Viral DNA in human genomes, embedded there from ancient infections, serves as an antiviral that protects human cells against certain current viruses, according to new research.
The article, “Evolution and antiviral activity of a human protein of retroviral origin,” published Oct. 28 in Science, provides proof of principle for this effect.
Previous studies have shown that fragments of ancient viral DNA, called endogenous retroviruses, in the genomes of mice, chickens, cats and sheep provide immunity against modern viruses that originate outside the body by blocking them from entering host cells. Although this study was performed with human cells in culture in the laboratory, it shows that the antiviral effect of endogenous retroviruses probably exists for humans as well.
The research is important because further research could uncover a group of natural antiviral proteins that lead to treatments without autoimmune side effects. The work reveals the possibility of a genome defense system that has not been characterized, but could be quite extensive.
“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,” said Cedric Feschotte, professor of molecular biology and genetics in the College of Agriculture and Life Sciences. John Frank, Ph.D. ’20, a former graduate student in Feschotte’s lab and now a postdoctoral researcher at Yale University, is the study’s first author.
Endogenous retroviruses make up about 8% of the human genome, at least four times the amount of DNA that makes up the genes that code for proteins. Retroviruses introduce their RNA into a host cell, which is converted to DNA and integrated into the host genome. The cell then follows the genetic instructions and produces more viruses.
In this way, the virus hijacks the cell’s transcriptional machinery to replicate. Retroviruses typically infect cells that are not passed from one generation to the next, but some do infect germ cells, such as an egg or sperm cell, opening the door for retroviral DNA to be passed from parent to child, eventually becoming into permanent elements in the host genome.
For retroviruses to enter a cell, a viral coat protein binds to a receptor on the cell’s surface, like a key in a lock. The envelope is also known as the spike protein for certain viruses, such as SARS-CoV-2.
In the study, Frank, Feschotte and their colleagues used computational genomics to scan the human genome and catalog all possible retroviral coat protein coding sequences that may have retained receptor-binding activity. They then performed further tests to detect which of these genes were active, that is, expressing gene products from the retroviral envelope in specific types of human cells.
“We found clear evidence of expression,” said Feschotte, “and many of them are expressed in early embryo and germ cells, and a subset is expressed in immune cells after infection.”
Once the researchers identified antiviral coat proteins expressed in different contexts, they focused on one, Suppressyn, because it was known to bind to a receptor called ASCT2, the cellular entry point for a diverse group of viruses called retroviruses. D. Suppressyn showed a high level of expression in the placenta and in very early human embryonic development.
They then performed experiments on cells similar to the human placenta, since the placenta is a common target for viruses.
The cells were exposed to a type D retrovirus called RD114, which is known to naturally infect feline species, such as the domestic cat. While other human cell types that do not express Suppressyn could be easily infected, placental and embryonic stem cells were not infected. When the researchers experimentally depleted the placental cells of Suppressyn, they became susceptible to RD114 infection; when Suppressyn was returned to the cells, they regained their resistance.
In addition, the researchers performed the reverse experiments, using an embryonic kidney cell line normally susceptible to RD114. The cells became resistant when the researchers experimentally introduced Suppressyn into these cells.
The study shows how a human protein of retroviral origin blocks a cellular receptor that allows viral entry and infection by a wide range of retroviruses that circulate in many non-human species. In this way, Feschotte said, ancient retroviruses integrated into the human genome provide a mechanism to protect the developing embryo against infection by related viruses.
Future work will explore the antiviral activity of other envelope-derived proteins encoded in the human genome, he said.
Co-authors include Carolyn Coyne, a virologist at Duke University School of Medicine, and José García-Pérez, a molecular biologist at the University of Granada, Spain.
The study was funded by Cornell, the National Institutes of Health, the University of Edinburgh Wellcome Trust Institutional Strategic Support Fund, the European Research Council, and the Howard Hughes Medical Institute.
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