According to new research, viral DNA embedded in human genomes from ancient infections acts as antivirals, protecting human cells from certain modern viruses.

The paper "Evolution and Antiviral Activity of a Human Protein of Retroviral Origin," published in the journal Science, demonstrates the effect in principle.

Despite the fact that this research was done on human cells in culture, it shows that endogenous retroviruses have an antiviral effect on humans.

The study is significant because it could discover a pool of natural antiviral proteins that could lead to treatments without autoimmune side effects. The research suggests the existence of a genome defence system that has yet to be identified 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 broad range of viruses," said Cedric Feschotte, professor of molecular biology and genetics in the College of Agriculture and Life Sciences. John Frank, PhD. '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 per cent of the human genome, which is more than four times the amount of DNA that makes up the genes that code for proteins.

Retroviruses enter a host cell and introduce their RNA, which is converted to DNA and integrated into the host's genome. The cell then replicates the virus in accordance with the genetic instructions.

To replicate itself, the virus hijacks the cell's transcriptional machinery. Retroviruses typically infect cells that do not pass from generation to generation, but some infect germ cells, such as an egg or sperm, allowing retroviral DNA to pass from parent to offspring and eventually become permanent fixtures in the host genome.

To enter a cell, a viral envelope protein binds to a receptor on the cell's surface, similar to a key in a lock. For some viruses, such as SARS-CoV-2, the envelope serves as a spike protein.

Frank, Feschotte, and colleagues used computational genomics to scan the human genome and catalogue all potential retroviral envelope protein-coding sequences that might still have receptor-binding activity. They then performed additional tests to determine which of these genes were active, i.e. 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 in germ cells, and a subset is expressed in immune cells upon infection."

After identifying antiviral envelope proteins expressed in various contexts, the researchers focused on one, Suppressyn, because it was known to bind a receptor called ASCT2, which serves as the cellular entry point for a diverse group of viruses known as Type D retroviruses.

Suppression was found to be highly expressed in the placenta and in very early human embryonic development. They then conducted experiments in human placental-like cells, as the placenta is a common viral target.

The cells were infected with RD114, a type D retrovirus known to naturally infect feline species such as the domestic cat. While other human cell types that did not express Suppressyn were easily infected, placental and embryonic stem cells were not infected. When the researchers depleted Suppressyn in placental cells, they became susceptible to RD114 infection; when Suppressyn was restored to the cells, they regained resistance.

Furthermore, the researchers conducted reverse experiments with an embryonic kidney cell line that is normally susceptible to RD114. When the researchers experimentally introduced Suppressyn into these cells, the cells became resistant.

The research demonstrates how a human protein of retroviral origin blocks a cell receptor that allows viral entry and infection by a wide variety of retroviruses found in many non-human species. In this way, ancient retroviruses integrated into the human genome, according to Feschotte, provide a mechanism for protecting the developing embryo from infection by related viruses.

According to him, future research will examine the antiviral activity of other envelope-derived proteins encoded in the human genome.