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November 22, 2022
Ancient viral DNA may help humans fight infections
At a Glance
- Researchers found that stretches of viral DNA long embedded in the human genome can produce proteins that help block infection by viruses.
- Further identification and study of these protective virus-based proteins could provide new insights for fighting viral infections.
Nearly one-tenth of the human genome contains snippets of viral DNA left over from ancient infections. These DNA fragments, called endogenous retroviruses (ERVs), have been passed along and modified over millions of years of evolution. Much of this viral DNA has eroded over time and is unlikely to have any function. But many embedded viral genes remain partly intact within the human genome. Some have evolved to become useful human genes.
Among the potentially useful DNA snippets from viruses are those encoding envelope proteins. Envelope proteins are normally found on the surface of viruses. They can latch onto cell-surface receptors, providing a gateway to viral entry. Earlier studies found that ERV-derived envelope proteins in the genomes of mice, cats, and sheep can block invasion by modern viruses. They do this by binding to cell-surface receptors and blocking entry by incoming viruses. But this had not been shown in humans.
To learn about the virus-fighting potential of human ERVs, a research team led by Dr. Cedric Feschotte of Cornell University scanned the human genome for sequences that might code for receptor-binding portions of envelope proteins. Results were reported in Science on October 28, 2022.
The team identified more than 1,500 sequences, including about 20 previously studied as human genes. Further analysis showed that most of the sequences appeared to be expressed, or turned on, in a variety of human tissues, most commonly in embryonic and immune cells.
The scientists took a closer look at one of the genes, called Suppressyn, to assess its antiviral potential. They found that Suppressyn is highly expressed in the early embryo and developing human placenta. The gene remains active as the fetus grows. Because the developing embryo can be especially vulnerable to viral infection, the scientists suspected that the prevalence of Suppressyn hinted at a protective role.
The function of the Suppressyn protein is poorly understood, but it is known to bind to a cell-surface receptor called ASCT2. Because ASCT2 is the receptor for a broad group of viruses called type D retroviruses, the researchers hypothesized that Suppressyn might block these viruses from entering human cells.
To assess Suppressyn’s protective capacity, the researchers exposed human placenta-derived cells to a type D retrovirus and found they were resistant to infection. In contrast, the virus could successfully infect other types of human tissues that did not express Suppressyn. When Suppressyn was removed from the placental cells, they became susceptible to infection. When Suppression was reintroduced, protection was restored. These findings suggest that Suppressyn is outcompeting type D viruses in binding to ASCT2 receptors, thereby preventing viral access to cells.
The study provides proof of principle that an ERV-derived envelope protein can protect against infection in human cells. The study also identified hundreds of ERV-derived sequences that can now be investigated for antiviral properties.
“The results show that in the human genome, we have a reservoir of proteins that have the potential to block a broad range of viruses,” Feschotte says.
—by Vicki Contie
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References: Evolution and antiviral activity of a human protein of retroviral origin. Frank JA, Singh M, Cullen HB, Kirou RA, Benkaddour-Boumzaouad M, Cortes JL, Garcia Pérez J, Coyne CB, Feschotte C. Science. 2022 Oct 28;378(6618):422-428. doi: 10.1126/science.abq7871. Epub 2022 Oct 27. PMID: 36302021.
Funding: NIH’s National Institute of General Medical Sciences (NIGMS); Champalimaud Foundation; Wellcome Trust; European Research Council; Howard Hughes Medical Institute; private donations.