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http://www.bioteach.ubc.ca/MolecularBiology/AMonksFlourishingGarden/

The DNA -> RNA -> Protein Pathway. RNA Polymerase = enzyme that makes mRNA from the DNA gene template. http://www.bioteach.ubc.ca/MolecularBiology/AMonksFlourishingGarden/. Plus-strand RNA Viruses.

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http://www.bioteach.ubc.ca/MolecularBiology/AMonksFlourishingGarden/

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  1. The DNA -> RNA -> Protein Pathway RNA Polymerase = enzyme that makes mRNA from the DNA gene template http://www.bioteach.ubc.ca/MolecularBiology/AMonksFlourishingGarden/

  2. Plus-strand RNA Viruses • Plus-strand RNA viruses have genomes comprised of RNA. They have no DNA in their replication cycles. • In most cases, the replication cycle takes place in the cytoplasm of the cells. • No involvement of the transcription machinery in the nucleus; so, the plus-strand RNA viruses produce their own enzymes for RNA transcription and replication, which recognize RNA as the template. • The plus-strand RNA viruses do use the host cell’s translation machinery to generate viral proteins. • Many plus-strand RNA viruses produce numerous viral proteins from a single “gene.”

  3. Types of Plus-Strand RNA Viruses with single-stranded, non-segmented plus-strand genomes Class

  4. Picornavirus Diseases • ENTEROVIRUSES (stable in GI tract) • Poliomyelitis • Hepatitis A Virus • Coxsackieviruses • Enteroviruses Types 68-72 • Echoviruses • RHINOVIRUSES (not stable in GI tract) • Common Cold • Numerous subtypes

  5. Fecal-Oral Transmission

  6. Enterovirus Pathogenesis: Target Tissues

  7. Poliovirus Pathogenesis • Only a fraction of patients develop paralytic disease • Asymptomatic infection – 90% • Abortive/minor illness – 5% • Non-paralytic progression to the CNS – 1%-2% • Paralytic poliovirus – 0.1%-2% • 3-4 days after minor illness • Virus infects motor neurons in anterior horn of spinal cord and the motor cortex

  8. Poliovirus Infection: Progression to CNS Disease http://www.vadscorner.com/outbreak.html

  9. Protection by Antibodies • Secretory antibodies can prevent primary infection • Serum antibodies prevent viremic spread to target tissues

  10. Poliovirus Vaccination • Salk Vaccine • Killed Virus (formalin inactivated) • IPV • Sabin Vaccine • Live, attenuated viruses • OPV • Attenuated strains can revert to virulent forms • Vaccinees shed the attenuated viruses in feces • Plusses • Minuses

  11. WHO Eradication of Poliovirus Eradication campaign started in 1988 Current target date for eradication: Beyond 2009 http://www.polioeradication.org/content/general/casemap.shtml

  12. Is Eradication Possible? • Oral Poliovirus Vaccine • Preferred for Third World Vaccination • Cheaper, No Sterile Needles Required • Campaign of usage has drastically reduced wild poliovirus transmission • Major issue is REVERSION of OPV strains to virulent forms • Laboratory Stocks • Poliovirus present in many laboratories around the World • Poliovirus contaminants in stocks of other viruses, i.e. Coxsackievirus, Rhinovirus • Bioterrorism • cDNA copies of poliovirus genome exist in many laboratories; transfection into tissue culture cells results in virus production • The poliovirus genome has been generated on a gene synthesizer (Plus-strand RNA viral genomes alone are infectious!)

  13. Picornavirus Diseases • ENTEROVIRUSES (stable in GI tract) • Poliomyelitis • Hepatitis A Virus • Coxsackieviruses • Enteroviruses Types 68-72 • Echoviruses • RHINOVIRUSES (not stable in GI tract) • Common Cold • Numerous subtypes

  14. Human Rhinovirus Structure 5’-NTR Open Reading Frame Encoding Polyprotein AAAAAAAA ~630 nts VPg ~7200 bases

  15. Human Rhinovirus Structure Virus exterior = protein shell Icosahedral shape Cross-section Viral RNA genome inside Protein capsid layer outside http://www.rcsb.org/pdb/molecules/pdb20_3.html

  16. Rhinovirus Life Cycle http://cumicro2.cpmc.columbia.edu/PICO/Chapters/Cellular.html#Receptor

  17. Rhinovirus Binding to Receptor and Antibodies ICAM-1 RECEPTOR BOUND TO RHINOVIRUS ANTIBODIES BOUND TO RHINOVIRUS http://www.rcsb.org/pdb/molecules/pdb20_3.html

  18. ICAM-1 Receptor Binds to Canyon on Rhinovirus Surface http://rhino.bocklabs.wisc.edu/virusworld/images/r14_rhino+receptor.jpg

  19. Rhinovirus Life Cycle http://cumicro2.cpmc.columbia.edu/PICO/Chapters/Cellular.html#Receptor

  20. Rhinovirus Polyprotein Processing: Method for Generation of Individual Viral Proteins http://www.ag.uidaho.edu/mmbb/p_gustin_k.htm

  21. Rhinovirus Life Cycle http://cumicro2.cpmc.columbia.edu/PICO/Chapters/Cellular.html#Receptor

  22. Rhinovirus Pathogenesis • Entry of virus into upper respiratory tract • Hands and fomites • Inhalation of droplets that contain virus • Unable to replicate in the GI tract (not stable to acid) • Receptor is ICAM-1 (Intercellular Adhesion Molecule 1) • Preferentially replicates at 33oC • Over 100 serotypes • Reason for repeat infections throughout lifetime • Antigenic sites change, but receptor-binding • site is protected

  23. Rhinovirus Pathogenesis

  24. Targets for Rhinovirus Therapy

  25. New Rhinovirus Therapies 62 million cases of Rhinovirus infection in U.S. each year Cause more than 50% of respiratory tract infections • Traditional vaccine approaches as with poliovirus not possible (too many serotypes), so antiviral therapies must exploit unique properties of the virus • Soluble ICAM-1: Blocks virus binding to its receptor • AG7088: 3C protease inhibitor (being formulated for intranasal delivery) • Pleconaril: Binds a pocket in the capsid; interferes with attachment and uncoating • Promising early clinical studies – reduction in disease length • Not approved due to possible drug-drug interactions • Reformulations being developed

  26. West Nile Virus

  27. Types of Plus-Strand RNA Viruses with single-stranded, non-segmented plus-strand genomes Class

  28. Flavivirus Gene Structure (West Nile Virus = member of Flavivirus family) Figure 1. Genomic structure of flaviviruses. The flavivirus genome is 11,000 to 12,000 nucleotides long. Both the 5'- and 3'- ends contain noncoding (NC) regions. The genome encodes 10 proteins, 3 of which are structural proteins (C, M, and E), and 7 of which are nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5). The M protein is synthesized as a precursor (prM) protein. The prM protein is processed to pr + M protein late in the virus maturation by a convertase enzyme (furin). http://www.cdc.gov/ncidod/eid/vol7no4/petersenG1.htm

  29. West Nile Virus Genetic Structure and Protein Expression www.med.sc.edu:85/ virol/flavi1.jpg

  30. West Nile Virus Structure http://www.cdc.gov/ncidod/eid/vol7no4/petersenG2.htm http://news.uns.purdue.edu/UNS/html4ever/031009.Kuhn.westnile.html

  31. West Nile Virus Replication Cycle *The WNV receptor in vertebrate cells is V3 integrin, which is highly conserved in vertebrates Figure 2 The WNV replication cycle. A. Attachment and entry of the virion. B. Uncoating and translation of the virion RNA. C. Proteolytic processing of the polyprotein. D. Synthesis of the minus-strand RNA from the virion RNA. E. Synthesis of nascent genome RNA from the minus-strand RNA. F. Transport of structural proteins to cytoplasmic vesicle membranes. G. Encapsidation of nascent genome RNA and budding of nascent virions. H. Movement of nascent virions to the cell surface. I. Release of nascent virions. SHA, slowly sedimenting hemagglutinin, a subviral particle that is also sometimes released. http://arjournals.annualreviews.org/doi/full/10.1146/annurev.micro.56.012302.160654;jsessionid=i8FGn3DIgEu8

  32. Coronaviruses • Another virus group with members responsible for the “common cold” • Coronavirus member in the news = SARS Virus http://www.lapublichealth.org/acd/images/SARS_CoV_Picture.gif

  33. Types of Plus-Strand RNA Viruses with single-stranded, non-segmented plus-strand genomes Class

  34. Coronaviruses http://www-micro.msb.le.ac.uk/335/Coronaviruses.html

  35. Coronaviruses http://www.csic.es/hispano/charlas/2002/m1/m1abr-02/m1abr-02.htm http://www.cmlab.csie.ntu.edu.tw/~jsyeh/SARS/images/coronavirus-Alankann.gif

  36. Coronaviruses http://www.learn-line.nrw.de/angebote/agenda21/archiv/03/05/coronavirus.jpg

  37. Coronavirus Receptor = ACE-2 ACE-2 = angiotensin-converting enzyme 2 Expressed in heart, lung, kidney, GI tract http://www.rndsystems.com/DAM_public/5531.gif

  38. SARS Virus Budding http://www1.lf1.cuni.cz/~hrozs/sarsu0403.htm

  39. Targets for SARS Therapy http://www.nyas.columbia.edu/sars/web/slide_presentations/s3_2/18.html

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