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Your Immune System Makes Its Own Antiviral Drug − And It's Likely One Of The Most Ancient

Antiviral drugs are generally considered to be a 20th century invention. But recent research has uncovered an unexpected facet to your immune system: It can synthesize its own antiviral molecules in response to viral infections.

My laboratory studies a protein that makes these natural antiviral molecules. Far from a modern human invention, nature evolved cells to make their own "drugs" as the earliest defense against viruses.

How antivirals work

Viruses have no independent life cycle – they are completely dependent on the cells they infect to supply all the chemical building blocks needed to replicate themselves. Once inside a cell, the virus hijacks its machinery and turns it into a factory to make hundreds of new viruses.

Antiviral drugs are molecules that inactivate proteins essential to the functioning of the virus by exploiting the fundamental differences in the way that cells and viruses replicate.

One key difference between cells and most viruses is how they store their genetic information. All cells use DNA to store their genetic information. DNA is a long, chainlike molecule built from four different chemical building blocks, each representing a different "letter" of the genetic code. These building blocks are connected by chemical bonds in a head-to-tail fashion to produce strings of millions of letters. The order of these letters spells out the genetic blueprint for building a new cell.

Many viruses, however, store their genetic information using RNA. RNA is built from a chain of four chemical letters, just like DNA, but the letters have slightly different molecular structures. RNA is single-stranded, while DNA is double-stranded. Viral genomes are also much smaller than cellular genomes, typically only a few thousand letters long.

When a virus replicates, it makes many copies of its RNA genome using a protein called RNA polymerase. The polymerase starts at one end of the existing RNA chain and "reads" the string of chemical letters one at a time, selecting the appropriate building block and adding it to the growing strand of RNA. This process is repeated until the entire sequence of letters has been copied to form a new RNA chain.

One class of antiviral drugs interferes with the RNA copying process in a cunning way. The head-to-tail construction of the RNA chain requires each chemical letter to have two connection points – a head to connect to the previous letter and a tail to allow the following letter to be added on. These antivirals mimic one of the chemical letters but crucially lack the tail connection point. If the RNA polymerase mistakes the drug for the intended chemical letter and adds it to the growing RNA chain, the copying process stops because there is nothing to attach the next letter to. For this reason, this type of antiviral drug is called a chain-terminating inhibitor.

Viperin as antiviral producer

Previously, researchers thought that chain-terminating antiviral drugs were strictly a product of human ingenuity, developed from advances in scientific understanding of viral replication. However, the discovery that a protein in your cells named viperin synthesizes a natural chain-terminating antiviral has revealed a new side of your immune system.

Viperin works by chemically removing the tail connection point from one of the four RNA building blocks of a virus's genome. This converts the building block into a chain-terminating antiviral drug.

This strategy has proved to be highly effective for treating viral infections. For example, the COVID-19 antiviral remdesivir works in this way. A viral RNA polymerase has to join together many thousands of letters to copy a virus's genome, but an antiviral drug has to fool it only once to derail its copying. An incomplete genome lacks the necessary instructions to make a new virus and becomes useless.

Moreover, although cells also have their own polymerases, they never replicate RNA like viruses do. This potentially allows chain-terminating antiviral drugs to selectively inhibit viral replication, reducing unwanted side effects.

Clearly, viperin does not fully protect against all RNA viruses – otherwise no RNA viruses would make you sick. It seems that some viral RNA polymerases, such as those in poliovirus, have evolved to discriminate against the antiviral molecules that viperin synthesizes and blunt their effect. However, viperin is only one arm of your immune system, which includes specialized cells and proteins that protect you from infection in other ways.

Ancient antivirals

Scientists discovered viperin about 20 years ago while searching for genes that turn on in response to viral infections. However, figuring out what viperin actually does proved very challenging.

Viperin's function was particularly puzzling because it resembles an ancient group of proteins called radical SAM enzymes that are usually found in bacteria and molds. Notably, radical SAM enzymes are extremely rare in animals. Exposure to air rapidly inactivates them, and researchers thought they likely didn't work in people. It's still unclear how viperin avoids inactivation.

Researchers were clued in to viperin's function when they noticed that the gene coding for viperin is next to a gene involved in synthesizing one of RNA's building blocks. This observation led them to examine whether viperin might modify this RNA building block.

Following this discovery, researchers identified viperinlike proteins across all kingdoms of life, from ancient bacteria to modern plants and animals. This meant that viperin is a very ancient protein that evolved early in life, probably well before the advent of multicellular organisms – because even bacteria must fight viral infections.

As more complex life forms evolved, viperin was retained and integrated into the complex immune systems of modern animals. Thus, this most recently discovered arm of your immune system's defenses against viruses is likely the most ancient.

This article is republished from The Conversation, a nonprofit news site dedicated to sharing ideas from academic experts. The Conversation is trustworthy news from experts. Try our free newsletters.

It was written by: Neil Marsh, University of Michigan.

Neil Marsh receives funding from the National Institute of General Medical Sciences to support his laboratory's work on viperin.

"Vampire Viruses" Viciously Attack Other Viruses — They May Be The Ultimate Antiviral Treatment

Have you ever wondered whether the virus that gave you a nasty cold can catch one itself? It may comfort you to know that, yes, viruses can actually get sick. Even better, as karmic justice would have it, the culprits turn out to be other viruses.

Viruses can get sick in the sense that their normal function is impaired. When a virus enters a cell, it can either go dormant or start replicating right away. When replicating, the virus essentially commands the molecular factory of the cell to make lots of copies of itself, then breaks out of the cell to set the new copies free.

Sometimes, a virus enters a cell only to find that its new temporary dwelling is already home to another dormant virus. Surprise, surprise. What follows is a battle for control of the cell that can be won by either party.

But sometimes a virus will enter a cell to find a particularly nasty shock: a viral tenant waiting specifically to prey on the incoming virus.

I am a bioinformatician, and my laboratory studies the evolution of viruses. We frequently run into "viruses of viruses," but we recently discovered something new: a virus that latches onto the neck of another virus.

A world of satellites

Biologists have known of the existence of viruses that prey on other viruses — referred to as viral "satellites" — for decades. In 1973, researchers studying bacteriophage P2, a virus that infects the gut bacterium Escherichia coli, found that this infection sometimes led to two different types of viruses emerging from the cell: phage P2 and phage P4.

Bacteriophage P4 is a temperate virus, meaning it can integrate into the chromosome of its host cell and lie dormant. When P2 infects a cell already harboring P4, the latent P4 wakes up and uses the genetic instructions of P2 to make hundreds of its own small viral particles. The unsuspecting P2 is lucky to replicate a few times, if at all. In this case, biologists refer to P2 as a "helper" virus because the satellite P4 needs P2's genetic material to replicate and spread.

Subsequent research has shown that most bacterial species have a diverse set of satellite-helper systems, like that of P4-P2. However, viral satellites are not limited to bacteria. Shortly after the largest known virus, mimivirus, was discovered in 2003, scientists also found its satellite, which they named Sputnik. Plant viral satellites that lurk in plant cells waiting for other viruses are also widespread and can have important effects on crops.

Viral arms race

Although researchers have found satellite-helper viral systems in pretty much every domain of life, their importance to biology remains underappreciated. Most obviously, viral satellites have a direct impact on their "helper" viruses, typically maiming them but sometimes making them more efficient killers. Yet that is probably the least of their contributions to biology.

Satellites and their helpers are also engaged in an endless evolutionary arms race. Satellites evolve new ways to exploit helpers, and helpers evolve countermeasures to block them. Because both sides are viruses, the results of this internecine war necessarily include something of interest to people: antivirals.

Recent work indicates that many antiviral systems thought to have evolved in bacteria, like the CRISPR-Cas9 molecular scissors used in gene editing, may have originated in phages and their satellites. Somewhat ironically, with their high turnover and mutation rates, helper viruses and their satellites turn out to be evolutionary hot spots for antiviral weaponry. Trying to outsmart each other, satellite and helper viruses have come up with an unparalleled array of antiviral systems for researchers to exploit.

MindFlayer and MiniFlayer

Viral satellites have the potential to transform how researchers understand antiviral strategies, but there is still a lot to learn about them. In our recent work, my collaborators and I describe a satellite bacteriophage completely unlike previously known satellites, one that has evolved a unique, spooky lifestyle.

Undergraduate phage hunters at the University of Maryland, Baltimore County, isolated a satellite phage called MiniFlayer from the soil bacterium Streptomyces scabies. MiniFlayer was found in close association with a helper virus called bacteriophage MindFlayer that infects the Streptomyces bacterium. However, further research revealed that MiniFlayer was no ordinary satellite.

MiniFlayer is the first satellite phage known to have lost its ability to lie dormant. Not being able to lie in wait for your helper to enter the cell poses an important challenge to a satellite phage. If you need another virus to replicate, how do you guarantee that it makes it into the cell around the same time you do?

MiniFlayer addressed this challenge with evolutionary aplomb and horror-movie creativity. Instead of lying in wait, MiniFlayer has gone on the offensive. Borrowing from both "Dracula" and "Alien," this satellite phage evolved a short appendage that allows it to latch onto its helper's neck like a vampire. Together, the unwary helper and its passenger travel in search of a new host, where the viral drama will unfold again. We don't yet know how MiniFlayer subdues its helper or whether MindFlayer has evolved countermeasures.

If the recent pandemic has taught us anything, it is that our supply of antivirals is rather limited. Research on the complex, intertwined, and at times predatory nature of viruses and their satellites, like the ability of MiniFlayer to attach to its helper's neck, has the potential to open new avenues for antiviral therapy.

This article was originally published on The Conversation by Ivan Erill at the University of Maryland, Baltimore County. Read the original article here.

Learn Something New Every Day

Vampire Viruses Prey On Other Viruses To Replicate Themselves − And May Hold The Key To New Antiviral Therapies

Viruses can get sick in the sense that their normal function is impaired. When a virus enters a cell, it can either go dormant or start replicating right away. When replicating, the virus essentially commandeers the molecular factory of the cell to make lots of copies of itself, then breaks out of the cell to set the new copies free.

Sometimes a virus enters a cell only to find that its new temporary dwelling is already home to another dormant virus. Surprise, surprise. What follows is a battle for control of the cell that can be won by either party.

But sometimes a virus will enter a cell to find a particularly nasty shock: a viral tenant waiting specifically to prey on the incoming virus.

A world of satellites

Biologists have known of the existence of viruses that prey on other viruses – referred to as viral "satellites" – for decades. In 1973, researchers studying bacteriophage P2, a virus that infects the gut bacterium Escherichia coli, found that this infection sometimes led to two different types of viruses emerging from the cell: phage P2 and phage P4.

Bacteriophage P4 is a temperate virus, meaning it can integrate into the chromosome of its host cell and lie dormant. When P2 infects a cell already harboring P4, the latent P4 quickly wakes up and uses the genetic instructions of P2 to make hundreds of its own small viral particles. The unsuspecting P2 is lucky to replicate a few times, if at all. In this case, biologists refer to P2 as a "helper" virus, because the satellite P4 needs P2's genetic material to replicate and spread.

Subsequent research has shown that most bacterial species have a diverse set of satellite-helper systems, like that of P4-P2. But viral satellites are not limited to bacteria. Shortly after the largest known virus, mimivirus, was discovered in 2003, scientists also found its satellite, which they named Sputnik. Plant viral satellites that lurk in plant cells waiting for other viruses are also widespread and can have important effects on crops.

Viral arms race

Satellites and their helpers are also engaged in an endless evolutionary arms race. Satellites evolve new ways to exploit helpers and helpers evolve countermeasures to block them. Because both sides are viruses, the results of this internecine war necessarily include something of interest to people: antivirals.

MindFlayer and MiniFlayer

Undergraduate phage hunters at the University of Maryland, Baltimore County isolated a satellite phage called MiniFlayer from the soil bacterium Streptomyces scabiei. MiniFlayer was found in close association with a helper virus called bacteriophage MindFlayer that infects the Streptomyces bacterium. But further research revealed that MiniFlayer was no ordinary satellite.

This image shows Streptomyces satellite phage MiniFlayer (purple) attached to the neck of its helper virus, Streptomyces phage MindFlayer (gray). (Credit:Tagide deCarvalho, CC BY-SA)

MiniFlayer addressed this challenge with evolutionary aplomb and horror-movie creativity. Instead of lying in wait, MiniFlayer has gone on the offensive. Borrowing from both "Dracula" and "Alien," this satellite phage evolved a short appendage that allows it to latch onto its helper's neck like a vampire. Together, the unwary helper and its passenger travel in search of a new host, where the viral drama will unfold again. We don't yet know how MiniFlayer subdues its helper, or whether MindFlayer has evolved countermeasures.

If the recent pandemic has taught us anything, it is that our supply of antivirals is rather limited. Research on the complex, intertwined and at times predatory nature of viruses and their satellites, like the ability of MiniFlayer to attach to its helper's neck, has the potential to open new avenues for antiviral therapy.

Ivan Erill is a Professor of Biological Sciences at the University of Maryland, Baltimore County. This article is republished from The Conversation under a Creative Commons license. Read the original article.

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