How HIV kills so many CD4 T cells

- [Voiceover] We know that in an untreated HIV infection, the levels of the virus rise up. They rise up to extremely high levels throughout our bloodstream and throughout our body. And that's because HIV is getting into our immune cells, right? They hijack our T cells and they use them to replicate and to make lots and lots of copies of themselves. But we also know that we see this massive drop off in our T cells, our CD4 cells in particular. So the question is, how is this happening? I mean, yeah, we see that these cells get infected, but why are so many of them dying? Do they all get infected, do they die when they get infected? Well, this question is one that scientists have been working on for decades, probably about 30 years so far. And it turns out that in an HIV infection, only about 5-10% of the immune cells that end up dying off are actually HIV infected. The remaining 90-95% that die off are not even infected. That's ridiculous, right? How's that even possible? Well, let's look at that a little bit. So why all these cells, both infected and non-infected are dying, it really comes down to a few causes. And we could talk about all the molecular detail involved in each of these causes, but I don't really want us to get bogged down in all the detail. So let's just focus on the concepts here. So here's an infected T cell, right? This guy's part of the 5-10% that dies off while infected. So here's our T cell. And inside our T cell you can see there's little bits of HIV RNA, and you can see new HIV particles budding off on the outside here, right? This guy's just cranking out more and more HIV particles. And actually, let's just put a bit of a red-colored haze around the edges here. And that's to remind ourselves that a lot of the infected cells die off while they're still traveling around in our blood stream. So this is just to show us where this is happening. So infected CD4 T cells, they're gonna die off either directly because of stuff the virus is doing within the infected cell, within themself, or because of how our immune system responds to them. Our immune systems don't particularly like when our cells get infected, and that's fair enough. But let's start down here, virus-related stuff. Remember that when a virus gets its RNA into our immune cell, this cell is considered to be infected at that point. So from here, our cell can die off in a few different ways. So first off, if HIV comes in and starts reverse transcribing, remember it works by reverse transcriptase, right? If it starts to reverse transcribe lots and lots of copies of viral DNA using its RNA, our cell might start to take notice. We start to notice these viral transcripts building up. And we actually have a specific protein in our cells called IFI16, and it's IFI16's job to be on the lookout for all this rogue DNA, DNA that really shouldn't be in our cells. So if IFI16 does take notice of all these viral transcripts building up, it activates an inflammatory cascade within the cell. And what ends up happening with this is the inflammatory cascade goes on to activate a self-destruct sequence within the cell, and we call this pyroptosis. Basically, the cell self-destructs because of the really, really, inflammatory environment inside the cell. And that's called pyroptosis. And keep this in mind, because this pyroptosis mechanism gets really, really important later on in the video, so keep that in mind. The second way an infected T cell might die off, do you remember integrase, that's the HIV enzyme that will grab on to this viral DNA here, drag it into the nucleus, and then try to integrate it into our DNA? Well, sometimes while integrase is getting its integration on, our cell sort of catches on to what's happening, so to speak. And our cell catches on because we have another cellular sensor called DNA-PK that senses when there's a break in our DNA. So at this point, our sensor's triggered, right? And then our cell's like, holy cow! We have an HIV infection! And it goes on to, again, trigger a self-destruct sequence. Except this one's slightly different to the one we saw earlier. This one's called apoptosis, which you may or may not have heard of in your cell biology class. Now apoptosis and pyroptosis are pretty similar, but they primarily differ in how they get triggered. Remember pyroptosis is triggered by inflammation, but apoptosis is triggered when specific cellular watchdogs, if you will, notice some critical damage happening in the cell, like the DNA damage we saw here. And finally another thing that might happen, is that let's say integrase actually does get the job done, and the viral DNA ends up integrated into our DNA. At that point we might start cranking out copies of virus, right? And remember that one of the last steps in creating viable HIV virus is that this viral protein, HIV protease, has to cleave up the viral precursors that have been made in our cell in order to activate 'em and to make 'em all "infectiousy." So what happens, I guess as a byproduct of that, is that the HIV protease also will cleave up and activate other proteins in our cell called caspases. Specifically a fragment of caspase number 8. There's lots of different kinds of caspases, but this one activates number 8. And caspases are pretty cool. Often when there's a problem within the cell, like there is right now, the caspases get activated and they trigger, you guessed it, a self-destruct sequence, in this case apoptosis again. So there are other ways that infected T cells can die, too. For example we've got another group of T cells called CD8 T cells. And when they see an infected CD4 cell, they get pretty upset, and they'll kill it off. And the reason it knows the CD4 cell's infected, by the way, is because infected CD4 cells start to display certain HIV proteins on their surface. For example, maybe they'll start to display ones from the HIV envelope, like GP120. Another thing to keep in mind is that remember after a month or so of being infected, we start to make antibodies to HIV? So these anti HIV antibodies might stick on to infected T cells and mark them for destruction by other immune cells. So everything we've talked about so far are really just concepts about how infected CD4 cells die. But like I mentioned earlier, it's been observed that a massive amount of immune cell loss in an HIV infection, actually the vast majority, is due to the death of CD4 T cells that are not even infected. And this loss of uninfected T cells is so huge that it's thought to be the major reason for immune system failure in an advanced HIV infection. Part of why there's such a huge loss of these uninfected cells is because when T cells get exposed to HIV, even if they don't get infected by it, they start to produce this protein on their surface that causes them to hone in on our lymph nodes. They start to travel to our lymph nodes. And the reason for this is, because, remember, the lymph nodes are the areas in our immune system where our immune cells go to get exposed to new types of bacteria and other bugs that they're supposed to be fighting, right? They're kinda like training grounds for our immune cells. So we know that lymph nodes are just this massive hotbed for HIV particles in an infection, right? Remember, that's part of why we see the swollen glands and the raised lymph nodes in acute HIV infections. Because dendritic cells are bringing HIV to lymph nodes and immune responses start to happen there. So anyway, you end up with this really large amount of uninfected T cells all within your lymph nodes. And actually, let me draw in this creamy-colored haze here. So that reminds us that all of this cell death is gonna primarily happen within our lymph tissue. So what happens in here is pyroptosis again. Remember it's programmed cell death, like apoptosis, but initiated by a different mechanism. It's driven by this crazy amount of inflammation. So let me set the scene for you here. So you get HIV trying to infect a CD4 T cell in here, right? But remember that IFI16 protein we talked about earlier. That protein notices all of these viral transcripts building up, right? And when it notices that, it activates a caspase, caspase 1 this time. And caspase 1 does something really, really interesting. It starts to stimulate the creation of this pro-inflammatory molecule called interleukin-1 beta inside our cell. And interleukin-1 beta, what it does, is it creates this really inflammatory environment inside the cell. And remember what happens when you have a massively inflammatory environment in the cell? The cell might end up being destroyed by pyroptosis. And, indeed, that's exactly what happens here. You can actually think of it like a grenade going off. And I think we all know that grenades suck, because of shrapnel that they release that causes damage to bystanders. And in fact, there is a similar thing that happens here. So the shrapnel after pyroptosis are all of these little pro-inflammatory interleukin-1 beta particles that then get exposed to all the other CD4 cells around the area, right? All the cells that have come in to try to control the HIV infection. So when they get showered in interleukin-1 beta, they start to develop a seriously inflammatory environment inside themselves as well. So what ultimately happens is that they undergo pyroptosis as well. And you get this chain reaction of pyroptosing cells creating this huge loss of CD4 cells that weren't even infected in the first place. The other thing is that you end up with this state of chronic inflammation, right? All throughout your body. And that's because of all these pro-inflammatory signals that are being released. And this chronic inflammation that develops keeps activating your immune cells, essentially 24/7. And that'll eventually wear out your immune cells and lead to even more cell death. So before, we used to think that we lost the majority of our CD4 cells because of HIV infecting each cell, leading to apoptosis of that one cell. But now we know that it's this ridiculous amount of pyroptosis and the resulting chain reactions of more and more and more pyroptosis that it causes that's responsible for the vast majority of CD4 cell loss in HIV infection.