danielle blondel – laboratoire de virologie moléculaire et structurale umr cnrs 2472-inra 1157...
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Danielle Blondel – Laboratoire de Virologie Moléculaire et Structurale UMR CNRS 2472-INRA 1157CNRS- Gif sur Yvette
RNA viruses
I.Introduction to viruses 1. Definition 2. Diversity : nature and structure 3. Classification
II. Animal RNA viruses replication strategies 1. Plus-stranded RNA viruses (Ex : Poliovirus) 2. Negative-stranded RNA viruses 2a) Non –segmented (Ex : Rabies virus) 2b) Segmented (Ex : Influenza virus) 3. Double-stranded RNA viruses (Ex : Rotavirus) 4. Retroviruses 5. Variability of viral genomes
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What are viruses?
The viruses responsible of diseasesIn humans and animals
Viral diseases are known since several thousands of years
• 3700 BC : The first written record of a virus infection is from ancient Egypt which shows a temple priest with typical signs of paralytic poliomyelitis.
• 2500 BC : chineses recognized the nature and the specific characters of small pox
• 460 BC : Mumps was described by Hippocrate
• 50 BC : Rabies was described by Virgile and Homère
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1796 : Jenner and the vaccination against smallpoxEdward Jenner used cowpox to successfully vaccinate a child.Vaccination against smallpox was almost universally adopted worldwide during the nineteenth century.
1885 : Pasteur and rabies vaccination 1881: Louis Pasteur began to study rabies in animals. Over several years, he developed methods to produce attenuated virus preparations which would protect from challenge with virulent virus.1885, he inoculated a child, with the first artificially produced virus vaccine.
The first success
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In plants• Tobacco mosaic virus (VMT) (Ivanowsky 1892/
beijerink 1898)• Tomato mosaic virus
In bacteria• Bacteriophages (1917, 1947, 1952)
Viruses responsible of diseases
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Before the definition of virus
1. The agent must be present in every case of the
disease.
2. The agent must be isolated from the host and
grown in vitro.
3. The disease must be reproduced when a pure
culture of the agent is inoculated into a healthy
susceptible host.
4. The same agent must be recovered once again from
the experimentally infected host.
Koch’s Postulates :
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Toward the definition of virus
1891 : Ivanowski showed that extracts from diseased tobacco plants could transmit disease to other plants after passage through ceramic filters fine enough to retain the smallest known bacteria. Tobacco mosaic virus (VMT) is filterable
1898 : Beijerinick confirmed and extended Iwanowski's results on Tobacco mosaic virus and was the first to develop the modern idea of the virus as “contagium vivum fluidum” (soluble living germ).
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1930 : Electron microscopy determination of the composition, structure and morphology of viruses .
Ex: VMT with rod shaped
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Virus definition:
• Virus particles (virions) themselves do not grow or
undergo division
• Viruses have only one type of nucleic acid
They lack the genetic information which encodes
apparatus necessary for the generation of metabolic
energy or for protein synthesis (ribosomes)
They are therefore absolutely dependent on the host
cell for this function.
Therefore, they are absolute parasites
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Virus diversity
• There is more biological diversity within viruses than in all the rest of the bacterial, plant and animal kingdoms put together.
• This results comes from the success of viruses in parasitizing all known groups of living organisms.
Classification was required
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The basis of the classification
• Initially, classification was based : - on common pathogenic properties - on common organ tropisms and common ecological
and transmission characteristics
• Since 1930, informations of the structure and composition of viruses started to emerge.
Therefore, taxonomy was based on the structure and composition of the virus particle
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Now:
Viruses are classified according to the nature andstructure of their genome :
Order : -virales
Family : -viridae
Sub-family : -virinae
Genus : -virus
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Ordre Famille Sous famille Genre Hôte / exemple
Mononegavirales
Paramyxovirinae
Paramyxovirus Vertebrate / parainfluenza 1 Virus
Morbillivirus Vertebrate / meales virus
Rubulavirus Vertebrate / mumps virus
Pneumovirinae Pneumovirus Vertebrate / respiratory syncitial virus
Rhabdoviridae
Lyssavirus Vertebrate / rabies virus
Vesiculovirus Vertebrate / vesicular stomaitis Virus
Ephemerovirus Vertebrate / bovin ephemerale fever virus
Cytorhabdovirus Plants / yellow mosaic virus
Nucleorhabdovirus Plants / potato yellow dwarf virus
Filoviridae Filovirus Vertebrate / Ebola virus
Paramyxoviridae
Mononegavirales order
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ICTV Virosphere
Today , there are 4000 viruses
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RNA viruses
Lwoff, Horne et Tournier,1962
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DNA Viruses
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Structures of Viruses
1. Core nucleic acid
2. Protein coat or capsid - composed of a large number of sub-units - role of protection 3. Envelope or not (some are nude)
virion size range is ~10-400 nm in diameter
Viruses contain :
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Diversity of viral genomes
1. the nature of the nucleic acid : - DNA
- RNA2. the structure - single-stranded - double-stranded 3. the shape - linear, circular - segmented, non-segmented
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1. helical :- rod shaped (structures of plant viruses)- Bacteriophages- Nucleocapsids of enveloped viruses
2. icosahedral - « spherical» viruses
The capsids : two types of symmetryProtective coat made of repeating sub-units of proteins
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Two types of viruses /membrane
have a membrane derived from the host cell membrane but modified by insertion of viral proteins (glycoproteins)
• Nude viruses
• Enveloped viruses
Vesicular Stomatitis virus Ebola virusInfluenza virus
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Viral cycle
1.Adsorption and attachment to cell membrane via receptors
2. Penetration and uncoating
3. Biosynthesis of viral RNA and proteins
4. Maturation : nucleic acid and viral proteins assembly
5. Release of virions by budding
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1. Adsorption and attachment to cell membrane via specific receptors
2. Penetration and uncoating Envelope and capsid are removed and viral nucleic
acid is released into the cell
Viral cycle
The nature of the receptor is responsable of the viral tropismThe receptor can be a protein, a sugar or a complex lipid…
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• Enveloped viruses : two possible mechanisms of fusion
Stratégies de décapsidation p 137
Fusion between the viral membrane and the cellular membrane
Fusion between the viral membrane and the endosomal membrane
Non-enveloped viruses may cross the plasma membrane directly or may be taken up into endosomes. They then cross (or destroy) the endosomal membrane.
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3. Expression and replication of viral genomes
4. Assembly of viral nucleic acid and viral proteins
5. Release Budding of enveloped virus
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RNA viruses replication strategies
The strategy of viral replication depends on the type of nucleic acid involved
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Replication of RNA viruses are quite complex
Single-stranded RNA viruses contain either positive-sense or negative-sense RNA.
By convention, positive sense RNA serves as messenger RNA
If positive sense, viral RNA serves as mRNA for production of viral proteins
If negative-sense, no viral proteins can be made until viral mRNA is available then need to make a positive strand (by a viral RNA enzyme)
Then, the different strategies of replication of RNA viruses result in the synthesis of viral messenger RNA
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Messenger RNA
RNA ss positivePolarity
PicornaFlaviCaliciAstro
TogaCoronaArteriNodaTetra
Genomic RNA= mARN
Retro
RhabdovirusFiloBornaParamyxoOrthomyxoBunyaViral RdRp
Transcriptaseinverse
dsDNA
RNA pol IIcellulaire
ds RNA
ReoBirna
ambisens RNA
Arena(bunya)
RNA ss negative Polarity
Viral RdRp
Viral RdRp
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Positive strand RNA viruses
The genomic RNA is translated by the cellular machinery for translation of viral proteins
In these viruses, the genomic RNA is the same sense as mRNA and so functions as mRNA. This mRNA is translated immediately upon infection of the host cell
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examples :
Prototype member : Poliovirus (Picornaviridae)
Human rhinovirus (Picornaviridae)
Hepatitis C (Flaviviridae)
Synthesis of one and large polyprotein precursor of the structural and non
structural by proteolytic clivage
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The poliovirus
The genomic RNA has two characteristics :1) The 3’end is polyadenylated 2) The 5’end is not capped but is covalently associated to
a small protein of 22aa (VPg) and it forms a secondary structure called IRES.
The poliovirus has an RNA-dependant RNA polymerase.
AUG nt743VPg
AAAAA
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Poliovirus (Picornavirus)
ProteasesRNA synthesis
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New virions
Viral proteinsnon structural
Polyprotein precursor of viral proteins
TranslationMaturation cleavage
and structural
Picorna and Flaviviruses
genome(+)
antigenome(-)replication Enzymes
genome(+)
c
replication
5’3’
5’
5’c
+sense
-sense
+sense
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Negative strand RNA viruses
The genomic RNA is negative sense (complementary to mRNA) and must therefore be copied into the complementary plus-sense mRNA before proteins can be made.
Thus, besides needing to code for an RNA-dependent RNA-polymerase (RdRp), these viruses also need to package it in the virion so that they can make mRNAs upon infecting the cell.
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Non segmented negative strand viruses : the mononegavirales
The genome is a single-stranded RNA of negative polarity (10 à 15kb) associated to the nucleoprotein N.
The first step is the transcription of the genome by the RNA polymerase packaged by the virus and the polymerase that has polyadenylation and capping.
3’ 5’
3’ 5’1. transcription
5’ 3’Antigenome (+)
Genome
2. Replication
Genome(-)
mRNA
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Mononegavirales order
Ordre Famille Sous famille Genre Hôte / exemple
Mononegavirales
Paramyxovirinae
Paramyxovirus Vertebrate / parainfluenza 1 Virus
Morbillivirus Vertebrates / meales virus
Rubulavirus Vertebrates / mumps virus
Pneumovirinae Pneumovirus Vertebrates / respiratory syncitial virus
Rhabdoviridae
Lyssavirus Vertebrates/ rabies virus
Vesiculovirus Vertebrates / vesicular stomaitis Virus
Ephemerovirus Vertebrates / bovin ephemerale fever virus
Cytorhabdovirus Plants / yellow mosaic virus
Nucleorhabdovirus Plants / potato yellow dwarf virus
Filoviridae Filovirus Vertebrates / Ebola virus
Paramyxoviridae
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55 000 persons die of rabies each year.
Enveloped virus genome : negative single-stranded
RNA(~12kb)
5 proteins G : glycoprotein
N : nucleoprotein L : RNA polymeraseP : phosphoprotein
M : matrix Nucleocapsid (RNA-N) Helical symetry
Rabies virus
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Besides the order of mononegavirales, there are viruses (like orthomyxoviridae) that have many fragments of negative polarity. Their genome are segmented
Example: Influenza virus
Their replication strategies are identical
Segmented negative strand RNA viruses
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Influenza virus
Enveloped virusgenome: negative ss segmented RNA (8 segments)
2 glycoproteins:-HA (H1 à H15)-NA (N1 à N9)
HA
NA
M2
M1
M1
NS2
genome
M2
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PAPB2 PB1
5’ UUU 3’ viral RNA
3’PAPB2 PB1
cellular mRNA
3’
PAPB2 PB1
Cap-snatching
•The RdRp (PA, PB1, PB2)
has no the activity required
for the capping of the mRNA.
• but the RdRp has endonuclease activity
required to snatch capped primers from
host pre-mRNAs for viral transcription
(Cap-snatching).
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Transcription
RNA -dependent RNA Polymerase
packaged in the virion
mARNTranslation
Transcription
mRNA
rhabdo, filo, borna, paramyxo, orthomyxovirus
genome(-) (nucleocapsids)
Progeny virus
replication RNA-dependent RNA polymerase
antigenome(+) (nucléocapsids)
genome(-) (nucléocapsids)
Viral proteins
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2 steps:1. Transcription of a part of the genome in messenger RNA encoding capsid proteins and RNA polymerase
2. Transcription of a part of the antigenome in messenger RNA encoding other viral proteins
Examples: arenavirusand some bunyavirus
5’
5’
3’
transcription
5’
mRNA
3’ genome
antigenomemRNA
transcription
There are viruses which contain ambisens genome
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Double-stranded RNA Viruses
Example : reoviridae (reovirus and rotavirus)
• Genome with 10 and 11 segments of ds-RNA
• The virus contains a ds RNA dependent RNA polymerase
• The transcription is asymetric : one of the ds-strand is transcribed
• The transcription takes place inside the subviral particle that contains all the activities required for the capping of messenger RNA.
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Rotavirus
Nude virustriple capsid
11 segments of dsRNA
6 structural proteins6 non structural proteins
Rotaviruses are found worldwide, causing major diarrhea-associated hospitalization and 600,000-850,000 deaths per year.
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RNAdb
ARN(-)
Proteins
Transcription RNA-dependent RNA pol
Packaged in the virion
mRNA
Progeny virus
Reoviridae and Birnaviridae
Partial assembly
double strand RNAprogeny
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Retroviridae
These viruses contain a genomic RNA that will be used as a template for the synthesis of DNA by a reverse transcriptase
2 examples:Virus de l’immunodéficience humaine (HIV 1 and 2)Virus de la leucémie des cellules T humaines (HTLV )
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Retrovirus
Enveloped virus Genome : RNA
Proteins : products ofGag, Pol, Env genes
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mRNA
Proteins
Progeny virus
dsDNAReplication
Retrovirus
Parental RNA
RNA
TranscriptionRNA pol II integrated DNA
(provirus)
Integration in thecellular DNA
linear DNA
tRNA and reverse transcriptase
packaged in the virion
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4) 3’5’ 3’
PB’ gag’ pol’ env’ U’3 R’ U’5
3)3’
5’
env’ U’3 R’ U’5
PB gag pol PP
U3 R U5 PB5’
5) 3’ PB’ gag’ pol’ env’ U’3 R’ U’5
6)
U3 R U5 PB5’
U’3 R’ U’5 PB’
7)
LTRLTR
U3 R U5 PB gag pol env U3 R U5
2) 5’3’
3’
R’ U’5
PB gag pol env U3 R
R’ U’5
1) 5’3’
R U5 PB gag pol env U3 R3’
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Viral quasispeciesThe virale polymerases (RdRp, RT) are very inaccurate : lack of proofreading mechanism
Error rate : 1/10000
This results in viral variants or quasispeciesand confers significant adaptation potential through the selection of mutants best suited to a new environment.
- Escape from immune responses- Faster replicating, more aggressive strains- Broader cell tropism - Escape to antiviral therapies.