Fighting COVID with COVID

Date:
July 7, 2021
Source:
Penn State
Summary:
Researchers design a new COVID-19 therapy that uses a defective
version of the SARS-CoV-2 virus to drive the disease-causing
version to extinction.



FULL STORY ==========================================================================
What if the COVID-19 virus could be used against itself? Researchers
at Penn State have designed a proof-of-concept therapeutic that may be
able to do just that. The team designed a synthetic defective SARS-CoV-2
virus that is innocuous but interferes with the real virus's growth, potentially causing the extinction of both the disease-causing virus
and the synthetic virus.


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"In our experiments, we show that the wild-type [disease-causing]
SARS-CoV- 2 virus actually enables the replication and spread of our
synthetic virus, thereby effectively promoting its own decline," said
Marco Archetti, associate professor of biology, Penn State. "A version
of this synthetic construct could be used as a self-promoting antiviral
therapy for COVID-19." Archetti explained that when a virus attacks a
cell, it attaches to the cell's surface and injects its genetic material
into the cell. The cell is then tricked into replicating the virus's
genetic material and packaging it into virions, which burst from the
cell and go off to infect other cells.

'Defective interfering (DI)' viruses, which are common in nature, contain
large deletions in their genomes that often affect their ability to
replicate their genetic material and package it into virions. However,
DI genomes can perform these functions if the cell they've infected also harbors genetic material from a wild-type virus. In this case, a DI genome
can hijack a wild-type genome's replication and packaging machinery.

"These defective genomes are like parasites of the wild-type virus,"
said Archetti, explaining that when a DI genome utilizes of a wild-type genome's machinery, it also can impair the wild-type genome growth.

In addition, he said, "given the shorter length of their genomes as a
result of the deletions, DI genomes can replicate faster than wild-type
genomes in coinfected cells and quickly outcompete the wild-type."
Indeed, in their new study, which published July 1 in the journal PeerJ, Archetti and his colleagues found that their synthetic DI genome can
replicate three times faster than the wild-type genome, resulting in a reduction of the wild-type viral load by half in 24 hours.



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To conduct their study, the researchers engineered short synthetic DI
genomes from parts of the wild-type SARS-CoV-2 genome and introduced
them into African green monkey cells that were already infected with
the wild-type SARS-CoV- 2 virus. Next, they quantified the relative
amounts of the DI and WT genomes in the cells over time points, which
gave an indication of the amount of interference of the DI genome with
the wild-type genome.

The team found that within 24 hours of infection, the DI genome reduced
the amount of SARS-CoV-2 by approximately half compared to the amount of wild-type virus in control experiments. They also found that the the DI
genome increases in quantity 3.3 times as fast than the wild-type virus.

Archetti said that while the 50% reduction in virus load that they
observed over 24 hours is not enough for therapeutic purposes, presumably,
as the DI genomes increase in frequency in the cell, the decline in the
amount of wild- type virus would lead to the demise of both the virus
and the DI genome, as the DI genome cannot persist once it has driven
the wild-type virus to extinction.

He added that further experiments are needed to verify the potential of
SARS- CoV-2 DIs as an antiviral treatment, suggesting that the experiments could be repeated in human lung cell lines, and against some of the newer variants of SARS-CoV-2. Furthermore, he said, an efficient delivery
method should be devised. In further work that is still unpublished,
the team has now used nanoparticles as a delivery vector and observed
that the virus declines by more than 95% in 12 hours.

"With some additional research and finetuning, a version of this synthetic
DI could be used as a self-sustaining therapeutic for COVID-19."
Other Penn State authors on the paper include Shun Yao, postdoctoral
scholar in biology; Anoop Narayanan, associate research professor of biochemistry and molecular biology; Sydney Majowicz, graduate student
in molecular, cellular, and integrative biosciences; and Joyce Jose,
assistant professor of biochemistry and molecular biology.

The Huck Institutes of the Life Sciences at Penn State supported this
research.

========================================================================== Story Source: Materials provided by Penn_State. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Shun Yao, Anoop Narayanan, Sydney A. Majowicz, Joyce Jose, Marco
Archetti. A synthetic defective interfering SARS-CoV-2. PeerJ,
2021; 9: e11686 DOI: 10.7717/peerj.11686 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210706153039.htm

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