Viral Genetics

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Viral Genetics

  1. 1. VIRAL GENETICS <ul><li>PATHOGENESIS </li></ul><ul><li>LIFE CYCLES </li></ul><ul><li>VACCINE DEVELOPMENT </li></ul><ul><li>DRUG RESISTANCE </li></ul>www.freelivedoctor.com
  2. 2. VIRAL GENETICS “ DNA chromosomes of eukaryotic host organisms generally require geologic time spans to evolve to the degree that their RNA viruses can achieve in a single human generation.” www.freelivedoctor.com
  3. 3. VIRAL GENETICS <ul><li>VIRUSES GROW RAPIDLY </li></ul><ul><li>A SINGLE PARTICLE PRODUCES A LOT OF PROGENY </li></ul><ul><li>DNA VIRUSES SEEM TO HAVE ACCESS TO PROOF READING, RNA VIRUSES DO NOT SEEM TO </li></ul>www.freelivedoctor.com
  4. 4. NATURE OF GENOMES <ul><li>RNA or DNA </li></ul><ul><li>SEGMENTED OR NON-SEGMENTED </li></ul>www.freelivedoctor.com
  5. 5. GENETIC CHANGE <ul><li>MUTATION </li></ul><ul><li>RECOMBINATION </li></ul>www.freelivedoctor.com
  6. 6. ORIGIN OF MUTATIONS <ul><li>SPONTANEOUS </li></ul><ul><ul><li>tautomeric form of bases </li></ul></ul><ul><ul><li>polymerase errors </li></ul></ul>www.freelivedoctor.com
  7. 7. Tautomeric forms of bases most of time rarely www.freelivedoctor.com
  8. 8. ORIGIN OF MUTATIONS <ul><li>SPONTANEOUS </li></ul><ul><ul><li>tautomeric form of bases </li></ul></ul><ul><ul><li>polymerase errors </li></ul></ul><ul><ul><li>why do some viruses seem to alter very little, even though one would expect high mutation rates? </li></ul></ul><ul><ul><li>mutation rates usually higher in RNA viruses (lack of proof reading) </li></ul></ul>www.freelivedoctor.com
  9. 9. www.freelivedoctor.com
  10. 10. ORIGIN OF MUTATIONS <ul><li>SPONTANEOUS </li></ul><ul><li>PHYSICALLY INDUCED </li></ul><ul><ul><li>UV light , especially problem if no access to repair </li></ul></ul><ul><ul><li>X-rays </li></ul></ul><ul><li>CHEMICALLY INDUCED </li></ul>www.freelivedoctor.com
  11. 11. TYPES OF MUTATION <ul><li>POINT </li></ul><ul><li>INSERTION </li></ul><ul><li>DELETION </li></ul>www.freelivedoctor.com
  12. 12. PHENOTYPES <ul><li>PHENOTYPE </li></ul><ul><ul><li>the observed properties of an organism </li></ul></ul>www.freelivedoctor.com
  13. 13. PHENOTYPIC CHANGES <ul><li>CONDITIONAL LETHAL - multiply under some conditions but not others - wild-type (wt) grows under both sets of conditions </li></ul><ul><ul><ul><li>temperature-sensitive (ts) mutants do not grow at higher temperature (altered protein) </li></ul></ul></ul><ul><ul><ul><li>host-range mutants do not grow in all the cell types that the wt does </li></ul></ul></ul>www.freelivedoctor.com
  14. 14. PHENOTYPIC CHANGES <ul><li>PLAQUE SIZE </li></ul><ul><ul><li>may show altered pathogenicity </li></ul></ul><ul><li>DRUG RESISTANCE </li></ul><ul><ul><li>important in the development of antiviral agents </li></ul></ul><ul><li>ENZYME-DEFICIENT MUTANTS </li></ul><ul><ul><li>some genes can be ‘optional’ in certain circumstances </li></ul></ul>www.freelivedoctor.com
  15. 15. PHENOTYPIC CHANGES <ul><li>“ HOT MUTANTS” </li></ul><ul><ul><li>grow better at elevated temperature than wt </li></ul></ul><ul><ul><li>less susceptible to host fever response </li></ul></ul><ul><li>ATTENUATED MUTANTS </li></ul><ul><ul><li>milder (or no) symptoms </li></ul></ul><ul><ul><li>vaccine development </li></ul></ul><ul><ul><li>pathogenesis </li></ul></ul>www.freelivedoctor.com
  16. 16. GENETIC CHANGE <ul><li>MUTATION </li></ul><ul><li>RECOMBINATION </li></ul>www.freelivedoctor.com
  17. 17. RECOMBINATION <ul><li>Exchange of information between two genomes </li></ul>www.freelivedoctor.com
  18. 18. RECOMBINATION <ul><li>‘ classic’ recombination </li></ul>common in DNA viruses www.freelivedoctor.com
  19. 19. COPY CHOICE RECOMBINATION +ve strand 2 +ve strand 1 www.freelivedoctor.com template switch
  20. 20. COPY CHOICE RECOMBINATION +ve strand 2 +ve strand 1 www.freelivedoctor.com -ve strand recombinant -ve strand recombinant +ve strand continues copying
  21. 21. COPY CHOICE RECOMBINATION + strand - strand + strand www.freelivedoctor.com - strand
  22. 22. COPY CHOICE RECOMBINATION + strand + strand www.freelivedoctor.com
  23. 23. Other methods recombination <ul><li>Take advantage quirks in virus replication </li></ul><ul><ul><li>eg. Coronaviruses (include SARS virus) </li></ul></ul>www.freelivedoctor.com
  24. 24. RECOMBINATION - SOME USES <ul><li>mapping by recombination frequency </li></ul><ul><li>mapping by marker rescue </li></ul>www.freelivedoctor.com
  25. 25. RECOMBINATION - SOME USES marker rescue TK mutant HSV TK - mt www.freelivedoctor.com TK - wt TK wt HSV TK - wt
  26. 26. RECOMBINATION - SOME USES <ul><li>mapping by recombination frequency </li></ul><ul><li>mapping by marker rescue </li></ul><ul><li>development of recombinant viruses for vaccines and therapeutic reasons </li></ul>www.freelivedoctor.com
  27. 27. RECOMBINATION - SOME USES vaccinia virus vaccinia virus for use as rabies vaccine TK rabies G rabies G T K www.freelivedoctor.com
  28. 28. raccoon eating bait with rabies vaccine in it www.freelivedoctor.com
  29. 29. REASSORTMENT www.freelivedoctor.com
  30. 30. REASSORTMENT <ul><li>form of recombination (non classical) </li></ul><ul><li>very efficient </li></ul><ul><li>segmented viruses only </li></ul><ul><ul><li>can occur naturally </li></ul></ul><ul><li>used in some new vaccines </li></ul><ul><ul><li>eg for influenza and rotaviruses </li></ul></ul>www.freelivedoctor.com
  31. 31. <ul><li>cold adapted </li></ul><ul><li>temperature-sensitive </li></ul><ul><li>attenuated </li></ul><ul><li>live vaccine </li></ul><ul><li>intranasal delivery </li></ul><ul><li>approved 2003 </li></ul>adapted fromTreanor JJ Infect. Med. 15:714 INFLUENZA VIRUS www.freelivedoctor.com
  32. 32. NON-SEGMENTED NEGATIVE STRAND RNA VIRUSES <ul><li>no classical recombination </li></ul><ul><li>no copy choice </li></ul><ul><li>no reassortment </li></ul><ul><ul><li>least ability to exchange genetic material </li></ul></ul>www.freelivedoctor.com
  33. 33. other aspects of viral genetics www.freelivedoctor.com
  34. 34. COMPLEMENTATION <ul><li>Interaction at the functional level, NOT the nucleic acid level </li></ul>mutants which can complement are generally in different genes Progeny virus assembled using wt N and wt M proteins Genomes in progeny are either ts M or ts N www.freelivedoctor.com ts N wt M ts M wt N ts mutant 1 ts mutant 2
  35. 35. DEFECTIVE VIRUSES <ul><li>lack gene(s) necessary for a complete infectious cycle </li></ul><ul><li>‘ helper’ virus provides missing functions </li></ul>www.freelivedoctor.com package me! copy me! package me! copy me! genome
  36. 36. DEFECTIVE VIRUSES <ul><li>some examples of defective viruses </li></ul><ul><ul><li>some retroviruses (use related helper) </li></ul></ul><ul><ul><li>hepatitis delta virus (uses unrelated helper) </li></ul></ul>www.freelivedoctor.com
  37. 37. DEFECTIVE INTERFERING (DI) VIRUSES (PARTICLES) <ul><li>decrease replication of helper virus </li></ul><ul><ul><li>compete for viral precursors, etc. </li></ul></ul><ul><li>may modulate wt infections </li></ul><ul><li>occur naturally eg. DI measles virus in subacute scelerosing panencephalitis - SSPE </li></ul>www.freelivedoctor.com
  38. 38. PHENOTYPIC MIXING no changes in genome possibly altered host range possibly resistant to antibody neutralization www.freelivedoctor.com
  39. 39. PHENOTYPIC MIXING PSEUDOTYPE www.freelivedoctor.com

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