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Lesson 4 Molecular Virology 1

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Lesson 4 Molecular Virology 1 Lesson 4 Molecular Virology 1. Introduction 1.1. Virus Definition Genetic elements made of living matter molecules, that are capable of growth and multiplication only in living cells DIFFERENCE WITH RESPECT TO OTHER GENETIC ELEMENTS: “They can exist in an extracellular phase that allows their spread” The extracellular form of the virus (i.e. virion) is metabolically inactive Introduction 1.2. The viral genome ssDNA dsDNA ssRNA dsRNA Genome variation (Phase) Circular or Linear / A single molecule or Segmented Size: 3-200kb (Phage G, 670 kb) Gene compaction (overlapping genes …) Introduction 1.3. Virus Classification 1. Depending on the host Prokaryotic viruses: Bacterial viruses = bacteriophages or phages; Archaeal viruses Eukaryotic viruses: protozoan- , fungi-, plant- , animal-viruses 2. Formal taxonomy: Taxonomic ranks (taxons): order , family, subfamily, genus and species. FAMILY: unique virion morphology, genome structure (replication strategies). e.g. Ortomixoviridae, Hepadnaviridae, Poxviridae 3. Baltimore classification: Type of genome and its method of replicaton Group I: dsDNA (except Group VII) Group II: ssDNA Group III: dsRNA Group IV: ssRNA , positive-sense Group V: ssRNA, negative -sense Group VI: Positive-sense ssRNA viruses that replicate through a DNA intermediate Group VII: dsDNA viruses that replicate through a ssRNA intermediate Introduction 1.4. The replication cycle of viruses 1. Attachment (adsorption) 2. Penetration (injection) Latency? 3. Synthesis of nucleic acids and proteins 4. Assembly and packaging 5. Release (lysis) Introduction 1.5. Attachment or Adsorption Interaction between proteins on the outside of the virus and cell receptors Receptors : proteins, carbohydrates, glycoproteins, lipids, lipoproteins or complexes Carry out normal functions in the cell. e.g., Lambda-MalT Related viruses may not share receptors The presence of receptors determine which cells are susceptible: • Species • Strain (phage typing) • Cell type • Tissue Examples: M13 / E. coli F+ Influenza virus/ Mucous membrane, red blood cells (Sialic acid) Measles / Any human cell, except red blood cells (CD46) 2. Prokaryotic Viruses ssRNA+ MS2 dsRNA ssDNA ØX174 M13 dsDNA*** T7 T4 Mu Lambda Prokaryotic Viruses 2.1. RNA phages MS2 Coliphage Expression (Transcriptional regulation is not possible ) Temporal programme based on accessibility to AUG codons (RNA structure): • The more accessible AUG is that of C (translated along the infection cycle) • Access to the AUG of P is limited. Translation of C grants access to the AUG of P • Protein C binds to AUG of P and inhibits its translation • The AUG of A is accessible only in nascent RNA+ molecules • The AUG of L is partially accessible only when ribosomes reach the stop of C Prokaryotic Viruses 2.2. ssDNA Phages (Group II) ssDNA +: replication must precede transcription Filamentous: M13 Icosahedral: ØX174 Prokaryotic Viruses 2.3. dsDNA Phages (Group I) • T-uneven phages: T7 • T-even phages: T4 • Mu phage Prokaryotic Viruses dsDNA Viruses T7 Phage Strategies to maximize genetic economy • Gene overlap • Internal translational reinitiation • Internal frame-shifts Genome : TEMPORAL EXPRESSION PROFILE: Injection of the genome / Order of genes Linear Left end .: Early genes 40kb RM system inhibitor T7 RNA polymerase Direct terminal repeat of 160 bp Inh. Cell. RNA pol Inh. Cell Expr First to penetrate Use the host RNA polymerase Replication Middle region : Intermediate genes Bidirectional Use T7 RNA polymerase One origin (closer to left end) Right end : Late genes Use T7 RNA polymerase Prokaryotic Viruses dsDNA Viruses T4 Phage Lytic Linear genome (169 kb) Complex capsid • Head • Neck (with collar) • Tail (tube + sheath) • End plate • Tail fibers Prokaryotic Viruses dsDNA Viruses: T4 TEMPORAL EXPRESSION PROFILE Sequential modification of the host RNA polymerase specificity: 1. Early genes: RNApol-σ 70 2. Intermediate genes: Modification of RNApol α subunit + phage proteins binding 3. Late genes: RNApol-σ Phage Replication Linear Genome: Ends? - Form concatamers through recombination Terminal repeats (3-6 Kb) - Sequence-independent Endonuclease - Regularly spaced cuts (> gene dotation) - Repeated ends - Permuted end sequences Prokaryotic Viruses dsDNA Viruses The Mu Bacteriophage Temperate Linear genome Replication through transposition Integration is necessary both for lysis and lysogeny Lysogeny Non-replicative Transposition C Protein Inhibits Transposase (repressor) Lytic cycle Replicative Transposition No repression Prokaryotic Viruses dsDNA Viruses: Mu Packaging 50-150 bp Mu=37 kb 1-2 kb Eukaryotic Viruses 3.1. Positive-strand RNA Picornaviridae Family Polioviruses Rhinoviruses Hepatitis A virus (HAV) Eukaryotic Viruses Positive strand RNA Viruses Picornaviridae - pico means small - Naked - Icosahedral - ssRNA + Eukaryotic Viruses Positive strand RNA Viruses Poliovirus Fam. Picornaviridae - Capsid: 4 proteins, (VP1- 4) x 60 - Intracellular cycle in the cytoplasm - Genome: 3’ –terminus poly-A tail (copied during replication) Absence of 5’ cap (Vpg protein) Vpg AAAAAA 7.5 kb - Polymerase is not present in the virion - Translation of viral proteins must take place before replication Eukaryotic Viruses Positive strand RNA Viruses: Poliovirus Degradation of EIF-4B (binding of the ribosome to the methylguanosine cap) Translation of host proteins is blocked Replication Requires priming!! : Vpg - UU Expression 1 ORF (6620 nt) 1 Polyprotein (proteolytic activity) Equal amount of every viral protein (anti-economic regulation) Eukaryotic Viruses 3.2. Negative-strand RNA viruses - Ortomyxovirus - Rhabdovirus - Ebola virus Eukaryotic Viruses Negative strand RNA Viruses Ortomyxovirus Fam. Ortomyxoviridae Influenza virus mixo = mucus New variants (antigenic shift): Epidemics Nucleocapsid: N Protein Transcriptase complex (endonuclease) Envelope: M Protein Hemagglutinin Neuraminidase Genome: Segmented in 8 RNA fragments Eukaryotic Viruses Negative strand RNA Viruses: Ortomyxovirus Transcriptase requires 5’ priming to initiate transcription: “stolen” caps Poly-A: Polymerase slippage Host’s mRNA Viral RNA Endonuclease 5’-G 5’-G 5’-G Primer 5’-G AAAAAAA Eukaryotic Viruses 3.3. dsRNA: Reoviridae Family REO: Respiratory Enteric Orphan Rotavirus: Childhood Diarrhea Naked Double-shell Icosahedral capsid (Transcriptase) Segmented Genome (10-12 dsRNA) Facilitates unwinding (replication) Antigenic shift Eukaryotic Viruses 3.4. DNA Viruses Pros The virus can utilize the cellular transcription machinery The virus con utilize part or all the replication machinery of the cell Cons Most cells in an organisms are in a non-division stage DNA in eukaryotic cells only replicates during the S-phase ssDNA Parvovirus dsDNA Papovaviridae (SV40) Papillomaviridae Adenoviridae Herpesviridae Poxviridae Eukaryotic Viruses 3.4.1. ssDNA Parvovirus Parvoviridae Genome: 4,5- 5 Kb (2 genes) 3’ Terminal hairpin Replication primer Depends on the replication machinery of the host cell Infect tumor cells or those infected with other viruses (e.g., Adenovirus) Eukaryotic Viruses 3.4.2. dsDNA Viruses Adenovirus Herpesvirus Poxvirus Eukaryotic Viruses dsDNA Viruses Adenovirus Adenoviridae Adeno : Gland Genome TP protein Linear of 36 kb Inverted terminal repeats (100-1800 pb) Naked Icosahedral virion - Replication and assembly in the nucleus - DNA is associated with histones Eukaryotic Viruses dsDNA Viruses: Adenovirus Replication - Virus-encoded replication proteins (DNA polymerase) - Primer : pTP-C - Initiates at either end: No Okazaki fragments Asynchronously ssDNA strand Cyclization, DBPs Eukaryotic Viruses dsDNA Viruses Herpesvirus Herpesviridae Herpes simplex Varicella-Zoster Epstein-Barr virus Latent in neurons of the sensory ganglia Multilayer Virion Linear Genome of 150 kb Envelope with spikes Amorphous Tegument Icosahedral Nucleocapsid Eukaryotic Viruses dsDNA Viruses: Herpesvirus TRANSCRIPTION α Genes (immediate early) - β Genes (delayed early) + γ Genes (late) + - REPLICATION In the nucleus Circularizes Rolling circle replication Concatamers ASSEMBLY In the nucleus Envelope via budding of the nucleus inner membrane Release through the endoplasmic reticulum dsDNA Viruses Poxvirus Poxviridae - The largest animal viruses (300nm Ø): Smallpox, Cowpox, Myxomatosis… - Replication IN THE CYTOPLASM VIRION Proteins envelope Genome : 150-200 kb Direct terminal repeat of 10 kb Covalently closed Replication?? Eukaryotic Viruses 3.5. Group VI: Retroviridae Rous sarcoma Virus (RSV) Envelope Human T-cell leukemia Virus (HTLV) Avian Myeloblastosis Virus (AMV) AIDS Virus (HIV) Glycoproteins Icosahedral Virion 2 copies of the genome (ssRNA +) Genome 2 copies of ssRNA + of 7-10 kb Nucleocapsid Direct terminal repeats Retrotranscriptase Cap and Poly-A Integrase tRNA from the previous host Not translated!! Eukaryotic Viruses Retrovirus ssRNA + Retrotranscription dsDNA in cytoplasm Integration in the genome Transcription: ssRNA + (genomes, mRNA) THE REVERSE TRANSCRIPTASE 4 activities : - RNA-dependent DNA polymerase - DNA-dependent DNA polymerase - RNase H, degrades RNA in DNA-RNA hydrids - Endonuclease Eukaryotic Viruses Retrovirus Retrovirus cccDNA Viral Integrase Host DNA LTR gag pol env LTR ssRNA + (mRNA, Genomes) Eukaryotic Viruses Retrovirus Expression (1 RNA = Genome) GENE ORGANIZATION Three regions: gag (capsid proteins + protease) Polyprotein pol ( Retrotranscriptase and Integrase) env ( Envelope glycoproteins).
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