A group of scientists led by scientists from the University of Utah Health and The Rockefeller University has discovered a genetic mutation found in mice and monkeys that interferes with viruses like HIV and Ebola.
According to the researchers, the discovery could eventually lead to the development of human medical interventions. The gene retroCHMP3 was discovered to be capable of preventing viruses from escaping human cells and infecting others.
“This was an unexpected discovery,” says Nels Elde, Ph.D., senior author of the study and evolutionary geneticist at the University of Utah Health’s Department of Human Genetics. “We were surprised that even a slight slowing of our cell biology throws virus replication off track.”
The retroCHMP3 gene encodes an altered protein that interferes with the ability of certain viruses to exit an infected cell and prevents them from infecting other cells. Normally, viruses encase themselves in cell membranes and then exit the host cell by budding off. RetroCHMP3 postpones that process long enough for the virus to no longer be able to escape.
RetroCHMP3 arose from a duplicated copy of the gene-charged multivesicular body protein 3, or CHMP3. While some animals, such as monkeys, mice, and birds, have retroCHMP3 or other variants, humans only have the original CHMP3. CHMP3 is well known in humans and other creatures for playing an essential role in cellular processes such as cellular membrane integrity, intercellular signaling, and cell division.
Based on this hypothesis, Elde and colleagues began investigating whether retroCHMP3 variants could be used as antivirals. In other laboratory experiments, a shorter, altered version of human CHMP3 successfully prevented HIV from budding off cells. The modified protein, however, also disrupted critical cellular functions, causing the cells to die.
Unlike the other researchers, Elde and his colleagues at the University of Utah Health had access to naturally occurring variants of CHMP3 from other animals. So, in collaboration with researchers Sanford Simon at The Rockefeller University, Phuong Tieu Schmitt and Anthony Schmitt at Pennsylvania State University, and others, they tried a different approach.
The Achilles Heel No More
They coaxed human cells to produce the version of retroCHMP3 found in squirrel monkeys using genetic tools. The cells were then infected with HIV, and the virus had difficulty budding off from the cells, effectively stopping them in their tracks. And this happened without interfering with metabolic signaling or other cellular functions that can lead to cell death.
“We’re excited about the work because we showed some time ago that many different enveloped viruses use this pathway, called the ESCRT pathway, to escape cells,” says Wes Sundquist, Ph.D., a co-corresponding author of the study and chair of the Department of Biochemistry at the University of Utah. “We always thought that this might be a point at which cells could defend themselves against such viruses, but we didn’t see how that could happen without interfering with other very important cellular functions.”
Elde believes that this represents a new type of immunity that can emerge quickly to protect against short-lived threats from an evolutionary standpoint.
“We thought the ESCRT pathway was an Achilles heel that viruses like HIV and Ebola could always exploit as they bud off and infect new cells,” Elde says. “RetroCHMP3 flipped the script, making the viruses vulnerable. Moving forward, we hope to learn from this lesson and use it to counter viral diseases.”
That lesson, in particular, “raises the possibility that an intervention that slows down the process may be insignificant for the host, but provide us with a new anti-retroviral,” according to Sanford Simon, Ph.D, a study co-author and professor of Cellular Biophysics at The Rockefeller University.
The study, “RetroCHMP3 Blocks Budding of Enveloped Viruses Without Blocking Cytokinesis,” will be published in Cell on October 14, 2021. The National Institutes of Health, the United States Department of Agriculture, the Burroughs Wellcome Fund, and a Pew Charitable Trusts Innovation Fund Award helped fund this study.
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