumorigenicity of
transformed cells in immunocompetent syngeneic rats is
determined primarily by the viral origin of the E1A
transcription unit, cells that synthesize Ad12 E1B proteins
are significantly more tumorigenic than matched cells
making Ad5 E1B proteins. The complexities of the
interactions among host defence systems and adenovirus-
transformed cells therefore remain far from completely
understood.
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