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The abstract of A synthetic defective interfering SARS-CoV-2 is as follows.

Abstract

Viruses thrive by exploiting the cells they infect, but in order to replicate and infect other cells they must produce viral proteins. As a result, viruses are also susceptible to exploitation by defective versions of themselves that do not produce such proteins. A defective viral genome with deletions in protein-coding genes could still replicate in cells coinfected with full-length viruses. Such a defective genome could even replicate faster due to its shorter size, interfering with the replication of the virus. We have created a synthetic defective interfering version of SARS-CoV-2, the virus causing the Covid-19 pandemic, assembling parts of the viral genome that do not code for any functional protein but enable the genome to be replicated and packaged. This synthetic defective genome replicates three times faster than SARS-CoV-2 in coinfected cells, and interferes with it, reducing the viral load of infected cells by half in 24 hours. The synthetic genome is transmitted as efficiently as the full-length genome, suggesting the location of the putative packaging signal of SARS-CoV-2. A version of such a synthetic construct could be used as a self-promoting antiviral therapy: by enabling replication of the synthetic genome, the virus would promote its own demise.

I've highlighted "in coinfected cells"" because it seems to be key to how this would work as a "self-promoting antiviral therapy". To my understanding, the competition happens only within cells that have been infected with both viruses.

Just for example to describe my question, let's say that in an infected individual undergoing antiviral treatment with a synthetic defective interfering virus only $1 \times 10^{-3}$ pulmonary epithelial cells are infected by either virus. A naive application of statistics suggests only $1 \times 10^{-3}$ of cells infected with the disease-causing virus would also be infected by the synthetic defective interfering virus, while 99.9% of them would not be.

At that point I don't see how this is helping; it would require a large fraction or perhaps most, rather than only a small fraction of all of the patients pulmonary epithelial cells to have been infected before enough competitive events would take place for the synthetic defective interfering virus to actually cause the disease-causing virus to be threatened with "extinction" due to competition.

Is that how this would actually have to work in practice?

Question: How would a "synthetic defective interfering SARS-CoV-2" work in practice? Wouldn't it require a large fraction of all cells to be infected?

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  • $\begingroup$ Could not find tags similar to competition and antiviral-therapy, help with tagging is appreciated. $\endgroup$
    – uhoh
    Commented Aug 20, 2021 at 22:42

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I'd like to add on Armand's answer about the delivery method of DI RNA. The author has stated that in additional work that’s nonetheless unpublished, the workforce has now used nanoparticles as a [supply vector][1] and noticed that the virus declines by greater than 95% in 12 hours. If the delivery efficiency of DI RNA is guaranteed, the fraction of coinfected cells should be a concern anymore.

Resources [1]: https://www.sciencedaily.com/releases/2021/07/210706153039.htm

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  • $\begingroup$ Interesting! What does "delivery efficiency of DI RNA is guaranteed" mean? Essentially 100^% of cells that the SARS-CoV-2 can potentially infect are already pre-infected by the defective interfering virus first? They would just go into each sell and not cause harm to it, but instead just "sit tight" and quietly wait for the disease causing virus to co-infect the cell? Or does it simply need to be a substantial fraction, and the "self-promoting antiviral therapy" makes so many DI viruses as soon as the disease-causing virus starts to co-infect that they can keep up locally with the infection? $\endgroup$
    – uhoh
    Commented Aug 31, 2021 at 7:46
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    $\begingroup$ Well, that’s the problem here: you can’t pre-infect the cells with DI virus first. In the absence of WT genome, the DI RNA, even though delivered into the cells, will quickly degrade inside the cells because they are unable to replicate and package their genome. Presumably, even a small amount of RNA can interfere with the WT virus and result in the demise of each the virus and the DI genome. But the current coinfection only results in a 50% reduction in virus load over 24 hours, and this shouldn't be sufficient for therapeutic function. $\endgroup$
    – Leading Biology
    Commented Sep 1, 2021 at 2:55
  • $\begingroup$ Okay thanks for the insight; I'm getting the idea now. $\endgroup$
    – uhoh
    Commented Sep 1, 2021 at 3:07
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The authors note in their article that this is only a proof of principle. In particular, they write "An efficient delivery method should be devised to increase the initial amount of DI RNA and to deliver it in vivo. "

Your question is well-founded, as nobody seems to know how such a therapy would actually work in practice.

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    $\begingroup$ Personally I don't think this strategy is useful, but I could be wrong. $\endgroup$
    – Armand
    Commented Aug 21, 2021 at 21:58
  • $\begingroup$ Thanks for your answer; I was afraid that I was missing something. I'm sure the competition is scientifically interesting by itself, and even if not a realistically viable therapy as-is it may offer insight into new antiviral schemes. $\endgroup$
    – uhoh
    Commented Aug 21, 2021 at 22:10

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