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  • Alex Cloherty

"Either/Or" or "Yes, and"? Virulence, Transmission, and Improv

Maybe you’ve heard already, but there was big news this week in the world of HIV research. There has been a lot of coverage on a paper in the highly respected scientific journal Science (the name says it all, doesn’t it?) - over 200 news articles since its release a few days ago on February 3rd, according to lead author Chris Wymant. Since there's already a host of stories out there, what I wanted to do here is pick out one major storyline that I found especially interesting of the story about the newly discovered “highly virulent variant of HIV-1 circulating in the Netherlands”. That of the relationship between virulence and transmission.

First of all, to understand why this paper or that storyline is of any interest in the first place, it helps to understand what virulence means. It’s a tricky word that has been thrown around a lot – and not always used correctly – over the course of the COVID-19 pandemic. I like the simple way that lead author Chris Wymant explained it in a seminar that I attended today. “Virulence is, to what extent the virus is burdening the host?” In other words, virulence refers to how sick (or dead) do people become when they catch a virus.

Oftentimes people mix up the concepts of virulence and transmissibility, which is understandable seeing as they are closely linked in a biological sense. While virulence refers to how sick the bug makes you, transmissibility is all about how easily the virus will spread. If one person infected with virus A will infect ten other people with virus A, but one person infected with virus B will infect one hundred others with virus B, virus B is more transmissible than virus A.

If you think about, for example, Ebolavirus versus the Omicron variant of SARS-CoV-2, some relation between virulence and transmissibility becomes clear. Ebola is very scary mostly because it is so deadly. Depending on the particular strain of the Ebola virus, it can have a mortality of between 40% and 90%. In other words, if ten people are infected with Ebola virus in an outbreak, at least four of them will probably die. However, the transmissibility of Ebola virus is relatively low, probably mainly because relatively intimate contact is required for one person to infect another. The virus can only jump to a new ‘host’ if it is directly introduced into the bloodstream, for instance by a cut or a needle poke, or onto so-called ‘mucosal’ surfaces like the gut, for instance by eating infected meat. Ebola, therefore, can be considered to have a relatively high virulence, but low transmissibility.

Omicron, on the other hand, is a different story. The high rate of asymptomatic Omicron cases (as suggested by early data out of South Africa) and the fact that this latest SARS-CoV-2 variant of concern rapidly spread across the entire globe respectively attest to its relatively low virulence and high transmissibility, at least as compared to Ebolavirus.

Ok, so virulence and transmissibility can be linked. But what does that have to do with this new story on an HIV strain in the Netherlands? Well, this study in particular has caught many scientists’ attention because the authors found something relatively unusual and especially interesting against the backdrop of discussion about SARS-CoV-2 evolution: a viral strain that seems to be both more virulent, and more transmissible.

Oftentimes, the story of virulence and transmissibility is summarized as such: the more virulent a virus gets, the more likely it will kill its current host, before it can be transmitted to a new host. So, more virulence leads to less transmission. However, although this can be a useful simplification, in the end it is just that: a simplification. The more accurate story would include a classic, “it depends”. The exact relationship between viral virulence and viral transmissibility depends on the virus.

In the case of HIV, historical studies have shown us that virulence and transmissibility are very closely linked, because of the biology of the virus. When somebody is first infected with HIV, there is initially lots of virus floating around in their body. In scientific parlance, there is a “high viral load” at this onset of infection. Then, after a few weeks, the immune system gets the virus (sort of) under control, and the viral load drops to a stable “set point”. The amount of virus in the body of an untreated person living with HIV can stay very low for years – up to a decade or more. But, if the infection is left untreated, the “viral load” will eventually climb again, at first slowly, and then rapidly, as the HIV-1 progressively destroys the immune system of its human host. As the amount of virus increases and in turn the immune system functioning is crippled, the human host will then develop “AIDS”: acquired immunodeficiency syndrome.

At the in-between point after infection and before development of AIDS in an untreated person living with HIV, the amount of circulating virus matters. The stable “set point” in the amount of virus circulating in their body can differ, depending on the exact strain of HIV-1 a person is infected with. And, the more circulating HIV-1 there is in a person’s body (a higher “set point”), the more likely they are to both infect other people (higher transmissibility) and develop AIDS sooner (higher virulence). In other words, to pass from person to person, HIV seems to need a certain degree of virulence, as well as a certain degree of transmissibility. In the case of HIV, it’s not an “either/or” scenario with virulence and transmissibility – it can be a “yes, and”.

This is exactly what the new publication from Wymant and colleagues describes. They found a new strain of HIV-1 that is both particularly virulent, and particularly transmissible. Interestingly, the increased virulence of this new strain also wasn’t explainable by only the high viral “set point” that was seen in people infected with it. There was something else going on with this virus that made it particularly good at decimating human immune systems, even when the higher amount of circulating virus was accounted for. But exactly what that “something else” is, we still don’t know. There are so many different mutations in this newly discovered strain that it's hard to say exactly why it is particularly virulent and transmissible. Because there are simply so many unique genetic quirks in this variant, it’s not easy to figure out which quirk has which effect. Despite not knowing all of the molecular details, though, this is a very interesting case study in a virus evolving both increased virulence and transmission – which hasn’t often been so concretely demonstrated before now.

But never fear, there is also good news! Amongst all of those mutations in this new strain, there was only one that would be expected to lead to drug resistance – and that one mutation is already a well-known one that we can handle by using a combination treatment of many different drugs at once. And for how virulent it is, the current “test-and-treat” guidelines seem to have done a pretty good job at keeping this variant in check. As lead author Chris Wymant put it, “this study underlines the importance of guidelines that we already have in place: regular testing for those at risk, and immediate [treatment] initiation upon diagnosis”.

Indeed, one of the final conclusions of the authors of this study is simple: viral infections should be prevented where possible, and treated where not. They write, “Widespread treatment is helpful to prevent new virulent variants, not harmful... Put simply, ‘viruses cannot mutate if they cannot replicate’... and ‘the best way to stop it changing is to stop it’.

Until next time,

Here's some more "Yes, and" talk, and a video about decluttering HIV. To keep you busy ;)

~ Alex

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