Antibodies that keep ancient viral DNA in check may inform new treatments

After viruses infected our evolutionary ancestors, bits of viral DNA lodged themselves into their genomes - and we still carry around genetic remnants of those viruses now. Known as endogenous retroviruses, these pieces of ancient invaders aren't able to produce infectious viruses in humans, but they can in mice if not kept in check.

Yale researchers have now uncovered the immune cells in mice that keep these endogenous retroviruses from being reactivated, and it turns out these cells can recognize all sorts of harmful viruses.

The findings, published Nov. 8 in the journal Science Immunology, expand scientists' understanding of mammalian immunity and may lead to a sort of broad-spectrum virus treatment in the future, the researchers say.

From previous research, scientists knew that immune cells called B cells played a role in keeping endogenous retroviruses inactive in mice, having observed that the retroviruses were able to yield infectious particles in mice without B cells. But which B cells were responsible - as there are several types - remained unclear.

"We wanted to identify the B cells that bind to the surface of these endogenous retroviruses," said Akiko Iwasaki, Sterling Professor of Immunobiology at Yale School of Medicine and senior author of the study. "So we used an approach wherein we bait the B cells."

To do this, the researchers made viral-like particles that had the shell of a virus but none of the genetic material, rendering them harmless. In some of the empty shells, the researchers inserted envelope proteins, which make up the outer layer of endogenous retrovirus particles. Other empty shells had all of the other proteins and lipids found on the surface of these cell types, but no envelope protein.

"We then introduced B cells to these shells as baits and looked for the ones that bound only to the envelope proteins, sorting out the cells that bound to other proteins and lipids," said Iwasaki. "We found that they were not the conventional B cells most immunologists study. The ones binding to the envelope protein were B-1 cells, which are more ancient immune cells that all of us make and are considered 'innate-like' in that they have characteristics of both innate and adaptative immunity. B-1 cells produce so-called natural antibodies of the IgM type."

Iwasaki is also a professor of dermatology and of molecular, cellular, and developmental biology in Yale's Faculty of Arts and Sciences, a professor of epidemiology at Yale School of Public Health, and an investigator of the Howard Hughes Medical Institute.

The researchers then found that the B-1 cells were binding to sugar chains attached to the envelope protein, sugar molecules that were much less complex than those found on healthy cells in mammals.

"These viral envelopes, for some reason, express this form of immature terminal sugar molecule that looks very different from our healthy cells," said Iwasaki. "And that's what these B-1 cells are recognizing."

Curious as to whether envelopes of other viruses would be similarly recognized by B-1 cells, the researchers tested several, including those of SARS-CoV-2 (the virus that causes COVID-19), influenza A virus, and HIV.

"Pretty much all of the envelope viruses we tested were detected by the natural antibodies made by B-1 cells through terminal sugar molecules," said Iwasaki. "We believe this is a fundamental mechanism of how innate-like B cells recognize envelope viruses."

With their broad range of viral recognition, these cells may represent a useful tool for combating viruses, she said. For instance, antibodies developed to mimic those produced by B-1 cells and their ability to recognize many types of viruses may be particularly helpful during outbreaks of novel viruses for which people do not yet have treatments or immune defenses.

Iwasaki's lab is also studying human versions of these cells.

"It turns out humans have similar innate-like B cells that bind to surface sugars of viruses," said Iwasaki. "So we're looking into them to learn more about the specificity of these cells."

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