- [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.