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The researchers discovered that stretches of viral DNA long embedded in the human genome can produce proteins that help block virus infection. Further identification and study of these virus-based protective proteins could provide new insights to combat viral infections.
Nearly a tenth of the human genome contains bits of viral DNA left over from past infections. These bits of DNA, called endogenous retroviruses (ERVs), have been passed on 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 partially intact within the human genome. Some have evolved to become useful human genes.
Among the potentially useful DNA fragments of viruses are those that code for the coat proteins. Envelope proteins are normally found on the surface of viruses. They can attach to cell surface receptors, providing a gateway for the virus. Previous studies found that ERV-derived envelope proteins in the genomes of mice, cats, and sheep can block the invasion of modern viruses. They do this by binding to cell surface receptors and blocking the entry of incoming viruses. But this had not been demonstrated 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 encode portions of envelope proteins that bind to the receiver. The 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 activated in a variety of human tissues, most commonly 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 in the 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 not well understood, but it is known to bind to a cell surface receptor called ASCT2. Because ASCT2 is the receptor for a large group of viruses called D-type retroviruses, the researchers hypothesized that Suppressyn could block the entry of these viruses into human cells.
To assess the protective ability of Suppressyn, the researchers exposed cells derived from human placenta to a D-type retrovirus and found that they were resistant to infection. Conversely, the virus could successfully infect other types of human tissues that do not express Suppressyn. When Suppressyn was removed from placental cells, they became susceptible to infection. When the suppression was reintroduced, the protection was restored. These findings suggest that Suppressyn is outperforming D-type viruses in binding to ASCT2 receptors, 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 wide range of viruses,” says Feschotte.
—by Vicki Contie
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, García Pérez J, Coyne CB, Feschotte C. Sciences. 2022 October 28; 378 (6618): 422-428. doi: 10.1126/science.abq7871. Epub Oct 27, 2022. PMID: 36302021.
Money: the NIH National Institute of General Medical Sciences (NIGMS); Champalimaud Foundation; Welcome Trust; European Research Council; Howard Hughes Medical Institute; private donations.
Source: news.google.com