By Belinda Smith
Australian doctors recently added another drug to their repertoire of Covid-19 treatments - one that stimulates the body's immune system to intercept and destroy the virus.
The drug, called sotrovimab, is an addition to a handful of green-lit treatments, most of which help calm inflammation caused by the immune system's overreaction to the virus.
But only one approved drug, remdesivir, interrupts a virus's rampage within our cells, where millions of copies of the virus are made and sent out to infect more cells - and people.
So why is it so hard to break the lifecycle of viruses such as SARS-CoV-2, which causes Covid-19 disease?
In a way, Covid-19 is a disease of two stages, says Raymond Schinazi, who develops antiviral drugs at Emory University.
During the first stage of the disease, the virus makes copies of itself in your body, often without producing symptoms.
In the second, your body's immune system kicks in. For some people, this progresses to severe disease as their immune system attacks organs and causes inflammation.
The idea of treating the early stage of the infection with antivirals is to stop people from progressing to the point where severe disease sets in.
But remdesivir, the only direct-acting antiviral approved for use in Covid-19 in Australia, isn't spectacular, says Sharon Lewin, an infectious disease researcher and director of the Doherty Institute.
"It gives you a little bit of time, it reduces your time in hospital and may potentially have a small mortality benefit, but it's not dramatic."
Viruses are, at their most basic, a bunch of genetic instructions encased in a protein shell.
There are variations. Some have extra layers, like a membrane around their shell. There are a couple of types of genetic code they can use, too. Some have DNA like us, and others use a similar molecule called RNA.
But unlike bacteria, which can survive and reproduce outside our body, viruses need a host - they're not free-living organisms, says Greg Moseley, a molecular virologist at Monash University.
This means a virus can't make more copies of itself, or replicate, on its own. To do that, it must infect and commandeer a host cell.
Think of a cell as a miniature factory, with different biological machines making different cell components.
When a virus gets in there, it takes over, hijacking the cell's biological machinery, which reads the virus's genetic instructions and churns out components for the virus instead.
The virus bits are assembled into new viruses, which depart the cell, destroying it on their way out.
The fact that viruses use our cells to replicate means "it can actually be quite difficult, in many cases, to make a drug that will target a virus without at the same time affecting the normal biology of our cells," Dr Moseley says.
And until 70 years ago, few thought it possible.
It starts with herpes...
One of the first to dabble in antivirals was William Prusoff, an American pharmacologist who, in the 1950s, looked for ways to disrupt the herpes simplex virus lifecycle.
A crucial aspect of the replication cycle of any virus is making copies of its own genetic material out of genetic building blocks, which are then packaged up in the protective protein shell.
So Professor Prusoff synthesised a drug that mimicked one of those genetic building blocks, but had a slightly different structure.
When the fake building block was incorporated into the virus genome-building process, it stopped another building block from joining to it, bringing the operation - and viral replication - to a halt.
It turned out to be an effective treatment for herpes keratitis, or herpes of the eye, and laid the groundwork for another American pharmacologist, Gertrude Elion, to develop the first successful antiviral drug, acyclovir.
It's the active ingredient in cold sore creams you can buy in pharmacies.
Such almost-the-same-but-not-quite genetic building blocks, called nucleoside and nucleotide analogs, are behind many other antiviral drugs used today, including remdesivir.
But it was the human immunodeficiency virus or HIV epidemic of the 1980s where antiviral development really took off.
'Great success story' of HIV
HIV is a retrovirus - its genetic material is RNA, and when it infects a cell, it makes a DNA copy of its genome.
That DNA copy is then slipped into the DNA of the host cell where it can lay dormant until it's activated, forcing the cell to start churning out the virus.
To make that DNA copy, HIV needs a biological machine called reverse transcriptase. Throw a spanner in reverse transcriptase's works, and you can slow or stop the HIV virus in its tracks.
That's what the first HIV drug treatment, azidothymidine or AZT, did. It was a nucleoside analog; a fake building block that works in a similar way to those first herpes drugs.
It came with side effects, though, and the virus could quickly mutate and become resistant.
More classes of antiretroviral drug followed. Some were tiny molecules that literally wedged themselves into reverse transcriptase to stop it working, like a paper jam in a photocopier.
Others prevented another enzyme called protease from making the virus shell.
Yet another targeted integrase, an enzyme that, as its name suggests, integrates the DNA copy of the virus genome into the cell's DNA.
The real game-changer was combination therapy, Professor Lewin says.
And where people with HIV once had to take handfuls of tablets every day, treatment today consists of one tablet, taken daily, which keeps a lid on the infection, should the virus awaken from its latent stage.
"It really was the great success story of the last century," Professor Lewin says.
Antivirals can prevent HIV infection, too. One of the two antivirals in the widely used pre-exposure prophylaxis drug Truvada was developed by Professor Schinazi's team.
Hit hard and hit quickly
For an antiviral to be effective, it not only has to target a virus while leaving healthy cells alone, but it must also be very potent, capable of quickly knocking out pretty much an entire viral infection.
That's because viruses replicate in enormous numbers, sometimes churning out millions of new viruses in a matter of hours.
Some, such as RNA viruses, don't have any genetic "proofreading", which means their genetic code can change or mutate very quickly, Dr Moseley says.
Many viruses are good at hiding from the body's immune system too.
Dr Moseley's lab is investigating how viruses modify their host cell to become efficient virus factories, and the tricks viruses use to shut down the host cell's immune defences so they can better replicate and spread.
Then there are the genome lurkers; retroviruses such as HIV and herpes simplex virus that hide in our DNA.
Drugs can't yet scrub HIV DNA out of our own, but Professor Lewin's lab at the Doherty Institute is looking for a cure - to "wake up" the virus from its latent stage and get rid of it for good.
The one big disease that can be cured with direct-acting antivirals is hepatitis C.
Like HIV, it was discovered in the 1980s, but it has no latent form.
Professor Schinazi and his fellow researchers developed treatments which have a near 100 per cent cure rate.
"So there, we're actually clearing the liver of virus, completely clearing it," Professor Schinazi said.
"And basically … the virus is completely eradicated."
So what does this mean for COVID-19?
SARS-CoV-2 doesn't have anywhere to hide either. It doesn't integrate its genetic code into ours.
But when it comes to emerging viruses, the fastest way to find effective treatments is to repurpose drugs already tried and tested for other diseases.
This isn't necessarily a speedy process, but it's faster than designing drugs from scratch.
"You can cut out a significant amount of the research and development and go relatively rapidly into trials for efficacy and safety," Dr Moseley says.
"[To repurpose an antiviral] can still take a couple of years at least.
"So it's not rapid, but it's rapid compared with the full drug development pipeline."
For example, remdesivir was originally developed for hepatitis C, then used in Ebola.
But it has a major drawback. A course of remdesivir typically involves daily intravenous injections over a week or more, Professor Schinazi says.
An ideal Covid-19 antiviral would be one that's cheap and easy to make, and given as a tablet to anyone as soon as they tested positive or became symptomatic, so it can crush the virus before it has a chance to kick off an immune overreaction.
Professor Schinazi's lab at Emory is still investigating new, better antivirals to treat diseases such as HIV, but he's also turned attention to Covid-19.
"We're making headway, but not as fast as we would like," he says.
"I hope we'll have antivirals soon, in the next year or less.
"And I hope that we will be better prepared for the next pandemic, because we've got to learn a lot from this one."