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What are the mechanisms for genetic variation in RNA viruses?

RNA viruses are far more susceptible to genetic variation than DNA viruses, often resulting in important consequences for pathogenecity and immunogenicity. 4 mechanisms have been described.

  1. Mutation
  2. Recombination
  3. Reassortment
  4. Rearrangement

Mutation

RNA polymerases are at least 1000-10000 times more prone to error than DNA polymerases. This is responsible for the far higher mutation rates for RNA viruses. Often there are hot spots for mutation in the viral genome, in particular antigenic sites recognized by virus-neutralizing antibodies such as in the case of HIV. This is thought to be one of the mechanism used by HIV to evade the immune response of the host. Similar mutation is responsible e antigenic shift in influenza A and B viruses, leading to periodic epidemics. However, in other viruses such as polioviruses, although mutations occur regularly in the genome, the antigenicity remains unchanged because the antigenic site is made of more than one polypeptide. Mutations also account for the emergence of drug resistance in viruses such as HIV. In asymtomatic patients treated with AZT, AZT resistant strains will eventually emerge. What part they play in the progression of the disease is unknown, since it is thought that they are less pathogenic than the AZT susceptible strains.

Recombination

Recombination may occur where there is dual infection with similar viruses of different strains. Recombinations readily occur between the three strains of oral poliovirus vaccine (OPV). This has been postulated to play an important role in the safety of OPV. A single change at base 472 in OPV type 3 is responsible for the loss in neurovirulence for OPV type 3. When OPV is given, back mutation at base 472 readily occurs. However, because of extensive recombination with OPV1 and OPV2, neurovirulence is rarely seen as a result. It has also been postulated that recombination may lead to new strains of viruses. eg. there is now data to suggest that Western Equine Encephalitis Virus is a recombinant between Eastern Equine Encephalitis Virus and Sindbis Virus.

Reassortment

Where the virus genome consists of multiple discontinuous distinct pieces of RNA as in the case of influenza and rotaviruses. Reassortment of the individual pieces of RNA may occur in a dual infection leading to the production of new genotypes. This mechanism is postulated to account for the major antigenic shift of influenza A. A completely new subtype of influenza A had arisen approximately every 20 years this century and is responsible for major pandemics. The new subtype is thought to arise from the reassortment between animal and human influenza viruses in an animal host such as the pig, so that the haemagglutinin and perhaps the neuraminadase gene from the animal stain is introduced into the human strain. Although there is no direct proof that natural reassortment is responsible for the antigenic shift of influenza A, the process has been seen in the laboratory. Reassortment of RNA fragments also occur in case of rotaviruses the genome of which consists of 11 distinct pieces of double stranded RNA.

Gene Rearrangement

Gene rearrangement is seen in chronic rotavirus infection in children with immunodeficient syndromes. The electropherotypes which emerge 1 year later is very different to that of the original strain. The rearranged genes may consist of a translated region and an untranslated duplicated region. Therefore these viruses have additional nucleotides in their sequence. Atypical PAGE profiles are common in group A. In one case, a novel protein has been identified in one such isolate. The biological properties of this virus was also different. The precise role played by these viruses with rearranged genes is not known.

To conclude, besides a much higher rate of mutation than DNA viruses, other mechanisms, in the form of gene recombination, reassortment and rearrangement may lead to greater genetic variation. The genetic variability of RNA viruses play an important in their pathogenicity.

 

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