Springer, Encyclopedic Reference Of Cancer (2001) Ocr 7.0 Lotb.pdf

20 Adenovirus
mately 36 kilobases (kb) size. There are seven
capsid proteins, among them hexon, penton
base and fiber, which are the major constituents
of the adenoviral capsid. Internalisation of the
viral particle during infection requires the interaction
of the fiber and the penton base with surface
proteins of the cell. At least five virally-encoded
proteins are associated with the viral
DNA. Adenoviruses have been identified in
many species and more than 50 different serotypes
have been isolated from humans alone.
The individual serotypes are distinguished by
different parameters such as immunological
properties, tumorigenicity and DNA sequence.
Some serotypes may cause more serious infectious
diseases such as epidemic keratoconjunctivitis,
gastroenteritis or hemorrhagic cystitis.
Adenovirus is being used as a gene carrier
for ! gene therapy. Most adenoviral vectors
(see below) are derived from the serotypes 2
and 5 (Ad2, Ad5) which are frequent causes
for mild colds. During childhood most individuals
will become immunized against different
adenoviral serotypes by natural infection. Ad2
and Ad5 are not oncogenic in humans and have
a good safety record based on vaccination studies
that have been performed in military recruits
two to three decades ago. As detailed
below, during natural infection of permissive
cells the adenoviral DNA is transcribed, replicated
and packaged into capsids within the nuclei
of infected cells. Similar to other DNA
viruses, two main phases can be distinguished
during infection:
* an early phase that is characterized by the
expression of the ! early virus genes E1, E2,
E3 and E4 and
* a late phase after onset of viral replication in
which the viral structural proteins are produced.
Characteristics
Infection and viral transcription
A productive infectious cycle takes approximately
two to three days and under optimal
conditions about 1,000 to 10,000 infectious particles
are produced in every infected cell. The
infection begins with the attachment of the
virus particle to the cell surface via interaction
of the tip of the capsid fiber protein with the
membrane protein CAR (Coxsackie-Adenovirus
receptor). As it is apparent from the
name, CAR is also used by some coxsackie
viruses for adhesion to the cell surface and
has been recently identified as a transmembrane
protein of unknown function. The adenoviral
particle is internalized by receptormediated
endocytosis into clathrin-coated
pits requiring a secondary interaction of the
penton base with an av-integrin. Following endocytosis
the viral particle is sequentially disassembled,
initally losing the fiber proteins, later
most of the other viral structural proteins. Finally,
the viral DNA is released as a DNA-protein
complex through nuclear pores into the
nucleus of the host cell. Shortly thereafter, transcriptional
activation of the early genes E1A
and E1B initiates a complex transcriptional
program designed to first replicate the viral
DNA and later to generate new infectious viral
particles. The activation of early and late transcription
units follows a relatively well understood
transcriptional pattern. The gene products
of the E1A and E1B genes are involved
in the activation of both viral and cellular
genes. Under certain conditions, in particular
if infection of a cell does not result in a productive
but rather abortive infection (abortive infection
= the infectious cycle is blocked at an
early stage following infection of the host
cell), cellular transformation may be a consequence.
The E2A and E2B gene products are involved
in the replication of the viral genome
and include the viral DNA polymerase (Ad-
Pol), the terminal protein (TP) and the DNAbinding
protein (DBP). The E3 and E4 gene
products have diverse functions leading to
transcriptional activation of other promoters,
preferential export of viral RNAs out of the nucleus
of infected cells and suppression of host
defences. With the replication of the viral genome
approximately six hours after infection,
late phase transcription units are activated.
Most of the late phase porteins are capsid proteins
or proteins that are involved in the organisation
and packaging of the viral genome inside
the viral capsid. The most active promoter