[ad_1]
Sep 30, 2021 10:00 AM
A national team of researchers, led by scientists from the University of Utah Health and Rockefeller University, determined how a genetic mutation found in mice and monkeys interferes with viruses such as HIV and Ebola. They say the discovery could eventually lead to the development of medical interventions in humans
The gene, called retroCHMP3, encodes an altered protein that disrupts the ability of certain viruses to exit an infected cell and prevent it from infecting other cells.
Normally, some viruses lock themselves up in cell membranes and then sprout out of the host cell. RetroCHMP3 delays this process long enough that the virus cannot escape.
“It was an unexpected discovery,” says Nels Elde, Ph.D., lead author of the study and evolutionary geneticist in the Department of Human Genetics at the U of U Health. “We were surprised to find that slowing down our cell biology a bit disrupts the replication of the virus. “
The study appears online September 30 ahead of the October 14 issue of Cell.
RetroCHMP3 is originally a duplicated copy of a gene called charged multivesicular body protein 3, or CHMP3. While some monkeys, mice, and other animals have retroCHMP3 or other variants, humans only have the original CHMP3.
In humans and other creatures, CHMP3 is well known to play a key role in cellular processes essential for maintaining cell membrane integrity, intercellular signaling, and cell division.
HIV and some other viruses hijack this route out of the cell membrane and infect other cells. Based on their research, Elde and his colleagues suspected that the CHMP3 duplications they discovered in primates and mice prevented this from happening as protection against viruses like HIV and other viral diseases.
Building on this notion, Elde and other scientists began to explore whether variants of retroCHMP3 might function as an antiviral. In lab experiments conducted elsewhere, a shorter, modified version of human CHMP3 was successful in preventing HIV from budding cells. But there was a problem: the modified protein also disrupted important cell functions, causing cells to die.
Unlike other researchers, Elde and her colleagues at U of U Health had naturally occurring CHMP3 variants from other animals. So, in collaboration with researchers Sanford Simon from Rockefeller University, as well as Phuong Tieu Schmitt and Anthony Schmitt from Pennsylvania State University, they tried a different approach.
Using genetic tools, they coaxed human cells to produce the version of retroCHMP3 found in squirrel monkeys. Then they infected the cells with HIV and found that the virus was having trouble getting out of the cells, essentially stopping them in their tracks. And this happened without disrupting metabolic signaling or associated cell 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., co-author of the ‘study. and Chairman 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 this could happen without interfering with other very important cellular functions.”
From an evolutionary standpoint, Eldus believes this is a new type of immunity that can arise quickly to protect against short-lived threats.
“We thought the ESCRT pathway was an Achilles heel that viruses like HIV and Ebola could still exploit when they sprout and infect new cells,” Elde explains. “RetroCHMP3 reversed the script, making viruses vulnerable. In the future, we hope to learn from this lesson and use it to fight viral diseases. “
Specifically, this lesson “raises the possibility that an intervention that slows down the process may be of no consequence to the host, but provide us with a new antiretroviral,” says Sanford Simon, Ph.D, co-author of the study and a professor of cell biophysics at Rockefeller University.
####
In addition to Drs. Elde and Sundquist, Lara Rheinemann, University of Utah and University of Utah scientists, Diane Miller Downhour, Gaelle Mercenne, Kristen Davenport, Christina Necessary, and John McCullough contributed to this study.
The study, “RetroCHMP3 blocks the budding of enveloped viruses without blocking cytokinesis”, appears in the October 14, 2021 issue of Cell. This research was supported by the National Institutes of Health, the United States Department of Agriculture, the Burroughs Wellcome Fund, and a Pew Charitable Trusts Innovation Fund Award.
Research News Human Genetics Infectious Diseases HIV Ebola
[ad_2]
Source link