RNAVIRUSDIVNPATHO

The role of genetic diversity of RNA viruses in virulence and pathogenesis

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 Obiettivo del progetto (Objective)

'RNA viruses have the highest mutation frequencies in nature, which are in large part attributed to the low fidelity of their viral RNA-dependent RNA polymerases (RdRp). Explosive replication kinetics coupled with high mutation rates quickly generate highly diverse populations (quasispecies) maintained by mutation-selection balance. RNA virus quasispecies have been observed for nearly all RNA viruses, but whether genetic heterogeneity is a function or consequence of a the virus’ interaction with its host environment has been difficult to answer, particularly in vivo. Recently, we have developed a model system to study these questions by altering the RdRp fidelity of poliovirus, thereby changing the amount of genetic diversity present in a population. We showed that viral infectivity, dissemination and pathogenicity were dependent on the level of genetic diversity present within a viral population. We also showed that restricting genetic diversity strongly attenuates virus and may constitute a novel strategy to engineer live virus vaccines. However, the poliovirus model of infection of transgenic mice presents significant differences and limitations with respects to a natural host infection. To further extend our preliminary results, we are shifting the expertise acquired in these recent studies to a more natural model of infection, using the Coxsackie B3 virus. This new model of study will permit a more detailed determination of the role of genetic diversity in pathogenesis and a more realistic evaluation of modulating genetic diversity as a vaccine approach.'

Introduzione (Teaser)

The high mutation frequencies of RNA viruses are often responsible for their immune evasion properties as well as their high adaptation capacity. A European research initiative investigated the molecular mechanisms behind this phenomenon.

Descrizione progetto (Article)

RNA viruses are characterised by an extreme genetic diversity due to their high mutation rates.

In practice, this means that RNA virus populations exist as a collection of genetically similar, yet diverse variants which behave like a single species.

This phenomenon is described by the term quasispecies and functionally, it is believed to drive the high evolutionary rate of these viruses.The genetic heterogeneity of RNA viruses is attributed to the low fidelity nature of the viral RNA polymerases which lack the proof-reading capacity of DNA polymerases.

However, other driving forces such as RNA stability, recombination, and selective pressure, seem to drive the emergence of new mutations.

With this in mind, the EU-funded 'The role of genetic diversity of RNA viruses in virulence and pathogenesis' (RNAVIRUSDIVNPATHO) project aimed to connect the nature of the viral RNA polymerase with the observed high mutation frequencies of RNA viruses.Accumulating evidence indicates that modulating the fidelity of the RNA polymerase has the capacity to restrict the extent of genetic diversity present in a viral population.

Researchers worked on poliovirus and Coxsackie virus to confirm this correlation and also showed that restricting population diversity reduces virulence.

Another important finding entailed the cooperation between wild type and restricted virus species to restore pathogenicity and viral dissemination.At the same time, the strategy of polymerase fidelity modulation was explored as a novel approach for developing live virus vaccines in the poliovirus mouse model of infection.

The same method was used to impede the establishment of a persistent infection which is the common problem for Coxsackie virus and heart disease.

Collectively, the project findings underscored the potential of polymerase fidelity modulation as an alternative, safer vaccination approach.

Given that virus population diversity is the main factor in immune evasion, the new methods of changing the genetic diversity and adaptability of RNA viruses are expected to have a significant impact in the field of vaccine development.