Ancient Viral DNA in Human Genome Helps To Protect Against Infection

Published in Science, a new study has shown how DNA from viruses embedded into the human genome from ancient infections can help guard our cells against some present-day viruses.

Remnants of ancient viruses

Small fragments of DNA from ancient viruses – called endogenous retroviruses – can be found in the genomes of many animals, from mice and chickens to cats and sheep. Retroviruses insert their RNA into a host cell, which is first converted into DNA before being integrated into the host’s genome. This effectively hijacks the host’s cells, providing them with the genetic instructions required to produce more copies of the virus.

Such endogenous retrovirus sequences make up around 8% of the human genome – accounting for approximately four times the amount of protein-coding human genes. Nevertheless, these genes can support the host’s immunity against modern-day viruses by blocking them from entering host cells.

When retroviruses enter and infect a cell, a so-called “envelope protein” on the virus binds to a receptor on the host cell’s surface, like a key fitting into a lock. If retroviruses infect germ cells – such as sperm and egg cells – then these viral DNA sequences can be passed from one generation to the next, potentially becoming permanently incorporated into the host genome.

In the current study, the researchers scanned the human genome using computational genomics, recording DNA sequences that potentially code for retroviral envelope proteins with preserved receptor binding abilities. Once identified, the researchers determined which of these genes were “active”, i.e., could express retroviral envelope gene products in particular types of human cells.

Viral protection during embryonic development

With the identification of candidate antiviral envelope proteins completed, the researchers narrowed their focus down to a single protein in this list called Suppressyn. This protein is known to bind to a receptor called ASCT2, which itself is linked to permitting a group of viruses called type D retroviruses to enter host cells.

Interestingly, the researchers found that Suppressyn is highly expressed in tissues associated with early human embryonic development such as the placenta, a common target for viruses. “We found clear evidence of expression, and many of them are expressed in the early embryo and in germ cells, and a subset are expressed in immune cells upon infection,” explained Cedric Feschotte, professor of molecular biology and genetics at Cornell University and senior author of the study.

Running experiments using a variety of lab-cultured human cells, the researchers exposed cells to a type D retrovirus called RD114. They found that placental-like cells and embryonic stem cells were not readily infected by RD114, whereas the other cell types were.

Furthermore, depleting Suppressyn levels in these placental-like cells made them vulnerable to RD114 infection, and reintroducing Suppressyn brought back their resistance to the virus. When the researchers introduced Suppressyn to embryonic kidney cells that are usually vulnerable to RD114, they too gained resistance, highlighting the key role of Suppressyn in viral immunity.

Uncovering a retroviral defense system

These findings demonstrate how this human protein of retroviral origin blocks a receptor that allows infection of host cells by a broad range of retroviruses, suggesting the presence of a potentially extensive and uncharacterized defense system. Feschotte goes on to describe that, in this way, ancient retroviruses in the human genome can assist in protecting embryos against infection by related viruses.

Despite this study being performed in lab-cultured human cells (in vitro), these findings provide proof-of-principle that these effects could also occur in humans. Feschotte explains that the next steps for this study will include the exploration of other envelope-derived proteins found in the human genome.

Reference: Frank JA, Singh M, Cullen HB, et al. Evolution and antiviral activity of a human protein of retroviral origin. Science. 2022;378(6618):422-428. doi: 10.1126/science.abq7871

This article is a rework of a press release issued by Cornell University. Material has been edited for length and content.