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Transmission electron microscope image of SARS-CoV-2. IMAGE POINT FR/NIH/NIAID/BSIP/Universal Images Group via Getty Images
  • Defective copies of the genetic material of coronaviruses arise naturally when these replicate.
  • Some of these copies are effectively parasites: They cannot replicate on their own, but they can exploit intact viral genomes to make copies of themselves and infect other cells.
  • Researchers have now created a defective version of SARS-CoV-2, the virus causing COVID-19, that interferes with and outcompetes the original virus in cell cultures.
  • In theory, injecting the synthetic virus into a person with SARS-CoV-2 could lead to the demise of both viruses.

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According to a poem by Augustus De Morgan, “Great fleas have little fleas upon their backs to bite ’em, And little fleas have lesser fleas, and so ad infinitum.”

It seems this is true even for viruses — the smallest of all parasites — which in turn have smaller viruses that parasitize them.

Biologists at Pennsylvania State University (Penn State) in University Park have exploited this universal law of nature to create a parasite of SARS-CoV-2 that they believe could treat COVID-19.

Coronaviruses, such as SARS-CoV-2, replicate by injecting their molecular blueprint, or genome — which is a single strand of RNA — into a host cell.

The infected cell copies the viral genome and churns out the proteins that it encodes, which are then used to build new virus particles. These break out of the cell and go on to infect other cells.

Sometimes, however, mistakes happen during the copying process, which can result in the creation of a smaller genome that is missing some of the genes needed to make the virus’s proteins.

By itself, this defective genome is incapable of making new virus particles and infecting other cells.

But if it shares a host cell with an intact version of the same viral genome, it can exploit the other’s genes to replicate and go on to infect other cells.

Crucially, because these defective genomes are smaller, they can replicate faster and outperform the original, or “wild-type,” virus.

They can also interfere with their wild cousin’s replication, earning them the title defective interfering (DI) genomes.

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The biologists at Penn State synthesized a DI version of the SARS-CoV-2 genome that is around 90% shorter than the original.

The pared-down viral genome lacks the original’s protein-coding genes, but it still carries instructions for packaging itself into new virus particles.

The researchers introduced this genome into African green monkey cells growing in a lab culture. They then infected the cells with the wild-type SARS-CoV-2.

Their results suggest that the DI genome not only replicates 3.3 times as fast as SARS-CoV-2 but also disrupts its replication.

This reduced the viral load of infected cells by around half within 24 hours compared with control cell cultures.

“In our experiments, we show that the wild-type SARS-CoV-2 virus actually enables the replication and spread of our synthetic virus, thereby effectively promoting its own decline,” said Marco Archetti, Ph.D., associate professor of biology at Penn State.

“A version of this synthetic construct could be used as a self-promoting antiviral therapy for COVID-19,” he added.

The research appears in the journal PeerJ.

The authors claim that by enabling the replication of the synthetic genome, SARS-CoV-2 “would promote its own demise.”

They write:

“While the immediate 50% reduction in virus load we observed is arguably not enough for therapeutic purposes, efficacy would compound over time (as the DIs increase in frequency), and a higher initial efficacy could be obtained using a delivery vector and an improved version of the DI genome.”

Since writing the paper, the biologists have successfully used nanoparticles to deliver their DI virus into cells growing in culture. They are now testing these in live animals.

The next step will be to repeat their experiments in human lung cell cultures infected with SARS-CoV-2.

Medical News Today asked Prof. Archetti whether there is a risk that the DI virus could exacerbate the excessive immune reaction, or “cytokine storm,” seen in people with severe COVID-19.

“We don’t know. There’s always a reaction to exogenous [foreign] RNA, but there’s no reason to think that it should be more severe than with viral RNA,” he said.

He added that the treatment might be more effective if delivered earlier in the course of the disease.

“The earlier the better, probably, but we don’t know this yet,” he said.

Carolina B. López, an associate professor of microbiology and immunology in the School of Veterinary Medicine at Penn State in Philadelphia, has written about defective RNA genomes and their potential as antiviral treatments.

“[T]he phenomenon of interference is real and has been demonstrated for multiple viruses, so I don’t doubt that the defective virus that they created interferes with the standard virus and reduces its replication,” she told MNT.

“The problem is that interference is not a ‘sterilizing’ mechanism, i.e., it will not eliminate the standard virus, and eventually, this standard virus will pick up again and spread,” she said.

She explained that the interfering virus needs proteins produced by the standard virus to spread. When these are gone, as a result of interference, the defective virus will “die,” which will allow a resurgence of the standard virus.

“This is a well-described process, and the risk is that these waves of defective and standard virus lead to virus persistence. So you’ll solve a problem to create another,” she said.

“This is just an opinion, but the bottom line is that more research needs to be done before applying these concepts in real life,” she concluded.

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