Ancestral Antiviral Proteins May Protect Against Infection

By Gina Wynn

We can thank our ancestors for many of our inherited physical traits, including our eye color, height, and complexion. Now we may be able to add immunity to viral infections to that list, according to a recent Cornell University study.

When examining cultured human cells in the laboratory, researchers found that proteins from ancient viral DNA were passed down from our ancestors. These human endogenous retroviruses (HERVs) may provide immunity by preventing modern viruses from entering cells that could become hosts. Previous studies have already documented this occurrence in mice, chickens, cats, sheep, and other primates.

"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 research team member Cédric Feschotte, Cornell professor of molecular biology and genetics, as reported in the Cornell Chronicle article “Ancient viral DNA in human genome guards against infections.”

Feschotte’s former graduate student, John Frank, PhD, who is now a Yale University postdoctoral researcher, was the first author of the study. The group’s findings were published in the Science article “Evolution and Antiviral Activity of a Human Protein of Retroviral Origin."

A Pool of Protective Proteins

Further investigation could lead to the discovery of antiviral proteins that could help develop treatments that don’t cause autoimmune side effects. Because the proteins are already incorporated into human DNA, they aren’t seen as foreign to the body and don’t prompt an immune response.

Approximately eight percent of DNA in the human genome is made up of HERVs, which is at least quadruple the amount of DNA in the genes that code for proteins. Our genome could be harboring a vast defense system with significant implications for healthcare.

Gaining Genomic Access

Viruses, in the form of proviruses, can introduce their RNA into a host cell, where it is converted to DNA and integrated into the host’s genome. The hijacked cell then follows the genetic instructions from the virus to replicate it. If this occurs in germ or reproductive cells, the viral DNA becomes a permanent part of the genetic code and is passed down through generations.

HERVs are evidence of viruses that became fixed in the human genome millions of years ago. They are remnants of the countless pandemics to which humans have been exposed throughout history. Scientists believe these viruses were widespread in ancient human populations since they have also been found in chimpanzee, gorilla, and other primate genomes, according to the Aidan Burn article in Scientific American “How the Ancient Viral DNA in Our Genome Affects Disease and Development.”

"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."

The Key to Entry

To enter a cell, a virus first needs to be admitted by a viral envelope or spike protein. The envelope protein binds to a receptor on the cell surface, like a key in a lock, and opens the cell to admit the virus. For their study, Frank and team used computational genomics to scan the human genome to find viral envelope proteins that they could investigate.

After cataloging the potential retroviral envelope protein-coding sequences that potentially retained receptor binding activity, they identified which genes were actively expressing retroviral envelope gene products. The team found clear evidence of expression in the early embryo and germ cells. They also noted a subset of antiviral proteins that are expressed in immune cells upon infection.

Testing with Suppressyn

To test the susceptibility of different cell types to viral infection, the group focused on suppressyn (SUPYN), an antiviral envelope protein that is known to bind the alanine-serine-cysteine transporter 2 (ASCT2) receptor. SUPYN is prevalent in very early human embryonic development and placental cells, and ASCT2 is the cellular gateway for type D retroviruses.

Because placental cells are commonly targeted by viruses, Frank and his colleagues experimented with exposing human placental-like cells to RD114, a type D retrovirus that typically infects domestic cats and other felines. Although other human cell types not expressing SUPYN were easily infected, the placental and embryonic stem cells that did express SUPYN were not affected by the virus. When the team removed SUPYN from the cells, they became infected with RD114; when SUPYN was reintroduced, viral resistance returned.

Frank and his colleagues took their experimentation a step further and introduced SUPYN to embryonic kidney cells that don’t typically express it. Normally the cells are susceptible to RD114, but with the added SUPYN, they were resistant to the virus.

Infection Insight

These results demonstrate how a human retroviral protein can deny viruses entry into cells by using antiviral envelope proteins to block cell receptors. They provide insight into how ancient retroviruses in the human genome may protect developing embryos from infection by related viruses. Feschotte hopes to study other envelope-derived proteins in the human genome to see if they have the same antiviral effect on cells, according to the Cornell Chronicle article.

Pushing the Envelope

In a similar study conducted in 2017, researchers recreated an envelope protein that helped the HERV-T virus infect human cells by binding with the monocarboxylate transporter 1 (MCT1) receptor. Daniel Blanco-Melo, PhD, of The Rockefeller University in New York and colleagues published their findings in the eLife article “Co-option of an endogenous retrovirus envelope for host defense in hominid ancestors.”

The HERV-T retrovirus spread among our primate ancestors for around 25 million years and became extinct roughly 11 million years ago. By analyzing the genetic remains of HERV-T in the genomes of humans and related primates, the team was able to recreate the ancHTenv envelope protein.

The group’s analysis showed that the HERV-T provirus in hominid genomes includes an env gene (hsaHTenv) that has been uniquely preserved. Upon further investigation, they found that hsaHTenv caused the depletion of the MCT1 receptor. Because the MCT1 was not available to interact with the ancHTenv envelope protein, HERV-T was unable to enter the cells and they were not infected with the virus. These findings further illustrate the importance of the envelope/receptor relationship in viral transmission.

Assistance from Our Ancestors

In both these studies, viral envelope protein and receptor pairs associated with HERVs in our ancestral DNA were shown to affect immunity to ancient viruses. The results of both investigations demonstrated that the lack of either the viral envelope or the receptor blocked the viruses from entering and reproducing in cells.

These findings may have major implications for researchers testing for and developing disease treatments, especially for HIV and other viruses that integrate into host cell DNA, some cancers, and possible future pandemics.

Gina Wynn is a Thermo Fisher Scientific staff writer.