Gene Variant Found in Animals Could Help Develop New Antivirals

Gene Variant Found in Animals Could Help Develop New Antivirals
life cycle of influenza virus. Vector scheme

A gene mutation, seen naturally in both mice and monkeys, which blocks a virus’s ability to enter cells could be the answer to developing new antiviral therapies for infections such as Ebola and HIV in the future, according to new research.

The CHMP3 gene encodes a protein involved in the endosomal sorting complex required for transport (ESCRT) system, which is responsible for helping to move different proteins and cellular components around and between cells. Some viruses such as HIV, Ebola, and a number of enveloped viruses, exploit this system and use it to enter cells and transport viral material around the body.

Researchers based at the University of Utah and Rockefeller University have discovered a gene duplication of the CHMP3 gene, which they call RetroCHMP3, that has independently arisen in both mice and New World monkeys. This mutation seems to change the function of the gene and allows it to block ESCRT-dependent viral budding and therefore stop the infection process.

“This was an unexpected discovery,” says Nels Elde, senior author of the Cell study describing the work and an evolutionary geneticist in the Department of Human Genetics at University of Utah Health, in a press statement. “We were surprised that slowing down our cell biology just a little bit throws virus replication off its game.”

To try and assess if this mutation could help develop new antivirals for viruses that use this pathway to infect humans, the researchers expressed the mutation in a human cell line. When they infected the cell line with HIV, the virus seemed to be unable to spread from cell to cell as it would normally.

Importantly, this mutation does not seem to disrupt metabolic cell signalling or other cellular functions linked to ESCRT that could make the cells vulnerable to early death.

“We’re excited about the work because we showed some time ago that many different enveloped viruses use this pathway… to escape cells,” says Wes Sundquist, 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.”

In earlier studies in human cell lines that were also assessing if mutant CHMP3 could help block these viruses from spreading, the technique stopped viral spread but led to early cell death. The researchers in this study think that the similarity of their induced mutation to the one found naturally in squirrel monkeys may be why their cell line thrived, despite the presence of mutant CHMP3.

“Remarkably, retroCHMP3 proteins have evolved to reduce interactions with other ESCRT-III factors and have little effect on cellular ESCRT processes, revealing routes for decoupling cellular ESCRT functions from viral exploitation,” writes the team.

The researchers think the RetroCHMP3 mutation could be a type of evolved immunity that the animals have developed to help protect themselves against retroviruses, paramyxoviruses, and filoviruses.

“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.”