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Health and medicine
Course: Health and medicine > Unit 13
Lesson 7: HIV and AIDS- What is HIV/AIDS?
- What is HIV and AIDS?
- Transmission of HIV
- How HIV infects us: Mucous membranes, dendritic cells, and lymph nodes
- How HIV infects us: CD4 (T-helper) lymphocyte infection
- How HIV kills so many CD4 T cells
- Diagnosing HIV - Concepts and tests
- Treating HIV: Antiretroviral drugs
- HAART treatment for HIV - Who, what, why, when, and how
- Defining AIDS and AIDS defining illnesses
- Immune reconstitution inflammatory syndrome (IRIS) in AIDS
- Preventing an HIV infection
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How HIV kills so many CD4 T cells
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Want to join the conversation?
- At, why does IFI16 activate Caspase 1 when that will lead to further inflammation? Wouldn't it be better for the cell to just not activate Caspase 1? 8:30(5 votes)
- Yes, it would be better. There are lots of diseases where the inflammatory response is a bad thing and we would rather it didn't happen, or was a bit weaker. Unfortunately, IFI-16 doesn't get to make a decision; it is activated by the viral DNA, and goes on to perform its function of activating the caspase. IFI-16 doesn't know if the viral DNA belongs to HIV, or the flu, or something else. It just knows the cell has been invaded.
It's important to understand that this response, and inflammation in general, is enormously helpful in dealing with all the microbes that normally live inside us and nearly all of the microbes that live around us on Earth. If you didn't have these inflammatory pathways, you would die of infection immediately.
For example, when you are infected with a cold or flu, molecules such as IFI-16 become activated and help to alert the immune system which can then deal with it.
HIV is just a very unfortunate and nasty exception, in that our inflammatory response actually helps it spread and doesn't do anything to clear it. That's part of the reason why HIV is so deadly whereas most viruses are easy for us to deal with.(4 votes)
- If the T cell explode can it kill the HIV close to it?(1 vote)
- Such an interesting idea, but the explosion/bursting of the cell itself won't help us much. Moreover, it is harmful to us as well.
T cells are not designed like hypnozoites in human liver (liver stage of Plasmodium vivax which causes malaria), so its burst can let merozoites into the bloodstream and invade the host.
Our T cells can fight HIV or other 'enemies' only if intact.(2 votes)
- he said that interleukin 1 beta when cell dies creates inflammation in other CD4 T cells. I wonder does drugs which is used to treat humans with HIV to prolong their immune system intervenes in this process? 9:25(1 vote)
- What about the new meds that are CCR5 blockers? and isn't CCR5 also the entry for Cancer cells in malignancy?(1 vote)
- At, are CD8 cells also known as killer T cells? 5:51(1 vote)
- Yes! CD8 cells are known as killer T cells or more scientifically, they are called cytotoxic (cell killing) T cells(1 vote)
- Around, he said that T cells make copies of HIV. But how do they actually make copies of HIV? 0:22(1 vote)
- Why aren't all these mechanisms of destruction effective in fighting the infection and destroying the HIV virus?(1 vote)
- Our immune system could kill HIV?
We could get better?(1 vote) - how hiv deplete cd4 count(0 votes)
- HIV causes CD4 cells (monocytes, macrophages, dendritic cells and T-helpers) to initiate their self-destruct mechanisms - apoptosis or pyroptosis.(4 votes)
- What does RNA stand for, what is it used for, and is it?(0 votes)
- Ribonucleic Acid. It is used to translate proteins from the DNA code(2 votes)
Video transcript
- [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.