Poliovirus replication – many generations per cell

Poliovirus replication Viruses with RNA genomes can multiply quickly, but not very accurately. This means that errors, or mutations, occur when the RNA is copied to create new viruses. The advantage of this rapid, but mistake-filled, RNA replication process is that some of the mutations will be beneficial to the virus. This allows viruses to rapidly evolve, for example, to develop resistance against drugs.

Poliovirus is an RNA virus that can cause paralysis and death in humans. To prevent such infections, scientists have extensively studied the poliovirus and have developed effective vaccines against it that have eliminated the virus from all but a few countries. Because so much is known about the poliovirus and because it has a very simple structure, scientists continue to use the poliovirus as a model to study virus behavior.

One unknown aspect of the poliovirus’ behavior is how it replicates after invading a cell. Are all of its RNA copies made from the original viral RNA that first infected the cell, in what is known as a ‘stamping machine’ model? Or do the new copies of the RNA also get copied themselves in a ‘geometric replication mode’ that increases the likelihood of mutations and enables the virus to evolve more rapidly?

Viral RNA molecules are copied by one of the virus’s own proteins and so before the viral RNA can be replicated, it must first be translated to form viral proteins. When and where replication begins depends on the concentration of translated proteins around the RNA and so replication tends to begin in particular areas of the cell at different times. A recent paper used mathematical modeling to create computer simulations of the number of polioviruses in a cell that take into account these time and space constraints. By including random elements in the model, the simulated behavior more accurately follows experimentally recorded data than previously used models.

The results of the model led the authors to conclude that the poliovirus replicates by the ‘geometric mode’; as new copies of the poliovirus RNA are made, each copy goes on to make more copies. This means that in a single infected cell there are multiple generations of RNA, and each generation may undergo distinct mutations that are passed on to the next set of RNA copies. In fact, the average virus released from an infected cell is the great-great-great-granddaughter of the original virus that infected the cell. With so many different generations of virus coexisting in a cell, there are a lot of opportunities for new genetic combinations to occur and for viruses to evolve new abilities.

Experimentally guided models reveal replication principles that shape the mutation distribution of RNA viruses. (2015) eLife 4: e03753 doi: 10.7554/eLife.03753
Life history theory posits that the sequence and timing of events in an organism’s lifespan are fine-tuned by evolution to maximize the production of viable offspring. In a virus, a life history strategy is largely manifested in its replication mode. Here, we develop a stochastic mathematical model to infer the replication mode shaping the structure and mutation distribution of a poliovirus population in an intact single infected cell. We measure production of RNA and poliovirus particles through the infection cycle, and use these data to infer the parameters of our model. We find that on average the viral progeny produced from each cell are approximately five generations removed from the infecting virus. Multiple generations within a single cell infection provide opportunities for significant accumulation of mutations per viral genome and for intracellular selection.

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