Atlas de Genética

Atlas de Genética


DisciplinaGenética I16.539 materiais498.002 seguidores
Pré-visualização50 páginas
99DNA Viruses
Passarge, Color Atlas of Genetics © 2001 Thieme
All rights reserved. Usage subject to terms and conditions of license.
100
Retroviruses
Retroviruses are RNA viruses with a devel-
opmental cycle in which double-stranded DNA
is transcribed from the viral RNA genome and
integrated into the genome of the host. Specific
sequences of their genomes enable integrated
proviruses to become integrated into new sites.
When this happens, neighboring cellular
sequences are occasionally transported along to
a new region of the host genome or to the
genome of another cell (retrotransposon). Im-
portant retroviruses are the AIDS virus (HIV I)
and certain tumor viruses (see p. 314).
A. Retrovirus replication
After attaching to a cell surface receptor, the vir-
ion is taken into the cell. Immediately after
entry into the cell, the viral RNA genome is tran-
scribed into double-stranded DNA by an
enzyme complex called reverse transcriptase,
and the newDNA is integrated as a provirus into
the DNA of the host cell. The RNAs transcribed
from this DNA copy by cellular RNA polymerase
II serve either asmRNA for the synthesis of virus
proteins or as new virus genomes. Newly
formed virions leave the cell by a specific
process called exocytosis, without killing the
cell.
B. Genomes of the retroviruses
Several retroviruses cause tumors in mice
(mouse leukemia) or chickens (Rous sarcoma).
The only retrovirus identified to cause a tumor
in humans is HTLV (type 1 and 2) (human T cell
leukemia/lymphoma virus). HTLV viruses have
genetic similarities with the AIDS virus, which
causes acquired immune deficiency syndrome
(p. 314).
The RNA genome of a typical retrovirus contains
short repetitive (R) and unique (U) sequences at
both ends (RU5at the 5! end and U3R at the 3!
end). As a rule, three protein-coding genes lie
between them: gag (group-specific antigen),
pol (reverse transcriptase), and env (a gene that
codes for a glycoprotein that is built into the
lipidmembrane coat of the virion). The 5! end of
the genome contains a nucleotide sequence
that is complementary to the 3! end of a host
cell tRNA. This nucleotide sequence binds to
tRNA,which serves as a primer for the synthesis
by reverse transcriptase of viral DNA from the
virus genome RNA. At the 3! end of the genome,
HTLV viruses carry several other genes (px, lor,
tat, and others) that are involved in regulating
the transcription of the viral genes. The AIDS
virus (HIV I/II) contains further genes that do
not occur in other retroviruses. These include
vif (virion infectivity factor, formerly designated
sor), rev (regulator of expression of virion pro-
teins), and nef (negative factor, formerly orf).
The general structure of the genome is more
complex than shown here.
C. DNA synthesis of a retrovirus
Reverse transcriptase transcribes the RNA
genome into DNA by RNA-dependent DNA
polymerase activity and catalyzes subsequent
steps by means of DNA-dependent DNA poly-
merase activity. Furthermore, the reverse tran-
scriptase has RNAase activity for degrading the
RNA of the newly formed RNA/DNA hybrid
molecule. The first step in replicating the retro-
virus genome is initiated by a primer of host cell
tRNA, which is hybridized to the 5! end of the
RNAgenome (1). After synthesis of the first DNA
strand and removal of the tRNA primer, synthe-
sis of the second DNA strand (plus strand)
begins at the RU5 region (2). Here, the pre-
viously formed minus DNA strand serves as the
primer (3). As DNA synthesis is continued, the
remaining RNA is degraded (4), and the DNA
plus strand is synthesized to completion (5, 6).
The double-strandedDNA copy of the virus con-
tains long terminal repeats (LTR) at both ends.
These enable the viral DNA intermediary step to
be integrated into the host cell DNA, and they
contain the necessary regulatory sequences for
transcribing the provirus DNA (see p. 102).
(Figures adapted fromWatson et al., 1987).
Reference
Watson, J.D. et al.: Molecular Biology of the
Gene, 3rd ed. Benjamin/Cummings Publish-
ing Co., Menlo Park, California, 1987.
Fundamentals
Passarge, Color Atlas of Genetics © 2001 Thieme
All rights reserved. Usage subject to terms and conditions of license.
101Retroviruses
Passarge, Color Atlas of Genetics © 2001 Thieme
All rights reserved. Usage subject to terms and conditions of license.
102
Retrovirus Integration and
Transcription
Integration of the DNA copy of a retrovirus into
the host cell DNA occurs at a random location.
This may alter cellular genes (insertion muta-
tion). The viral genes of provirus DNA are tran-
scribed by cellular RNA polymerase II. The re-
sultingmRNA serves either for translation or for
the production of new RNA genomes, which are
packaged into the virion. Some retrovirus
genomes may contain an additional viral onco-
gene (v-onc). Viral oncogenes are parts of cellu-
lar genes (c-onc) previously taken up by the
virus. If they enter a cell with the virus, they
may change (transform) the host cell so that its
cell cycle is altered and the cell becomes the
origin of a tumor (tumor virus) (see p. 320).
A. Retrovirus integration into
cellular DNA
In the nucleus of the host cell, the double-
stranded DNA (1, virus DNA) produced from
virus genome RNA first forms a ring-shaped
structure (2) by joining LTRs (long terminal re-
peats). This is possible because the LTRs contain
complementary nucleotide sequences. Recog-
nition sequences in the LTRs and in the cellular
DNA (3) allow the circular viral DNA to be
opened at a specific site (4) and the viral DNA to
be integrated into the host DNA (5). Viral genes
can then be transcribed from the integrated
provirus (6). As a rule, the provirus remains in
the genome of the host cell without disrupting
the functions of the cell. One exception is the
AIDS virus, which destroys a specific population
of lymphocytes (helper T cells) (see p. 310). The
genomes of vertebrates (including man) con-
tain numerous DNA sequences that consist of
endogenous proviruses. In mice, they may rep-
resent up to 0.5% of the total DNA. The genomes
of higher organisms also contain LTR-like
sequences that are very similar to those of an
endogenous retrovirus. These sequences can
change their location in the genome (mobile
genetic elements or transposons). Since many
of them have the fundamental structure of a
retrovirus (LTR genes), they are designated ret-
rotransposons (see pp. 76 and 252).
B. Control of retrovirus transcription
The LTRs are important not only for integration
of the virus into cellular DNA, but also because
they contain all regulatory signals necessary for
efficient transcription of a viral gene. Typical
transcription signals are the so-called \u201cCCAAT\u201d
and \u201cTATA\u201d sequences of promoters, which are
respectively located about 80 and 25 base pairs
above the 5! end of the sequence to be tran-
scribed. Further upstream (in the 5! direction)
are nucleotide sequences that can increase the
expression of viral genes (enhancer). Similar
regulatory sequences are located at the 5! ends
of eukaryotic genes (see section on gene tran-
scription). Newly synthesized viral RNA is
structurally modified at the 5! end (formation
of a cap). Furthermore, numerous adenine resi-
dues are added at the 3! end (polyadenylated,
poly(A), see p. 214).
C. Virus protein synthesis by
posttranscriptional modification of
RNA
The RNA transcripts synthesized from the pro-
virus by cellular RNA polymerase II serve either
for the translation into virus-coded proteins
(gag, pol) or as the genome for the formation of
new virions. Some of the RNA is spliced to form
new mRNAs that code for coat proteins (env).
(Figures after Watson et al., 1987).
Reference
Watson, J.D. et al.: Molecular Biology of the
Gene, 3rd ed. Benjamin/Cummings Publish-
ing Co., Menlo Park, California, 1987.
Fundamentals