Ancient viral DNA in the human genome protects against infection

Viral DNA embedded in human genomes from ancient infections serves as antiviral agents, protecting human cells from certain contemporary viruses, new research suggests.

The publication “Evolution and Antiviral Activity of a Human Protein of Retroviral Origin” published October 28 in Scienceprovides the 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 to modern viruses that originate outside the body by preventing them from entering host cells. Although this study was performed using human cells in culture in the laboratory, it shows that the antiviral effects of endogenous retroviruses are likely to exist in humans as well.

The research is important because further investigation could uncover a pool of natural antiviral proteins that could lead to treatments without autoimmune side effects. The work reveals the possibility of a genomic defense system that has not yet been characterized but could be quite extensive.

“The results show that we have a reservoir of proteins in the human genome that have the potential to block a wide range of viruses,” said Cedric Feschotte, professor of molecular biology and genetics at the College of Agriculture and Life Sciences. John Frank, Ph.D., a former graduate student in Feschotte’s lab and now a postdoctoral fellow 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 into DNA and integrated into the host’s genome. The cell then follows the genetic instructions and produces more virus.

In this way, the virus hijacks the cell’s transcription machinery in order to replicate itself. Typically, retroviruses infect cells that are not passed from one generation to the next, but some infect germ cells, such as host genomes.

In order for retroviruses to enter a cell, a viral coat protein binds to a receptor on the cell’s surface, much like a key goes into 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 colleagues used computational genomics to scan the human genome and catalog all potential retroviral coat protein coding sequences that may have retained receptor-binding activity. Then they ran additional tests to determine which of those genes were active — meaning they were expressing retroviral envelope gene products in specific human cell types.

“We found clear evidence of expression,” Feschotte said, “and many of them are expressed in the early embryo and germ cells, and a subset is expressed in immune cells upon infection.”

After identifying antiviral envelope proteins expressed in a variety of contexts, the researchers 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 known as type D retroviruses. Suppressyn showed high levels of expression in the placenta and in very early human embryonic development.

They then performed experiments in human placenta-like cells, 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 domestic cats. While other human cell types that do not express suppressyn could be easily infected, the placental and embryonic stem cells were not infected. When researchers experimentally depleted placental cells from Suppressyn, they became susceptible to RD114 infection; When Suppressyn was returned to the cells, they regained resistance.

In addition, the researchers performed reverse experiments using an embryonic kidney cell line that is 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 virus entry and infection by a broad spectrum of retroviruses circulating 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 from infection by related viruses.

Future work will examine 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 Jose Garcia-Perez, a molecular biologist at the University of Granada, Spain.