Sun. Dec 5th, 2021

In this interview, we spoke with Dr. Nels Elde about his latest research that led to the discovery of a new gene in monkeys that could help develop new antiviral drugs.

What provoked your recent research into antiviral drugs?

We were curious as to whether a cellular process exploited by viruses, including HIV, could somehow develop resistance despite high levels of genetic preservation.

There is a constant need for new antiviral drugs to treat various viruses, including HIV and Ebola. Why is it often difficult to detect and develop new antiviral drugs?

Many antiviral agents target specific virus features or functions, and viruses can quickly develop resistance with simple amino acid substitutions. Here we looked at how hosts can change from a genetic point of view. This solves a challenge, and we believe that evolution could have solved the second challenge of cell toxicity with trial and error of mutation and selection over millions of years.

Antiviral concept

Image Credit: O-IAHI / Shutterstock.com

The charged multivesicular body protein 3 (CHMP3) is a human gene involved in cellular processes. How did CHMP3 duplicate to ‘retroCHMP3’, and what’s the role of retroCHMP3 in virology?

There is a wild natural history here where an old retrotransposon, an “selfish” genetic element, made a mistake while replicating himself in the ancestors of apes from the new world. Instead, it copied the gene encoding CHMP3, and this copy diverged to what we discovered and called retroCHMP3 in modern squirrel monkeys.

RetroCHMP3 seems to delay some important cellular processes a bit, and this seems catastrophic for encapsulated viruses like HIV and Ebola that need this process to complete virus replication cycles.

Can you describe how you conducted your latest research on retroCHMP3 as an antiviral agent?

We just started by comparing genes like CHMP3 in many genomes of primates and rodents. The surprise was extra copies of CHMP3 in some genomes, but not others. This fueled our curiosity.

What did you discover?

Some of these extra copies, which we called retroCHMP3, had features that are consistent with being antiviral. The coding region of the gene was shortened with a premature stop codon. This results in a protein with robust activity that blocks virus release from infected cells.

Egernabe

Image credit: Artem Verkhoglyad / Shutterstock.com

In previous research, the modified protein also disrupted important cellular functions, but in your new research, this did not happen. Why was this?

Twist were additional point mutations in the gene that allow cells to tolerate retroCHMP3 without killing them or causing overt toxicity.

How could your research help develop new antiviral drugs for humans?

This provides a roadmap for a new approach to antiviral drugs. Modify cell biology a little bit in ways that are destructive to virus replication.

RetroCHMP3 itself may be productively developed as an antiviral agent used genetically as part of future interventions that carry out somatic mutations and / or additions as part of autologous stem cell therapies.

The ongoing COVID-19 pandemic has shown us that when we work together, scientific progress can be made fairly quickly. How could this level of collaboration be applied to antiviral drugs and their development?

Accelerated traces are very possible as shown with the groundbreaking mRNA-based vaccines developed for SARS-CoV-2 in the last year. In these cases, it could be a matter of turning points where pandemics disrupt our lives in ways that shake everyone’s attention and break down traditional barriers to progress.

Similarly, for antiviral drugs, we may be on the verge of several new interventions such as Merck’s new molnupiravir. I hope the pipeline fills up quickly because cocktail approaches may be needed to avoid the rapid development of resistant SARS2.

What are the next steps for you and your research?

We are back to the starting line and across the map, chasing our curiosity about evolution at host-virus interfaces.

Where can readers find more information?

About doctor Nels Elde

Nels Elde is an evolutionary geneticist in the Department of Human Genetics and an investigator at the Howard Hughes Medical Institute at the University of Utah. He studies how interactions between infectious microbes and their hosts result in evolutionary conflicts similar to arms races.Dr.  Nels El

The work reveals the far-reaching effect of viruses on the development of essential host cell processes. Nels co-hosts the science podcast This week in evolution (https://www.microbe.tv/twievo/). He was the recipient of a John D. and Catherine T. MacArthur Foundation scholarship in 2020.

.

Leave a Reply

Your email address will not be published. Required fields are marked *