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Mechanisms of Viral Variation

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McMaster University
Laura Parker

Mechanisms of Viral Variation (Lecture 22) Viral genetic variation and its consequences • Viruses evolve rapidly because of their propensity for genetic variation and shirt generation time • Viruses with the greatest genetic variability are most able to evade human responses, elude protection by vaccination, and acquire drug resistance. • Important consequences of viral genetic variation: o Host range o Virulence o Tissue tropism o Ability to elicit an immune response o Ability to react with host antibodies o Susceptibility to antiviral drugs • Genetic diversity in viruses is a combination of 2 main mechanisms  mutation and recombination o RNA viruses generally show far greater genetic diversity the DNA viruses because the replication enzymes are more error-prone o Those RNA viruses with the greatest variability are myxoviruses (i.e. influenza) and the retroviruses (i.e. HIV) Differing mutation rates of RNA and DNA viruses • RNA viruses have higher mutation rates (so high that genome cannot be defined) • Most single nucleotide substitutions are the result of nucleotide misincorporation because viral RNA pol. lack editing fxns. • RNA virus genome is an average of related genomes  “quasispecies” or “swarm” o Isolate – sample of viruses from single individual o Strain – collection of highly related genomes o Genome – nucleic acid molecules that comprise the entire genetics content of a single virus particle • Propagation of a cDNA clone of an RNA virus genome is far less error prone  cDNA cloning fixes the sequences of individual viral genomes for further study. Mechanisms for persistence of mutations in viral populations • Lethal mutation abolish fxn of essential genes  can be rescued by coinfecting (phenotypic mixing) • Neutral mutation can persist in population (genetic drift) • Adaptive mutation confer a growth advantage under particular conditions and are fixed by selection (i.e. envelope protein that abolishes neutralizing antibody binding to envelope protein) Neutralization of viruses by antibodies • Antibody response to viruses o Viruses elicit production of specific antibodies from host o May be elicited by viral surface proteinsm internal components of disrupted virions, or viral products released by cells or expressed on surface of cell • Virus neutralization – decrease in the infectious titer of a viral preparation following exposure to antibodies (because antibody interferes with steps leading to release of viral genome into host cells) • Mechanisms of viral neutralization by antibodies o Reversible neutralization – antibody-virion complex relatively unstable  bindingis of low affinity  Antibody attached by only one of its multiple binding sites  Generally interferes with attachment of virus to cell surface  High ratio of antibody to virus required  neutralization depends on saturation o Stable neutralization – antibody-virion complex does not dissociate readily  Antibody molecules that bind to 2 sites of the virion  greatly increases the stability of the complex  Stable neutralization does not require saturation of the virion surface with antibody molecules – single bound antibody sufficient to neutralize  Attachment not prevented  instead later step preceeding delivery of the viral genome is affected  Specific mechanisms include alteration of capsid formation preventing release of viral genome or prevention of a conformational change required for delivery of the genome Vaccines • Vaccination – generation of antibody mediated and cellular immunity against specific viruses by administration of whole virions or their components  only known means of preventing viral diseases. • 2 types: o Whole virus vaccine - pathogenicity must be eliminated while ability to elicit antibody response retained  Killed (inactivated) virus vaccine – ability to express viral genes and to reproduce is eliminated by chemical treatment • Generally administered by injection • Elicit antibodies against surface components of virion • Immunity of relatively short duration – require boosters  Attenuated live virus vaccine – genetic changes abolish pathogenicity but not the ability to reproduce. Generally isolated from diff host or adapted to growth in different cell type • Can be administered orally • Harder to make • Call elicit immune responses against external and internal virion components and virally-encoded proteins expressed in infected cells • Generally cheaper • Immunity relatively long-lasting  elicit good IgA response • Disadvantage – possibility of genetic reversion to a pathogenic form and persistent infection with the vaccine strain o Subunit (component) vaccines – consist of whole viral proteins, generally expressed from molecularly cloned genes.  Efficacy requires that structure resembles that found in the intact virion Genetic variation in retroviruses • Retrovirus – positive stranded RNA viruses whose multiplication cycle includes an obligatory phase in which the viral genome exists as double stranded DNA • Contains 2 identical ssRNA molecules • Enters the cell by receptor-mediated endocytosis • Nucleoprotein contains virally encoded reverse transcriptase  copies ssRNA (viral) into dsDNA (linear) • The duplex DNA copy becomes integrated into host genome in a rxn that depends on virally-encoded integrase • Integrated retroviral genome – provirus, replicates along with host DNA • Proviral DNA transcribed by host RNA pol. II • Some of these RNA copies are spliced and translated into structural components of the virion or the viral protease, integrase, and reverse transcriptase enzymes, others are packaged into nascent virions. • Infection is non-cytolytic Variability introduced during retroviral multiplication • Variability generated at 2 stages of the retroviral life cycle: o Conversion of the viral RNA genome to a DNA copy (reverse transcription)  Variability introduced by infidelity of reverse transcriptase and recombination between the 2 copies of the genome that are present in the viral particle o Transcription of an integrated DNA provirus into viral genomic RNA  Variability introduced by the infidelity of RNA pol. II and by “read-through” of transcripts into neighboring cellular sequence Mutation of retroviral genomes • Meas
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