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VIRUS REPLICATION STRATEGIES
Dr. Sobia Manzoor
MV, Lecture 06
Introduction
• Replication of genetic information is the single
most distinctive characteristic of living organisms,
which is accomplished with great economy and
simplicity among viruses.
• To achieve the expression, replication, and spread
of their genes, different families of viruses have
evolved diverse genetic strategies and life cycles
that exploit the biology and biochemistry of their
hosts in a variety of ways.
• Each infection represents an encounter
between the genetic program of a virus and
that of its host, defining host-viral
relationships.
• This also create opportunities for the rational
development of antiviral drugs and for
domesticating viruses as expression vectors,
live attenuated vaccines, and pesticides.
Diversity of Viral Genome Structures
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Different families of viruses have different genomes:
Double-stranded (ds) / single-stranded (ss) viruses
DNA / RNA viruses
positive, negative, or mixed (ambisense) polarity
linear or circular topology
single or multiple segments
The coding strategies of arenaviruses (family Arenaviridae)
and members of the Phlebovirus genus of the Bunyaviridae
differ from those of other negative-sense RNA viruses in
that some proteins are coded in viral-complementary RNA
sequences and others are coded in the viral RNA sequence.
The term ambisense RNA has been proposed to denote
these unique coding arrangements.
• Each variation has consequences for the
pathways of genome replication, viral gene
expression, and virion assembly.
• Viral taxonomy above the family level is
variable, with only 10 of 71 virus families
being assigned to the three orders that are
currently recognized.
Families and Genera of Viruses that Infect
Vertebrates
Genome
Virus Family
Adenoviridae
Polaritya
dsDNA
Both
Topologyb
Linear
Anellovirus genus
ssDNA
Negative
Asfarviridae
dsDNA
Circoviridae
Type
Genome Replication
Segments
1
Enzyme
Viral DdDp
Intracellular Site
Nucleus
Circular
1
Cellular DdDp
Nucleus
Both
Linear
1
Viral DdDp
Cytoplasm
ssDNA
Negative/
ambisense
Circular
1
Cellular DdDp
Nucleus
Hepadnaviridae
dsDNA
Both
Linear
1
Virion RTase
Nucleus/cytoplasm
Herpesviridae
dsDNA
Both
Linear
1
Viral DdDp
Nucleus
Iridoviridae
dsDNA
Both
Linear
1
Viral DdDp
Nucleus/cytoplasm
Papillomaviridae
dsDNA
Both
Circular
1
Cellular DdDp
Nucleus
Parvoviridae
ssDNA
Either
Linear
1
Cellular DdDp
Nucleus
Polyomaviridae
dsDNA
Both
Circular
1
Cellular DdDp
Nucleus
dsDNA
Both
Linear
1
Viral DdDp
Cytoplasm
Arenaviridae
ssRNA
Ambisense
Linear
2
Virion RdRp
Cytoplasm
Arteriviridae
ssRNA
Positive
Linear
1
Viral RdRp
Cytoplasm
Astroviridae
ssRNA
Positive
Linear
1
Viral RdRp
Cytoplasm
Birnaviridae
dsRNA
Both
Linear
2
Virion RdRp
Cytoplasm
Bornaviridae
ssRNA
Negative or
ambisense
Linear
1
Virion RdRp
Nucleus
Bunyaviridae
ssRNA
Negative
Linear
3
Virion RdRp
Cytoplasm
Caliciviridae
ssRNA
Positive
Linear
1
Viral RdRp
Cytoplasm
Coronaviridae
ssRNA
Positive
Linear
1
Viral RdRp
Cytoplasm
Deltavirus genus
ssRNA
Negative
Circular
1
RNA pol II
Nucleus
Filoviridae
ssRNA
Negative
Linear
1
Virion RdRp
Cytoplasm
Flaviviridae
ssRNA
Positive
Linear
1
Viral RdRp
Cytoplasm
Hepevirus genus
ssRNA
Positive
Linear
1
Viral RdRp
Cytoplasm
Nodaviridae
ssRNA
Positive
Linear
2
Viral RdRp
Cytoplasm
Orthomyxoviridae
ssRNA
Negative
Linear
6-8
Virion RdRp
Nucleus
Paramyxoviridae
ssRNA
Negative
Linear
1
Virion RdRp
Cytoplasm
Picornaviridae
ssRNA
Positive
Linear
1
Viral RdRp
Cytoplasm
Reoviridae
dsRNA
Both
Linear
10-12
Virion RdRp
Cytoplasm
Retroviridae
ssRNA
Positive
Linear
2 identical
Virion RTase
Nucleus/cytoplasm
Rhabdoviridae
ssRNA
Negative
Linear
1
Virion RdRp
Cytoplasm
Togaviridae
ssRNA
Positive
Linear
1
Viral RdRp
Cytoplasm
Viral Pathways and Enzymes
• As intracellular parasites, all viruses depend
heavily on functions provided by their host
cells.
• Nevertheless, almost all viruses encode and
express unique proteins including enzymes,
and many viruses exploit pathways of
information transfer.
• This is particularly evident among the RNA
viruses.
Variation In Replication Strategies
Whatever the structure and replication strategy
of their genomes, all viruses must express their
genes as functional mRNAs early in infection in
order to direct the cell's translational machinery
to make viral proteins.
mRNA
Complement
positive sense
negative sense
RNA Viruses
These viruses replicate their genomes via one of two unique
biochemical pathways:
• RNA-dependent RNA synthesis (RNA replication),
• RNA-dependent DNA synthesis (reverse transcription)
followed by DNA replication and transcription.
Both pathways require enzyme activities that are not usually
found in uninfected host cells and must therefore be
encoded in the viral genome and expressed during infection.
In some families of RNA viruses, the corresponding
polymerase and other associated enzymes with the viral
genome are co-packaged during the viral assembly.
DNA viruses
• Most DNA viruses undergo transcription,
replication and assembly in the nucleus, the
site of cellular DNA transcription and
replication.
• The exceptions are the poxviruses,
iridoviruses, and African swine fever virus,
which replicate their DNA genomes partly or
completely in the cytoplasm
• In contrast, most RNA viruses replicate in the
cytoplasm.
• Retroviruses integrate DNA copies of their
genomes into cellular chromosomes.
• Other notable exceptions are the orthomyxoand bornaviruses, whose linear negative-sense
RNA genomes replicate in the nucleus.
• The circular RNA genome of hepatitis delta
virus also replicates in the nucleus.
• Pathways of primary mRNA synthesis by DNA viruses
of animals
• ds DNA
ss DNA
Cellular DNA Polymerase
Cellular RNA Pol II
mRNA +
Pathways of primary mRNA synthesis by DNA
viruses of animals. *Hepadnaviruses replicate
via reverse transcription of an ssRNA
intermediate
ds DNA
Cellular RNA Pol II
Evasion of Host Cell Defense
• Many viruses express gene products that act to
circumvent one or more of the several different
antiviral defense mechanisms developed by host
organisms .
• Host defense mechanisms can be innate or
adaptive.
• Innate mechanisms involve apoptosis, interferon
production and RNA interference .
• Adaptive mechanisms of immunity include the
celland
antibody-mediated
immune
responses
• In different viruses, different mechanisms
inhibit
apoptosis,
intercept/suppress
interferon, obstruct RNA interference, and
either evade or suppress different arms of the
adaptive immune response.
• Pathways of primary mRNA synthesis by RNA
viruses of animals
• Pathways of primary mRNA synthesis by RNA
viruses of animals. How RNA viruses produce
mRNA at the start of infection depends on the
nature of the viral genome. ds, double
stranded; ss, single stranded.
RNA Replication Is Error Prone
• The polymerases that catalyze RNA replication
and reverse transcription have minimal
proofreading activities.
• Error rates are about 10,000 times higher than
those encountered during DNA replication.
• RNA viruses can evolve up to 1 million times
faster than DNA-based organisms
Quasispecies
• A quasispecie provides a fertile source of
phenotypic variants that can respond rapidly
to changing selection pressures by shifting its
composition.
Levels of Segmentation
Genes, mRNA and Proteins
Viral RdRps generally appear somewhat
restricted in their ability to access internal
promoter sites on RNA templates, within the
host cells.
Through evolution, different RNA virus families
have found three solutions:
• Proteolytic processing of poly protein
precursors to derive final protein products.
e.g. the picorna-, toga-, flavi-, and retrovirus
families
• In some other systems, different cis-acting RNA signals
are largely responsible for determining the relative
template activities of the complementary strands.
However, different host factors are involved here as
well.
• Unlike the enzymes that replicate DNA that usually
require primers, most RdRps can initiate RNA synthesis
de novo.
• However, there are exceptions: Picornavirus RdRps use
a small viral protein (Vpg) that is first covalently
uridylated, and then used as a primer for viral RNA
synthesis.
• In another mechanism of priming, the enzymes
encoded by orthomyxo- and bunyaviruses cleave short
capped oligonucleotides from host mRNAs and use
them to prime transcription.