Yoshiharu Uno, MD,PhD

What happens when natural viral RNA meets artificial RNA in human cells?

Does artificial RNA have any affect while the virus enters the cell and copies?

It is necessary to confirm the genetic changes and immune response of the virus produced when the virus and RNA-based vaccine are co-vaccinated in animal experiments.
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Further evidence supports controversial claim that SARS-CoV-2 genes can integrate with human DNA

https://www.sciencemag.org/news/2021/05/further-evidence-offered-claim-genes-pandemic-coronavirus-can-integrate-human-dna

A team of prominent scientists has doubled down on its controversial hypothesis that genetic bits of the pandemic coronavirus can integrate into our chromosomes and stick around long after the infection is over. If they are right—skeptics have argued that their results are likely lab artifacts—the insertions could explain the rare finding that people can recover from COVID-19 but then test positive for SARS-CoV-2 again months later.

Stem cell biologist Rudolf Jaenisch and gene regulation specialist Richard Young of the Massachusetts Institute of Technology, who led the work, triggered a Twitter storm in December 2020, when their team first presented the idea in a preprint on bioRxiv. The researchers emphasized that viral integration did not mean people who recovered from COVID-19 remain infectious. But critics charged them with stoking unfounded fears that COVID-19 vaccines based on messenger RNA (mRNA) might somehow alter human DNA. (Janesich and Young stress that their results, both original and new, in no way imply that those vaccines integrate their sequences into our DNA.)

Researchers also presented a brace of scientific criticisms, some of which the team addresses in a paper released online today by the Proceedings of the National Academy of Sciences (PNAS). “We now have unambiguous evidence that coronavirus sequences can integrate into the genome,” Jaenisch says.

SARS-CoV-2, the virus that causes COVID-19, has genes composed of RNA, and Jaenisch, Young, and co-authors contend that on rare occasions an enzyme in human cells may copy the viral sequences into DNA and slip them into our chromosomes. The enzyme, reverse transcriptase, is encoded by LINE-1 elements, sequences that litter 17% of the human genome and represent artifacts of ancient infections by retroviruses. In their original preprint, the researchers presented test tube evidence that when human cells spiked with extra LINE-1 elements were infected with the coronavirus, DNA versions of SARS-CoV-2’s sequences nestled into the cells’ chromosomes.

Many researchers who specialize in LINE-1 elements and other “retrotransposons” thought the data were too thin to support the claim. “If I would have had this data, I would have not submitted to any publication at that point,” says Cornell University’s Cedric Feschotte, who studies endogenous retrovirus chunks in the human genome. He and others also said they expected higher quality work coming from scientists of the caliber of Jaenisch and Young. In two subsequent studies, both posted on bioRxiv, critics presented evidence that the supposed chimeras of human and viral DNA traces are routinely created by the very technique the group used to scan for them in chromosomes. As one report concluded, the human-virus sequences “are more likely to be a methodological product, [sic] than the result of genuine reverse transcription, integration and expression.”

SARS-CoV-2, the virus that causes COVID-19, has genes composed of RNA, and Jaenisch, Young, and co-authors contend that on rare occasions an enzyme in human cells may copy the viral sequences into DNA and slip them into our chromosomes. The enzyme, reverse transcriptase, is encoded by LINE-1 elements, sequences that litter 17% of the human genome and represent artifacts of ancient infections by retroviruses. In their original preprint, the researchers presented test tube evidence that when human cells spiked with extra LINE-1 elements were infected with the coronavirus, DNA versions of SARS-CoV-2’s sequences nestled into the cells’ chromosomes.

In the new PNAS paper, the team provides evidence that artifacts alone can’t explain the detected levels of virus-human chimeric DNA. The scientists also show that portions of LINE-1 elements flank the integrated viral genetic sequence, further supporting their hypothesis. And they have collaborated with one of the original skeptics, Stephen Hughes of the National Cancer Institute, who suggested an experiment to clarify whether the integration was real or noise, based on the orientation of the integrated viral sequences relative to the human ones. The results support the original hypothesis, says Hughes, a co-author of the new paper. “That analysis has turned out to be important,” he says.

“The integration data in cell culture is much more convincing than what was presented in the preprint, but it’s still not totally clean,” says Feschotte, who now calls Jaenisch’s and Young’s hypothesis “plausible.” (SARS-CoV-2, he notes, can also persist in a person for months without integrating its genes.)