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  • Alex Cloherty

How do viruses develop resistance?

This post is in answer to a question posed by my good friend Jesse. Most people have heard about antibiotic resistance in bacteria, but we don't hear as much about viruses developing resistance. Jesse asked about how viruses develop resistance, and what is being done to address this problem.

I'd like to start by mentioning that antiviral resistance is a somewhat different problem than antibacterial resistance, at least on a social level. In the case of bacteria, a lot of the problem with resistance is due to a massive over-use of antibiotics – in medicine, but especially in agriculture. The deadly problem of antibacterial resistance is much more due to human overuse of antibiotics than the analogous problem of antiviral resistance. That being said, the basic principle behind bacterial and viral resistance is the same: microbes evolve, resulting in resistant bugs.

On Microbial Mondays, we've already discussed a little about virus evolution as it applies to the flu vaccine, so today we're going to switch things up and use HIV as our model organism. In the case of HIV, evolution happens very quickly. This is because of an enzyme that is unique to this virus, called reverse transcriptase. To understand why reverse transcriptase is so special, we'll have to back up a step to understand why HIV itself is a pretty weird virus.

As you might remember from a previous Microbial Mondays post, not all viruses DNA for their genetic code. This is weird if you compare this to us humans and all other known animals, plants, and bacteria: we use DNA for our "book of life". Contrastingly, some viruses use RNA, a related molecule that is used in animals (including humans) as an intermediate between DNA and the protein-machines that power life. Most of these "RNA viruses" never make any DNA at all, going directly from RNA to protein in the usual fashion of living organisms. HIV, however, is different.

Using its reverse transcriptase enzyme, HIV is able to make DNA out of its RNA. The discovery of reverse transcriptase was pretty astonishing to biologists. Before this enzyme was found, it was pretty radical, something like running about wearing a tin foil hat, to suggest that information could flow in the "reverse" direction from RNA to DNA. But, this is just what HIV does.

This ability of HIV to make its RNA into DNA is at the root of both why it is so difficult to cure. When a person is newly infected with HIV, the first thing the virus will do is get into its first target cell. There, the virus will do two things. Like all viruses, the HIV will make many more copies of itself, so that the resultant baby viruses can go on and infect many more cells. Unfortunately for us, HIV also does something else even more insidious. Using reverse transcriptase, it turns its RNA genome into DNA, and then glues this DNA version into our human DNA. In a way, the virus then becomes a part of us, blending in with our own genes. From this point on, the virus is made by our cells as if it were always a part of us. In other words, baby viruses are made in the same way that new human proteins are made. This means that to cure HIV, all of the HIV DNA that is embedded within our own human cells would have to be removed, which is a problem akin to removing 100 needles in a haystack without damaging a single strand of hay.

Reverse transcriptase also plays a role in the evolution of HIV and its "escape" from antiviral medicines. When the reverse transcriptase enzyme makes DNA, it makes a lot of mistakes. You can think of reverse transcriptase like a typewriter inside the virus, which has to churn out millions of copies of its RNA, its "book of life", in a short amount of time. Reverse transcriptase functions like a writer fanatically punching the keyboard of a typewriter; mistakes are bound to happen. Also analogous to a typewriter, there's no simple delete button for reverse transcriptase. Some mistakes can be found and fixed with the virus' version of correction fluid, but many errors go unnoticed.

These mistakes in the viral DNA are the basis of HIV evolution. Remember, after the HIV DNA is made, information flows in the "normal" way: from DNA to RNA to protein. That means that changes in the DNA of HIV will eventually lead to changes in the proteins of HIV – and proteins are the machines which do all the work that makes the virus a virus. These all-important viral proteins are also the targets of antiviral drugs. This is a good thing, because if an antiviral medication can target and mess with a key viral protein machine, the virus won't be able to do its virus thing anymore. But, there is also a dark side: if viral proteins change, because viral DNA has changed, antiviral medications may no longer be able to find and mess with the proteins anymore.

Now that we've laid out the problem, how about the solution? To understand how we address HIV resistance, we need to zoom out and think on the population level of viruses. Remember, in an infected person, there isn't just one virus meandering about. There is a whole population of viruses, which as much (or even more!) variation as a human population in a large and diverse country. When the DNA of one virus changes because of a reverse transcriptase typewriter-style error, that will only change the DNA of that first virus and its offspring. Other "families", known as strains, of viruses may not change in any significant way, and yet other strains might end up with a typo in a different part of the HIV book of life. This variation between strains means that not all of the individual viruses within one infected human will be resistant to the same drugs. Currently, the best way we can fight the problem of resistance is to take this variation into account, and try to out-smart viral evolution.

In most countries, it is now common practice to treat HIV-infected patients with a variety of different antiviral drugs, which each target different proteins in the virus. Usually, doctors will also do some tests to try to find out if the virus strains infecting their patient are already resistant to the standard drugs - in the same way that doctors will test infectious bacteria for resistance to make sure they give you the right antibiotic. From there, a selection of different antiviral drugs will be chosen for the patient to take at the same time, so that many different proteins of HIV are targeted. It's very unlikely that the collective virus strains will be able to survive all of the drugs simultaneously. You can think of this like a search for a criminal at large in London. If we only search for the criminal on foot (i.e. with one drug), he or she could also get away by bus, metro, boat, helicopter… You get the idea. It's much better to cover all possible routes of escape at the same time (i.e. with multiple drugs), in order to force the criminal either into hiding or into our waiting handcuffs.

In an HIV-infected patient, the virus meets different fates simultaneously: HIV goes into hiding, and also gets caught. With good drug treatment, almost all of the viruses are destroyed, sometimes so well that the HIV-infected patient isn't even contagious anymore. But at the same time, the virus is still in hiding. As we discussed above, the HIV's DNA is still imbedded within the cells of the patient, mixed in with the human DNA. This is why it is so important for HIV-positive patients to continue taking their drugs, even if they aren't infectious anymore. Because the "criminal" DNA of the HIV is still in hiding, as soon as the "police force" of antiviral drugs retires, the virus can come out to wreak havoc once more. What's more, if you take antivirals at first, and then stop before your prescription is up (or, in the case of a lifelong infection like HIV, if you ever stop), you encourage only the nastiest strains, or the craftiest criminals, to stick around in your system.

In a Darwinist manner, only the viruses that are strongest, or most resistant, will survive the first batch of antiviral drugs, meaning that they will be the ones to contribute most to the overall population of viruses around after a prematurely terminated medication bout. In simpler words, if an HIV-infected patient stops taking their antiviral meds, they are allowing the most dangerous strains of HIV to flourish inside their own body, and maybe go on to infect others. The same is true if you stop taking your antibiotics before your prescription is up: you encourage the nastiest, most drug-resistant strains of bacteria to flourish.

That's all for this week. Until next time – now you know why you should take your prescribed antimicrobials to the end of the prescription! No drug resistance for us, no siree.

- Alex

PS. For further reading on HIV antiretroviral resistance, you can check out this review paper.

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