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A virus that is incapable of self-replicating: a new in vitro study model

In order to fight the COVID-19 pandemic, it is necessary to understand how the virus operates and the kind of immune reaction it triggers. To do so, the virus’ cycle needs to be studied by infecting model cells in vitro. Since SARS-CoV-2 is highly transmissible, it has to be studied in type 3 laboratories where safety rules are amongst the strictest possible. Very few research teams are equipped with this level of protection, which slowing our overall capacity to study the virus.

However, researchers in the medical universities of Galveston (Texas) and Saint Louis (Missouri) have developed a virus model derived from SARS-CoV-2. It can be used in labs where microbiological security is at type 2 level, which is much less constraining. This model is a virus whose stages of entry into the cell and its neutralization can be studied, but which is not able to self-replicate.

The model has 2 components:

  • firstly, the RNA of SARS-CoV-2 from which a section has been removed, notably that part which codes the envelope protein (E). This is situated in the virus membrane. It is involved in several processes of the virus’ life cycle, such as such as assembly, budding, formation of the envelope and pathogenesis. Deprived of the E protein, the virus is unable to spread.
  • secondly, the laboratory’s human cells, which manufacture a number of viral proteins, such as the E protein, that is, exactly those which the truncated virus can no longer produce.

When the modified viral RNAs are inserted into cells, complete viral particles are produced since the proteins not expressed by the viral genome are expressed in these cells. The particles thus produced can infect conventional cell-lines one time. They are unable to replicate, since their RNA does not permit them to produce the E protein, and thereby new virions.

This can be schematically represented as follows:

The researchers are of course sure that no complete SARS-CoV-2 particle capable of replication has been produced by this system. In addition, the virulence of these viral particles has been checked by injecting them into hamsters and mice. They were thus able to show that the virions produced within their system have a greatly reduced level of virulence, do not spread within the organism, and do not cause illness.

These researchers have therefore been able to construct and characterize a non-replicating SARS-CoV-2 study model that can be used in a lab with type 2 microbiological security and is therefore more accessible to the scientific community. This model can be used for neutralization tests, for the characterization of antiviral molecules or for the evaluation of potential vaccines.

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