- So now we're in the lymph node.
We're looking at how HIV,
brought to the lymph node
by either one of our
well-intentioned dendritic cells
or maybe by a macrophage,
manages to infect
our T helper cells, a.k.a.
our CD4 lymphocytes.
Well, it all sorta
comes down to receptors.
On our T helper cell membranes,
we have two to three
receptors that help HIV
gain access to these cells.
We have the CD4 receptor, which is sorta
the primary receptor that HIV needs,
and we have either one or
both of CCR5 and CXCR4,
CXCR4 being much less prevalent.
CCR5 is really the preferred co-receptor
that most strains of HIV need to bind.
But these are both called
co-receptors in this context here.
So, what's important about
these particular receptors
is that HIV happens to have a protein,
This thing here called
Gp120, on its envelope.
The outer part of the virus here,
that interacts really
well with these receptors.
You can almost think of it
as a lock and key setup.
These receptors here are some of the locks
that need to be open to gain
access to our T helper cell,
and unfortunately for us, HIV has the key.
This Gp120 protein on its surface.
So how does it work?
Well, Gp120 on the HIV envelope,
it first binds the CD4
receptor on a T helper cell.
This binding between
the two sort of induces
a confirmational change in
the CD4 receptor protein here,
and it allows our co-receptor
here, either CCR5 or CXCR4,
to grab a hold of this complex
and pull the viral membrane
and the T cell membrane closer together.
And when they get close enough,
this little stalk here, the
stalk of the Gp120 protein,
it sorta pierces through
our T cell membrane,
and it pulls the viral
and the T cell membranes
even closer together, and
what ultimately happens
is that the two membranes
will fuse together,
which allows the HIV particle
to essentially inject,
now that it has access to the
inside of our T cell here,
it injects its genetic
material into our T cell,
inside this viral capsid here.
And that's in the form of
viral RNA, ribonucleic acid.
And this envelope is just sorta left
at the surface of our T cell here.
So once this capsid with viral RNA
and some viral enzymes enters our cell,
it gets degraded by some
of our cellular enzymes.
And this is essentially another
bad move on our cell's part,
because it releases the viral enzymes
and the viral RNA which
can now get to work
on taking over our T cell.
We kinda just got Trojan-horsed in a way.
And, you know, most viruses at this point
are happy to just use
our cellular machinery
like our ribosomes and our
cytoplasmic nucleotides
to make copies of themselves,
and they leave our DNA alone.
But not HIV, HIV's a little
sneakier than normal viruses.
And probably the key viral
enzyme among all of these
that allows it to be so sneaky
is this reverse transcriptase enzyme.
So what reverse transcriptase does
is it takes this viral RNA
here, the one that came with,
and it uses some of our nucleotides
that are floating around in the cytoplasm,
to revert this viral RNA
into a single strand of DNA.
It uses the viral RNA as a template
to synthesize a strand of DNA.
And then it synthesizes a
complementary strand of DNA
for the single strand,
so we end up with some
double-stranded viral DNA here.
And so right now, alarm bells are probably
rightfully ringing in our head, right,
we just went from single-stranded RNA
to single-stranded DNA
to double-stranded DNA,
that's not supposed to happen.
Remember the central dogma
from your biology classes
that said "we go from
DNA to RNA to proteins,"
and here we are doing the
exact opposite of that?
Well that's exactly what's happening,
we are doing the opposite, and that's why
HIV is called a retrovirus.
It subverts the central dogma
and it generates viral DNA from viral RNA.
Outrageous!
The other sneaky thing
about reverse transcriptase
I wanted to mention is that
it makes a lot of errors
doing all this polymerization,
all this synthesis.
It doesn't quite have
the proofreading ability
that our DNA polymerase enzymes have.
That obviously come in handy
when we're replicating our DNA.
So on a practical level,
what this means is that,
well A, lots of viral
polymerase errors equals
lots of mutations in the viral DNA.
And that means that over
time, the virus can develop
resistance to certain
antiviral medications,
because the medication eventually
might not be able to even
recognize the viral DNA.
And B, it's really hard to
make a vaccine against HIV
because even small changes
in the genes of the virus
might render the vaccine ineffective.
Remember, we're talking
about one cell here,
and the mutations that
happen within one cell,
but keep in mind that there's potentially
gonna be millions of HIV-infected T cells
in which HIV will be
mutating ever so often.
And actually, this reverse
transcriptase enzyme
is one of the targets for some of
the medication we use
to control HIV levels.
We try to block this viral
reverse transcriptase enzyme from working.
Anyways, back to our now
double-stranded DNA here.
Another viral enzyme called integrase
will come along and grab hold of it.
It'll then bring it to
the T cell's nucleus
and carry it through
one of our nuclear pores
into the nucleus.
>From there, and this is sort
of the point of no return
in an HIV infection, the
integrase enzyme nicks,
it makes a little cut
in our human T cell DNA,
and it allows this double-stranded HIV DNA
to integrate itself into our DNA.
And this step essentially establishes
the lifelong infection with HIV.
The viral DNA has sort of,
now become congruent with our own DNA.
So from here, a few
different paths can be taken.
Well, either this DNA
just sits here and just,
and isn't actively transcribed into mRNA,
and we call this a latent HIV infection,
when your cell has integrated
viral DNA into your own,
but is not actively doing
anything with that DNA,
or your DNA transcription
enzymes might come along,
this is usually the more
likely thing that happens.
So let's say RNA polymerases come along.
Well, it's gonna transcribe
this viral DNA here
just as if it was your own DNA,
so it'll start cranking
out viral mRNA transcripts,
which then leave the nucleus,
they find some ribosomes,
they, on the rough endoplasmic reticulum,
and they start to use the
ribosomes to make proteins
like new envelope proteins for example.
These envelope proteins
will then make their way
through our endoplasmic reticulum,
head up toward the cell surface,
right, our cell membrane,
and once enough get up there,
they start to coalesce a
bit, they cluster together.
And this is actually happening
in a lot of other places
on our cell membrane.
See, you can see all
the new Gp120 proteins
here on the surface of these
viral envelope segments.
And while this happening,
another key viral protein
is being made at the same time.
Actually, it's a viral polyprotein,
"poly" because it's
essentially multiple different
viral proteins laid out end-to-end
on one long protein strand.
So, these will include those viral enzymes
we talked about earlier, right,
reverse transcriptase, integrase,
as well as some other proteins
that the virus needs to be infectious.
So, all of these long viral polyproteins,
along with some viral RNA,
they also get brought up
to the surface, to the areas where
all the envelope proteins
have clustered together.
And so now, all of these components
can come together to start forming
a new, immature HIV particle.
And I say "immature" because it's not
quite ready to infect other cells yet,
one more thing has to
happen before it matures
and it's ready to be infectious.
It needs help from yet
another viral enzyme,
called a protease.
Proteases are special enzymes
that cleave up polyproteins
just like this one here,
into smaller proteins.
But they only cut at
specifically marked sites.
And this protease here, it does just that
with this long viral polyprotein
that's been made using our ribosomes,
so it snips it at a few different sites,
and we end up with what
all are the components
that an HIV particle needs to infect,
so for example, this might be
its reverse transcriptase here,
and this might be
integrase here, and so on.
So the protease starts cutting things up,
and while it's doing
its slicing and dicing,
these components here,
together they all start to bud
off the T cell as a new virion.
And shortly after it buds off,
the protease is finished
cleaving this long protein up.
So this is now a fully
mature HIV particle,
now that it's used this T cell to be made,
it's ready to go on
and infect other cells,
particularly of course, T helper cells.
But what happens with this T helper cell
that was infected?
Well, our old understanding
of it was just that
as tons and tons and tons of new virions
budded off of our infected T cell,
all of that budding off would
actually kill our T cell.
But recently it's been discovered
that things are a lot more
complicated than that.
In the vast majority of cases,
the T helper cell does die,
but it's not because of the
budding off of the virions.
It's most often because infection
and subsequent production
of HIV particles,
it sorta triggers this sort of
self-destruct mechanism within the T cell.
But I'll cover that in more detail
when we talk about how
HIV kills our T cells.
