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VIRAL GENETICS

• PATHOGENESIS

• LIFE CYCLES

• VACCINE DEVELOPMENT

• DRUG RESISTANCE

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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.”

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VIRAL GENETICS

• VIRUSES GROW RAPIDLY

• A SINGLE PARTICLE PRODUCES A LOT OF PROGENY

• DNA VIRUSES SEEM TO HAVE ACCESS TO PROOF READING, RNA VIRUSES DO NOT SEEM TO

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NATURE OF GENOMES

• RNA or DNA

• SEGMENTED OR NON-SEGMENTED

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GENETIC CHANGE

• MUTATION

• RECOMBINATION

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ORIGIN OF MUTATIONS

• SPONTANEOUS– tautomeric form of bases– polymerase errors

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Tautomeric forms of bases

most of time rarely

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ORIGIN OF MUTATIONS

• SPONTANEOUS– tautomeric form of bases– polymerase errors

why do some viruses seem to alter very little, even though one would expect high mutation rates?

mutation rates usually higher in RNA viruses (lack of proof reading)

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ORIGIN OF MUTATIONS

• SPONTANEOUS• PHYSICALLY INDUCED

–UV light , especially problem if no access to repair

–X-rays • CHEMICALLY INDUCED

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TYPES OF MUTATION

• POINT

•INSERTION

•DELETION

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PHENOTYPES

PHENOTYPE

– the observed properties of an organism

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PHENOTYPIC CHANGES

• CONDITIONAL LETHAL - multiply under some conditions but not others - wild-type (wt) grows under both sets of conditions

• temperature-sensitive (ts) mutants do not grow at higher temperature (altered protein)

• host-range mutants do not grow in all the cell types that the wt does

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PHENOTYPIC CHANGES

• PLAQUE SIZE– may show altered pathogenicity

• DRUG RESISTANCE– important in the development of antiviral agents

• ENZYME-DEFICIENT MUTANTS– some genes can be ‘optional’ in certain

circumstances

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PHENOTYPIC CHANGES

• “HOT MUTANTS”– grow better at elevated temperature than wt– less susceptible to host fever response

• ATTENUATED MUTANTS– milder (or no) symptoms– vaccine development– pathogenesis

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GENETIC CHANGE

• MUTATION

• RECOMBINATION

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RECOMBINATION

Exchange of information between two genomes

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RECOMBINATION‘classic’ recombination common in DNA viruses

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COPY CHOICE RECOMBINATION

template switch

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COPY CHOICE RECOMBINATION

continues copying

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COPY CHOICE RECOMBINATION

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COPY CHOICE RECOMBINATION

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Other methods recombination

• Take advantage quirks in virus replication

– eg. Coronaviruses (include SARS virus)

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RECOMBINATION - SOME USES

• mapping by recombination frequency

• mapping by marker rescue

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RECOMBINATION - SOME USES

marker rescue

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RECOMBINATION - SOME USES

• mapping by recombination frequency

• mapping by marker rescue

• development of recombinant viruses for vaccines and therapeutic reasons

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RECOMBINATION - SOME USES

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raccoon eating bait with rabies vaccine in it

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REASSORTMENT

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REASSORTMENT

• form of recombination (non classical)

• very efficient

• segmented viruses only– can occur naturally

• used in some new vaccines– eg for influenza and rotaviruses

31adapted fromTreanor JJ Infect. Med. 15:714

• cold adapted

• temperature-sensitive

• attenuated

• live vaccine

• intranasal delivery

• approved 2003

INFLUENZA VIRUS

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NON-SEGMENTED NEGATIVE STRAND RNA VIRUSES

• no classical recombination

• no copy choice

• no reassortment

– least ability to exchange genetic material

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other aspects of viral genetics

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COMPLEMENTATIONInteraction at the functional level, NOT the nucleic

acid level

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

ts mutant 1 ts mutant 2

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DEFECTIVE VIRUSES

• lack gene(s) necessary for a complete infectious cycle

• ‘helper’ virus provides missing functions

package me! copy me!

package me! copy me!

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DEFECTIVE VIRUSES

• some examples of defective viruses

– some retroviruses (use related helper)

– hepatitis delta virus (uses unrelated helper)

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DEFECTIVE INTERFERING (DI) VIRUSES (PARTICLES)

• decrease replication of helper virus

– compete for viral precursors, etc.

• may modulate wt infections

• occur naturally eg. DI measles virus in

subacute scelerosing panencephalitis - SSPE

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PHENOTYPIC MIXING

no changes in genome

possibly altered host range

possibly resistant to antibody neutralization

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PHENOTYPIC MIXING