Ancient viral DNA in human genome guards against infections

 

According to new research, viral DNA embedded in human genomes from previous infections acts as antivirals that shield human cells from certain viruses today. 

This effect is demonstrated in principle in the Science paper "Evolution and Antiviral Activity of a Human Protein of Retro-viral Origin," which was published on October 28.

Endogenous retroviruses, which are fragments of ancient viral DNA found in the genomes of mice, chickens, cats, and sheep, have previously been shown to provide immunity against modern viruses that originate outside the body by preventing them from entering host cells. Even though human cells in culture were used in this lab study, it suggests that endogenous retroviruses may also have an antiviral effect on humans.  

The study is significant because additional research may uncover a pool of naturally occurring antiviral proteins that could lead to treatments that do not have autoimmune side effects. The research reveals the possibility of a genome defense system that has yet to be identified but could be quite extensive

Cedric Feschotte, a professor of molecular biology and genetics in the College of Agriculture and Life Sciences, stated, "The results show that we have a reservoir of proteins that have the potential to block a broad range of viruses". These proteins can be found in the human genome. The study's first author is John Frank, 20, a former graduate student in Feschotte's lab who is now a postdoctoral researcher at Yale University.

Endogenous retroviruses represent around 8% of the human genome—no less than multiple times how much DNA makes up the qualities that code for proteins. The RNA that retroviruses inject into a host cell is transformed into DNA and integrated into the host's genome. Following the genetic instructions, the cell produces more virus

To replicate itself, the virus takes over the transcriptional machinery of the cell. Although some retro-viruses infect germ cells, such as an egg or sperm, which allows retro-viral DNA to pass from parent to offspring and eventually become permanent fixtures in the host genome, the majority of retroviruses infect cells that do not pass from one generation to the next.  

A viral envelope protein, similar to a key in a lock, binds to a receptor on the cell's surface in order for retroviruses to enter the cell. For some viruses, like SARS-CoV-2, the envelope also serves as a spike protein. 

Computational genomics was used by Frank, Feschotte, and colleagues to search the human genome for any retro-viral envelope protein-coding sequences that might have retained receptor binding activity. They then carried out additional tests to determine which of these genes were active—that is, expressing products of the retro-viral envelope gene in particular human cell types.   

Feschotte stated, "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," and "we found clear evidence of expression." 

Suppresses, one of the antiviral envelope proteins known to bind a receptor called ASCT2, the cellular entry point for a diverse group of viruses known as Type D retroviruses, was chosen as the focus of the study after the researchers had identified antiviral envelope proteins expressed in various contexts. Suppresses was expressed extensively throughout human embryonic development and the placenta 

Because the placenta is a frequent target for viruses, they then conducted experiments in cells that resemble human placentas. 

The cells were exposed to RD114, a type D retrovirus that is known to naturally infect domestic cats and other feline species. Placental and embryonic stem cells were not infected, in contrast to other human cell types that do not express Suppresses. Suppresses were experimentally removed from placental cells, making them susceptible to RD114 infection.  Resistance were restored when Suppresses was reintroduced into the cells. 

Reverse experiments were also carried out by the researchers with an embryonic kidney cell line that is normally susceptible to RD114. When Suppresses was experimentally introduced into these cells, the cells developed resistance

The study demonstrates how a retro-viral derived human protein inhibits a cell receptor that facilitates the entry and infection of numerous nonhuman retroviruses. According to Feschotte, this is how ancient retroviruses incorporated into the human genome serve as a safeguard against related viruses infecting the developing embryo.  

He stated that additional envelope-derived, human genome-encoded antiviral proteins will be investigated in future research. 

Carolyn, a virologist at the School of Medicine at Duke University, and Jose Garcia-Perez, a molecular biologist at the University of Granada in Spain, are co-authors.  

Cornell University, the National Institutes of Health, the Welcome Trust-University of Edinburgh Institutional Strategic Support Fund, the European Research Council, and the Howard Hughes Medical Institute contributed funding to the study