Virology

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POSITIVE-SENSE, NON-ENVELOPED, RNA VIRUS
* Includes picornavirus (polio, rhinovirus, HepA, coxsackievirus, echovirus), calcivirus (Norwalk virus), astroviridae (astrovirus), flaviviridae (HepC, yellow fever), togaviridae (rubella virus, sindbis), coronaviridae (SARS virus), large # of plant viruses (TMV, TRV, BMV, PVX, TEV, PVY) * All have positive sense genomic RNA acting directly as mRNA for protein synthesis; all contain RNA, protein and no lipid envelopes; plant and bacterial viruses contain single type of coat protein (animal picornavirus contain 4 types of coat protein) * After entry to host cell an uncoating, protein synthesis start directly from viral RNA and followed by replication and packaging * Translational strategies used: 1) synthesis of subgenomic RNAs (e.g, TMV), 2) formation of polyprotein, followed by post-translational processing to generate functional proteins (e.g. picornavirus) LECTURE 20: PICORNAVIRUS

* Picornavirus structure
* Icosahedral, T=1
* 27-30 nm in diameter
* 4 structural proteins, 60 copies of each per virion
* VP1,2,3 form canyon where cellular receptor binds, VP4 only visible on inside of particle, where contacts genomic RNA * Genome
* Ss (+) sense RNA, poly-A tail at 3’ end, VPg (Virion protein genomic) covalently linked to 5’ end in place of cap * VPg
* Attached to 5’ terminal pUpU of viral RNA via phosphodiester linkage with tyrosine-OH group * Function in streaming viral RNA toward ribosome for translation & role in replication * Monocistronic genome (contain 1 ORF) which encode large polyprotein polyprotein cleaved to yield structural and non-structural proteins * Proteolytic cleavage

* Polyprotein first cleaved into 3 protein precursors: P1, P2 and P3 * P1: precursor for capsid proteins; P2 and P3 precursors for polymerase and proteases * QG (glutamine-glycine) target for cleaved (viral protease 3C) * Translation

* 5’ noncoding (untranslated) region usually long and contain high degree of secondary structure * Cap-independent
* Picornavirus target cellular mRNA to inhibit their translation through cap-binding protein which inactivate (cap-dependent) cellular mRNA translation by cleaving eIF-4G * Translation of viral RNA followed by strong decrease in host cellular mRNA * Poliovirus has internal ribosomal entry site (IRES) whereby they internally initiate translation 2 cellular proteins (P52 and P57) bind to IRES and allow ribosome to bind * Replication

* After virus entry and uncoat, poliovirus RNA directly translated to produce proteins necessary for replication in cytoplasm * 3 virus specific RNA structures associated with membranous vesicles * 1) ssRNA lacking VPg

* 2) replicating intermediates (RI): negative stranded template * 3) replicative form (RF): end product of RNA replication * Protein 3D is RNA dependent RNA polymerase, proteins 2B, 2C, 3AB, 3CD also involved * All nascent RNA found with VPg attached at their 5’ end * Models for role of VPg in virus replication

* 1) VPg become uridinylated and acts as primer for – RNA synthesis * 2) host factor add poly-U to poly-A tail, forms hairpin and primes elongation of – strand, then later cleaved * Circular RNP complex used to initiate – RNA synthesis * Viral proteins 3CD and VPg, poly-A binding protein (PABP) and poly(rC) binding protein (PCBP) interact with each other and ends of viral RNA to form circular RNP complex * Inhibition of translation initiation allow clearance of viral RNA over time by elongation of translating ribosome to 3’ end of coding sequence * Once template RNA cleared of translating ribosome, VPg-pUpU associate with 3 end of viral...
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