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It comes acquainted
with different antigens.

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And recall that
what we were talking

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about was the following, that
there were several kinds of

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phagocytic cells. Phagocytic
cells are cells that

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chew up other things, both
macrophages and even more

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00:00:23,000 --> 00:00:27,000
frequently, dendritic cells,
many of which hang around lymph

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00:00:27,000 --> 00:00:33,000
nodes by the way. They
process antigens into

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oligopeptides. The
oligopeptides get presented on

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the surface of these cells.
Let's say, here's a macrophage,

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in the form of through the class 2
MHC molecules which are displayed on

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the surfaces of the cells. And,
here's a typical oligopeptide

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that has been chewed up from one
of the antigens that was previously

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internalized, eaten up by the
macrophage, a dendritic cell,

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and then presented on the surface.
Recall, then, we have an itinerant

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macrophage or dendritic cell.
Could we turn up the sound just a

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little, just a notch? Thank
you. And this dendritic cell

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or macrophage, I'll just
call it a macrophage for

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the moment, is then moving
largely through the lymph nodes,

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but wherever it moves, it's
carrying along this oligopeptide.

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And recall that we liken this voyage
of it to a Middle Eastern market

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where there's a lot of bazaar
stalls on either side of the road,

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and where instead of the usual male
merchants, there's a lot of female

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merchants hanging out. And
these females are called T

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helper cells. They're a
kind of T lymphocyte or T

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cell. TH refers to their function.
And here, all of these T helper

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cells, I'll indicate each of
them here as a pink circle.

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And these T helper cells display on
their surface to blow them up to a

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large size a T cell receptor
that is organized much the way

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immunoglobulin molecule and
antibody molecule's organized.

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That is to say, it has
variable and constant regions.

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It's generated through the
rearrangement of antibody-like genes.

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But it only functions, this
T cell receptor or as it's

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called in the trade the TCR, only
functions to sense the presence

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of antigens in the
extracellular space. In fact,

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it senses antigens in the
context of the MHC class 2.

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So here's an MHC class 2 molecule.
We can think of the MHC class 2 as

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being a hand, which is
presenting this oligopeptide.

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I haven't drawn a hand, but
you can pretend it's a hand.

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And this MHC class 2 is being
presented by either a macrophage or

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a dendritic cell. And
recall, we talked about the

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voyage of this macrophage or
dendritic cell through this street

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here, and all these T helper cells
are kind of lazily waiting along on

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the sidelines looking at what
this phagocytic cell is hocking.

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Most of the T helper cells are
totally uninterested in what he's

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hocking. But one of them is struck.
It's love at first sight, this one

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over here, let's say,
because her T cell receptor

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precisely recognizes this
oligopeptide in the context of the

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MHC class 2 molecule. And,
obviously I would like to draw

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00:04:00,000 --> 00:04:04,000
thousands of these T helper
cells here, each of which bears a

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00:04:04,000 --> 00:04:08,000
different T cell receptor on her
surface. I'm only showing one.

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And recall that after
they make this encounter,

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the T helper cell gets all
excited because she says,

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00:04:16,000 --> 00:04:20,000
oh, I can't believe it, you
have exactly the oligopeptide

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that's recognized by my receptor.
And so, she gets all excited, and

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what she does is she proliferates
because that's about all that

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excited cells can do. Well,
they can do other things,

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but again, we don't want
to talk about it. Anyhow,

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so this particular T helper cell
undergoes a clonal expansion,

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and is now activated, i.e. activated
not only psychologically but

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physiologically by having
encountered the antigen-presenting

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cell. The MHC class 2,
the macrophage is called an

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antigen-presenting cell. It's
using its MHC class 2 molecules

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to do so. Macrophages and dendritic
cells are pretty much similar in

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this respect. Macrophages go
all over the body in the tissues.

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Dendritic cells tend to inhabit the
lymph nodes. But from the point of

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view of our discussion today,
we can imagine that they're

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functionally essentially equivalent.
And having said that, now these T

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helper cells go looking
for a congenial B cell.

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00:05:34,000 --> 00:05:39,000
So, now we have a third actor in
the drama, and the congenial B cell

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looks like this. And, the
B cell has the following

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00:05:44,000 --> 00:05:49,000
thing. The B cell has also on its
surface, MHC class 2 molecules,

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which can be used in antigen
presentation. But the B cell has an

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addition as we said last time,
already, on its surface, IGM

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molecules. An IGM is
a brand of antibody.

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Keep in mind that really one of
the paradoxes that we haven't really

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fully settled on is the following
question or the following issue.

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How is it that when a B
cell sees a cognate antigen,

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why does it get stimulated?
In other words, what is it that

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induces the B cell to
start proliferating?

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00:06:29,000 --> 00:06:32,000
Here's another version of
what I showed you last time,

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where a B cell which makes the
right antibody gets stimulated,

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but a B cell that doesn't
does not get stimulated.

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And that's the issue we're
wrestling with right now.

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So here on the surface of
this B cell is an IGM molecule.

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Keep in mind an IGM molecule
is an antibody molecule.

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00:06:52,000 --> 00:06:56,000
Immunoglobulin means IG. It's
the earliest form of antibody

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that's made. Once again,
it is antigen specific.

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00:07:00,000 --> 00:07:05,000
Its variable region has been
rearranged through the fusion of

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00:07:05,000 --> 00:07:10,000
different VDJ segments
and somatic hypermutation.

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And, this B cell has a
very interesting property.

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This is a naïve cell, and
what this B cell does is as

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follows. It moves around the body,
and if this B cell happens to find

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an antigen, which is recognized
by its antibody, the IGM antibody.

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Then the B cell will bind this
antigen using its IGM molecule to do

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so. More importantly, it
will then internalize this

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antigen and chew it up into little
pieces, and then present it on it

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surface via the MHC class 2
molecule. So, let's just review what

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we've been saying. Before,
we were talking about

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macrophages and dendritic cells,
which gobbled up whatever they could,

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00:08:03,000 --> 00:08:07,000
processed whatever they gobbled up,
and put it on the surface again as

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00:08:07,000 --> 00:08:11,000
MHC class 2, and therefore the
macrophages and the dendritic cells

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00:08:11,000 --> 00:08:15,000
are really like sewer rates.
They'll just chew on anything and

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00:08:15,000 --> 00:08:19,000
they'll put it on their surface.
They're totally promiscuous in what

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they present on their surface.
But here, the B cell is doing

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something rather similar. But
the B cell isn't presenting

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00:08:27,000 --> 00:08:31,000
whatever it happens to
stumble across on its surface.

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00:08:31,000 --> 00:08:35,000
The B cell is extraordinarily
selective at what it presents on its

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surface. It only presents on its
surface those antigens which are

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recognized by its IGM molecule.
So here, it uses its IGM molecule

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to grab hold of this antigen.
It internalizes the antigen, and

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then presents it back on the
surface as an MHC class 2 molecule.

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So, there's a profound contrast in
the behavior of these two kinds of

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antigen-presenting cells. The
macrophages and dendritic cells,

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they just gobble up everything,
and whatever they find,

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00:09:06,000 --> 00:09:10,000
they put on their surface. They
don't care with MHC class 2.

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The B cell is extraordinarily
selective and specific.

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00:09:14,000 --> 00:09:18,000
It will pull in not through regular
phagocytosis. It will pull in using

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its IGM receptor,
specific antigens that are

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recognized by its IGM molecule,
and then externalize it using its

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00:09:26,000 --> 00:09:30,000
MHC class 2 molecule to do so.
Let's go back to the drama of the

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activated T helper cell, and
here's the activated T helper

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00:09:34,000 --> 00:09:39,000
cell. We'll draw her in pink.
The T helper cell has just had an

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encounter with a macrophage, or
dendritic cell. And, she's just

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left this marketplace. And
now, she's very excited.

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So here is her T cell receptor.
And she's very excited. She's

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putting out all kinds of
growth factors and multiplying

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all over the place. And she
starts looking again now for

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a B cell with which he can react.
Now, most of the B cells in the

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00:10:06,000 --> 00:10:10,000
body will not have an
epitope that she recognizes.

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00:10:10,000 --> 00:10:15,000
Most of the B cells in the body
will have picked up other kinds of

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things that happen to recognize
by their T cell receptor,

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and will present it on the surface.
A rare B cell will happen to

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internalize an antigen, and
put on the surface, which is the

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same antigen that was recognized
previously in the previous

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00:10:32,000 --> 00:10:37,000
encounter. And so, now
this T helper cell goes

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around looking for an attractive
male. What's an attractive male for

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00:10:42,000 --> 00:10:47,000
her? An attractive male for her is
one whose MHC class 2 molecule is

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00:10:47,000 --> 00:10:52,000
recognized directly in the context,
and this oligopeptide is recognized

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00:10:52,000 --> 00:10:57,000
by her T cell receptor. And
so, she'll come over here and

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she'll say excitedly to the B cell,
you can't believe what just happened.

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00:11:02,000 --> 00:11:05,000
She will say, I was just there.
I just went through the market.

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00:11:05,000 --> 00:11:09,000
I was sitting there in the
marketplace, and along came a

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00:11:09,000 --> 00:11:13,000
macrophage, and presented me with an
oligopeptide that exactly fit in my

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00:11:13,000 --> 00:11:17,000
T cell receptor. And
now, she says excitedly,

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00:11:17,000 --> 00:11:21,000
here I find a B cell has exactly the
same oligopeptide presenting it to

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00:11:21,000 --> 00:11:25,000
me. Isn't that a coincidence?
And the B cell says, come on lady,

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00:11:25,000 --> 00:11:29,000
get to the point. And she says,
I just had an encounter with a

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00:11:29,000 --> 00:11:33,000
macrophage dendritic cell. I
recognized the same oligopeptide

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00:11:33,000 --> 00:11:37,000
in the macrophage dendritic
cell that you have.

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00:11:37,000 --> 00:11:42,000
And, the B cell says, well,
I guess this must be some kind

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00:11:42,000 --> 00:11:46,000
of meaningful encounter, and
so these two cells get together.

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00:11:46,000 --> 00:11:51,000
And what happens now is that
the T cell, having recognized the

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00:11:51,000 --> 00:11:55,000
oligopeptide, presented on the
surface of the B cell now begins to

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send out signals to stimulate
the B cell to proliferate.

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And this B cell now begins to
proliferate. And this B cell now

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00:12:03,000 --> 00:12:07,000
begins to proliferate, as is
indicated on this overhead,

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and eventually it starts making IGM
molecules. It makes more of them,

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and then through the class switching
that we talked about last time,

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it'll make eventually IGG secreted
antibody gamma globulin molecules.

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So you see here the three essential
cell types that participate in this.

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00:12:22,000 --> 00:12:26,000
And why is it so complicated?
Because it's extraordinarily

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important that the immune
system doesn't inadvertently make

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00:12:30,000 --> 00:12:34,000
antibodies that are inappropriate to
express, because as we said before,

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if a certain of those antibodies and
indeed possibly many of them could

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be autoreactive. And what
do I mean by autoreactive?

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I mean reactive with self. They
could be antibodies that react with

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00:12:47,000 --> 00:12:52,000
one's own tissues. And in
so doing, they could create

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00:12:52,000 --> 00:12:57,000
series kinds of autoimmune diseases.
So, we have this sequence of

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00:12:57,000 --> 00:13:02,000
failsafe reactions. So,
when finally the decision for

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00:13:02,000 --> 00:13:06,000
the B cell to get activated depends
on a previous encounter with the

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00:13:06,000 --> 00:13:11,000
same oligopeptide by a
macrophage or dendritic cell,

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00:13:11,000 --> 00:13:15,000
the T helper cell acting as an
intermediary and now activating the

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00:13:15,000 --> 00:13:20,000
B cell, once the T cell tells the
B cell that the T cell has had a

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00:13:20,000 --> 00:13:24,000
previous encounter with
exactly the same oligopeptide,

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00:13:24,000 --> 00:13:29,000
on that occasion being presented
by a macrophage or dendritic cell.

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00:13:29,000 --> 00:13:32,000
And that is actually the mechanism
by which we get this clonal

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00:13:32,000 --> 00:13:36,000
expansion of B cells in the immune
system, and ultimately how we get

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00:13:36,000 --> 00:13:40,000
the productive antibody molecules.
I mean, this is the image I showed

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00:13:40,000 --> 00:13:44,000
you earlier, but I never really
explained to you what the biology

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00:13:44,000 --> 00:13:48,000
behind that is. I just
said that antigen encounter

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00:13:48,000 --> 00:13:52,000
on the part of the B cell causes
that B cell to enjoy clonal

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00:13:52,000 --> 00:13:56,000
expansion. And now, we've
gone through the detail of

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00:13:56,000 --> 00:14:00,000
deciding how three different
cell types interact,

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00:14:00,000 --> 00:14:04,000
collaborate with one another to
create the antibody response because

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00:14:04,000 --> 00:14:08,000
this B cell then goes on to
produce IGM as it already is doing,

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00:14:08,000 --> 00:14:12,000
and then eventually IGG, and
possibly a series of other

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00:14:12,000 --> 00:14:17,000
immunoglobulins, IGE
and IGA which have other

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00:14:17,000 --> 00:14:21,000
purposes. Now, all of this
actually is an important

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00:14:21,000 --> 00:14:25,000
prelude to our main topic
of discussion today, which is

190
00:14:25,000 --> 00:14:30,000
the disease of AIDS. And,
let me just add one other

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00:14:30,000 --> 00:14:35,000
detail to this because the ability
of a T helper cell to recognize MHC

192
00:14:35,000 --> 00:14:39,000
class 2 molecules depends on another
cell surface molecule expressed by

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00:14:39,000 --> 00:14:44,000
the T helper cell. And
this other T cell surface

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00:14:44,000 --> 00:14:49,000
molecule is called CD4. CD4,
we don't have to worry of what

195
00:14:49,000 --> 00:14:54,000
it stands for. CD4 is
not an antigen specific

196
00:14:54,000 --> 00:14:59,000
receptor. CD4, instead,
only recognizes MHC class 2

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00:14:59,000 --> 00:15:04,000
molecules no matter
what they're carrying.

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00:15:04,000 --> 00:15:09,000
So, there are MHC class 2 molecules
which I've implied to you can carry

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00:15:09,000 --> 00:15:14,000
thousands of different oligopeptides.
CD4 doesn't care what's being

200
00:15:14,000 --> 00:15:20,000
carried by the MHC class 2.
It just binds to MHC class 2

201
00:15:20,000 --> 00:15:25,000
molecules, thereby telling the T
helper cell that an encounter has

202
00:15:25,000 --> 00:15:31,000
been made with an
antigen-presenting cell.

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00:15:31,000 --> 00:15:36,000
So, the ligand for CD4 is part
of the MHC class 2 molecule.

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00:15:36,000 --> 00:15:42,000
Now, that all leaves us in a very
nice segue to the whole disease of

205
00:15:42,000 --> 00:15:47,000
AIDS. Let's just remember how the
disease of AIDS was discovered.

206
00:15:47,000 --> 00:15:53,000
In 1981, there were a group of five
young men who were all subsequently

207
00:15:53,000 --> 00:15:58,000
determined to be gay, be
homosexual, who were discovered

208
00:15:58,000 --> 00:16:04,000
in San Francisco to have a very
unusual kind of immunodeficiency.

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00:16:04,000 --> 00:16:08,000
They all had night sweats.
They got different kinds of

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00:16:08,000 --> 00:16:12,000
otherwise unusual diseases. For
example one of the things they

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00:16:12,000 --> 00:16:17,000
got was a disease called Kaposi's
sarcoma, which was otherwise known

212
00:16:17,000 --> 00:16:21,000
only in old southern Italian
and Jewish men, Kaposi's sarcoma.

213
00:16:21,000 --> 00:16:25,000
But these were young men, and
they were neither southern Italian

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00:16:25,000 --> 00:16:31,000
nor Jewish. They got
pneumocystis carinii,

215
00:16:31,000 --> 00:16:37,000
which is a microbial
infection of the lung. And,

216
00:16:37,000 --> 00:16:44,000
in fact, they got all kinds
of herpes virus infections.

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00:16:44,000 --> 00:16:50,000
And they were all seen in a cluster
by an alert physician who saw

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00:16:50,000 --> 00:16:57,000
something very unusual,
and therefore said, perhaps

219
00:16:57,000 --> 00:17:04,000
correctly, that they had
acquired immunodeficiency.

220
00:17:04,000 --> 00:17:05,000
Now, this acquired
immunodeficiency is a syndrome.

221
00:17:05,000 --> 00:17:07,000
A syndrome, by the way, for
your information, is a whole

222
00:17:07,000 --> 00:17:09,000
collection of symptoms that appear
together. That's what a syndrome

223
00:17:09,000 --> 00:17:11,000
means. So, this term AIDS came
from the fact that they had a whole

224
00:17:11,000 --> 00:17:13,000
series of symptoms.
And, this was an acquired

225
00:17:13,000 --> 00:17:15,000
immunodeficiency rather than a
congenital immunodeficiency rather

226
00:17:15,000 --> 00:17:17,000
than a congenital immunodeficiency
because given the complexity of the

227
00:17:17,000 --> 00:17:19,000
immune system, you can
imagine correctly that there

228
00:17:19,000 --> 00:17:21,000
are a lot of people in the world
who were born with congenitally

229
00:17:21,000 --> 00:17:23,000
defective immune systems that are
immunodeficient from birth because

230
00:17:23,000 --> 00:17:25,000
there's so many different proteins
involved in regulating all of these

231
00:17:25,000 --> 00:17:27,000
different immune responses.
But this was really different.

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00:17:27,000 --> 00:17:29,000
It was an acquired immunodeficiency.
It was seen in a very special

233
00:17:29,000 --> 00:17:31,000
subgroup, and so the race was on
over the next two years to figure

234
00:17:31,000 --> 00:18:02,000
out what
was going on.

235
00:18:02,000 --> 00:18:06,000
Now, by coincidence,
starting in 1970-'71,

236
00:18:06,000 --> 00:18:10,000
retrovirus research had begun.
And as it turned out, retrovirus

237
00:18:10,000 --> 00:18:14,000
search, President Nixon's war on
cancer, retrovirus research was

238
00:18:14,000 --> 00:18:18,000
motivated largely by the notion
that human cancers are caused by

239
00:18:18,000 --> 00:18:22,000
retrovirus infections. And,
that led to the war on cancer.

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00:18:22,000 --> 00:18:26,000
And the notion behind the war on
cancer was totally wrong because it

241
00:18:26,000 --> 00:18:30,000
turns out that only a minute
fraction of human cancers have

242
00:18:30,000 --> 00:18:34,000
anything to do with retrovirus
infections, although as we've said

243
00:18:34,000 --> 00:18:38,000
earlier, retroviruses proved to be
very important tools experimentally

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00:18:38,000 --> 00:18:43,000
for discovering proto-oncogenes
and oncogenes in the genome.

245
00:18:43,000 --> 00:18:47,000
But if you ask, what
fraction of human cancers are

246
00:18:47,000 --> 00:18:51,000
actually due to a human being
infected by a retrovirus?

247
00:18:51,000 --> 00:18:55,000
It's almost zero. It's a
small fraction of a percent.

248
00:18:55,000 --> 00:18:59,000
Nonetheless, in the 1970s, there
was an enormous effort made in

249
00:18:59,000 --> 00:19:03,000
trying to figure out all of
the biology of retroviruses.

250
00:19:03,000 --> 00:19:08,000
And by the late 1970s,
people concluded this was very

251
00:19:08,000 --> 00:19:13,000
interesting science.
Indeed, proto-oncogenes and

252
00:19:13,000 --> 00:19:18,000
oncogenes were discovered, but
that it was pretty irrelevant to

253
00:19:18,000 --> 00:19:23,000
understanding directly how human
cancer arose, which human cancers

254
00:19:23,000 --> 00:19:28,000
could be explained rather by
somatic mutations in the genome.

255
00:19:28,000 --> 00:19:33,000
In 1981, the AIDS infection arose.
And, what happened subsequently is

256
00:19:33,000 --> 00:19:37,000
that there was a race on to try to
find out what the infectious agent

257
00:19:37,000 --> 00:19:41,000
was because it seemed to
be an infectious agent.

258
00:19:41,000 --> 00:19:45,000
It was being spread from one gay
young man to another that was used

259
00:19:45,000 --> 00:19:49,000
to induce this. And
within two years,

260
00:19:49,000 --> 00:19:53,000
by 1983, the culprit retrovirus
had been found. I'm telling you this

261
00:19:53,000 --> 00:19:57,000
long song and dance to give
you the following insight.

262
00:19:57,000 --> 00:20:00,000
If there had not been a decade
of earlier retrovirus research,

263
00:20:00,000 --> 00:20:04,000
it could have taken the
scientific community many,

264
00:20:04,000 --> 00:20:07,000
many years to figure out what
was causing AIDS. But through

265
00:20:07,000 --> 00:20:11,000
happenstance, through a sheer
stroke of luck, by the time the first

266
00:20:11,000 --> 00:20:15,000
individuals suffering from
AIDS were encountered in '81,

267
00:20:15,000 --> 00:20:18,000
there was already a backlog
of a decade's worth of detailed

268
00:20:18,000 --> 00:20:22,000
retrovirus research, which
made it possible to discover,

269
00:20:22,000 --> 00:20:26,000
to discern almost within
months what was causing it.

270
00:20:26,000 --> 00:20:30,000
And, the agent that was
causing it was a retrovirus.

271
00:20:30,000 --> 00:20:33,000
The retrovirus here has indicated,
very schematically, these artists'

272
00:20:33,000 --> 00:20:37,000
drawings never have any resemblance
of what things really look like.

273
00:20:37,000 --> 00:20:41,000
And if they do, it's only by
coincidence. Let me borrow your

274
00:20:41,000 --> 00:20:45,000
laser pointer here for a second.
So here, and this is what a

275
00:20:45,000 --> 00:20:48,000
retrovirus looks like
just to give you a feeling.

276
00:20:48,000 --> 00:20:52,000
In the center, there are
two single stranded RNA

277
00:20:52,000 --> 00:20:56,000
molecules. The virus is diploid.
There's two copies of the genome

278
00:20:56,000 --> 00:21:00,000
for reasons we still
don't understand.

279
00:21:00,000 --> 00:21:03,000
Surrounding it is a so-called
nucleocapsid, which is responsible

280
00:21:03,000 --> 00:21:07,000
for protecting the RNA
molecules. These two pink dots are

281
00:21:07,000 --> 00:21:10,000
reverse-transcriptase molecules
because as you'll recall,

282
00:21:10,000 --> 00:21:14,000
when retroviruses infect a cell,
they carry the enzyme with them into

283
00:21:14,000 --> 00:21:18,000
the cell. You could say, why
don't they make it after they

284
00:21:18,000 --> 00:21:21,000
get into the cell? And it's
not totally obvious why,

285
00:21:21,000 --> 00:21:25,000
but this is what they do. There's
another shell of proteins out here.

286
00:21:25,000 --> 00:21:29,000
And then, beyond that is a lipid
bilayer. And this lipid bilayer is,

287
00:21:29,000 --> 00:21:33,000
as you may recall, stolen
from cell from which the

288
00:21:33,000 --> 00:21:37,000
virus is protruding because if you
look at retrovirus-infected cells,

289
00:21:37,000 --> 00:21:41,000
here's the plasma membrane
of a retrovirus-infected cell.

290
00:21:41,000 --> 00:21:45,000
Here you can see a nucleo-capsid
forming with the RNA molecules.

291
00:21:45,000 --> 00:21:49,000
And this shoves its way, protrudes
its way through the plasma membrane,

292
00:21:49,000 --> 00:21:53,000
stealing a patch of plasma
membrane from the infected cell,

293
00:21:53,000 --> 00:21:57,000
and at the same time this part of
the plasma membrane carries with it

294
00:21:57,000 --> 00:22:02,000
viral glycoproteins.
And viral glycoproteins,

295
00:22:02,000 --> 00:22:06,000
they're obviously glycosylated,
as are many other extracellular

296
00:22:06,000 --> 00:22:10,000
proteins. And in this case,
they're indicated with these yellow

297
00:22:10,000 --> 00:22:14,000
ovals, and these viral glycoproteins
are used to attach to subsequently

298
00:22:14,000 --> 00:22:18,000
infected cells so what happens is
that when the retrovirus gets out of

299
00:22:18,000 --> 00:22:22,000
the cell, I'll draw it
again schematically here,

300
00:22:22,000 --> 00:22:26,000
it has this glycoproteins coat
on it with the plasma membrane,

301
00:22:26,000 --> 00:22:30,000
and it uses these
glycoproteins spikes.

302
00:22:30,000 --> 00:22:34,000
I just won't put the yellow ovals on
them, to attach to cells which need

303
00:22:34,000 --> 00:22:39,000
to be infected. So, here's
a target cell that needs

304
00:22:39,000 --> 00:22:44,000
to be infected.
So, the target cell,

305
00:22:44,000 --> 00:22:49,000
and how does this virus know how to
attach to this cell and not to other

306
00:22:49,000 --> 00:22:54,000
cells? Because on the surface of
the target cell are certain cellular

307
00:22:54,000 --> 00:22:58,000
proteins, which are used
for normal cell physiology,

308
00:22:58,000 --> 00:23:03,000
which are there, and which the
virus has opportunistically developed

309
00:23:03,000 --> 00:23:08,000
an affinity for. So here
on the surface of a target

310
00:23:08,000 --> 00:23:13,000
cell might be a normal cellular
protein to which the viral

311
00:23:13,000 --> 00:23:18,000
glycoprotein combined. Or,
if you want to get technical,

312
00:23:18,000 --> 00:23:23,000
this enables the virus particle
to adsorb, to attach to.

313
00:23:23,000 --> 00:23:28,000
Notice the D here rather than the
B, to adsorb to the surface of the

314
00:23:28,000 --> 00:23:33,000
target cell. Importantly, what's
the cell surface protein of

315
00:23:33,000 --> 00:23:38,000
the target cell to which HIV virus
adsorbs? It's our old friend CD4.

316
00:23:38,000 --> 00:23:42,000
I.e. the HIV particle likes to
adsorb, preferentially adsorbs to

317
00:23:42,000 --> 00:23:47,000
the surface of cells that express
the CD4 molecule on the surface.

318
00:23:47,000 --> 00:23:52,000
Note, by the way, that just five
minutes ago, we described a totally

319
00:23:52,000 --> 00:23:57,000
different function of CD4. CD4
over here was said to represent

320
00:23:57,000 --> 00:24:01,000
the means by which the T helper cell
can recognize MHC molecules being

321
00:24:01,000 --> 00:24:06,000
displayed on the surface
of either of these dendritic

322
00:24:06,000 --> 00:24:11,000
cells or B cells. But here
we see CD4 in a totally

323
00:24:11,000 --> 00:24:16,000
different context. Here,
the CD4 represents the

324
00:24:16,000 --> 00:24:22,000
docking site to which the
viral glycoprotein can attach,

325
00:24:22,000 --> 00:24:27,000
enabling the virus, which came to
be called human immunodeficiency

326
00:24:27,000 --> 00:24:32,000
virus. In fact, the
virus was discovered by

327
00:24:32,000 --> 00:24:36,000
two groups simultaneously, one
of them called HDLV-3, the other

328
00:24:36,000 --> 00:24:41,000
called lymphadenopathy virus.
The first group was American.

329
00:24:41,000 --> 00:24:45,000
The second group was French,
and they allowed Herald Varmus,

330
00:24:45,000 --> 00:24:50,000
one of the co-discoverers of the
proto-oncogene to act as sort of the

331
00:24:50,000 --> 00:24:54,000
judge to see what it would be called
because there was great political

332
00:24:54,000 --> 00:24:59,000
tension. Would it get the American
or the French name depending on

333
00:24:59,000 --> 00:25:03,000
which of the two warring scientists,
and they were warring, could claim

334
00:25:03,000 --> 00:25:08,000
discovery? So, he had
a Solomonic decision.

335
00:25:08,000 --> 00:25:12,000
He decided to name it human
immunodeficiency virus.

336
00:25:12,000 --> 00:25:16,000
That was a compromise. And by
the way, some people in less than

337
00:25:16,000 --> 00:25:21,000
charitable mood say, well,
of course he named it human

338
00:25:21,000 --> 00:25:25,000
immunodeficiency virus because
those are almost his own initials.

339
00:25:25,000 --> 00:25:30,000
But, I think that's unfair.
These were his initials.

340
00:25:30,000 --> 00:25:34,000
Here's human immunodeficiency virus.
He named it for a perfectly good

341
00:25:34,000 --> 00:25:38,000
reason. Anyhow, that
broke the Franco-American

342
00:25:38,000 --> 00:25:42,000
diplomatic tension, and now
one began to realize that

343
00:25:42,000 --> 00:25:46,000
HIV or human immunodeficiency
virus attacked T helper cells and

344
00:25:46,000 --> 00:25:50,000
preferentially infected T helper
cells by virtue of the ability of

345
00:25:50,000 --> 00:25:54,000
the virus particle to dock itself
to the CD4 molecules presented on the

346
00:25:54,000 --> 00:25:58,000
surface of these cells. By the
way, what happens afterwards,

347
00:25:58,000 --> 00:26:02,000
after the virus becomes adsorbed
to the surface of an infectable cell

348
00:26:02,000 --> 00:26:07,000
such as a T helper cell. So,
here's the virus particle.

349
00:26:07,000 --> 00:26:13,000
Here's the surface of a T helper
cell. What happens then is these

350
00:26:13,000 --> 00:26:19,000
two lipid bilayers fuse with one
another so that now they became one,

351
00:26:19,000 --> 00:26:25,000
and now the internal contents, the
nucleocapsid which contains the RNA

352
00:26:25,000 --> 00:26:31,000
and the reverse transcriptase now
has direct topological access into

353
00:26:31,000 --> 00:26:36,000
the cytoplasm of the cell.
In fact, the glycoprotein,

354
00:26:36,000 --> 00:26:40,000
the yellow ovals there of human
immunodeficiency virus actually had

355
00:26:40,000 --> 00:26:44,000
two functions. First, it
specifically recognizes

356
00:26:44,000 --> 00:26:48,000
the CD4 molecules to which it
then anchors or adsorbs the virus

357
00:26:48,000 --> 00:26:52,000
particle. And secondly, it
also has fusing functions,

358
00:26:52,000 --> 00:26:56,000
i.e. it's capable of causing
the lipid bilayer of the virion,

359
00:26:56,000 --> 00:27:00,000
or the virus particle, to fuse with
that of the plasma membrane of the

360
00:27:00,000 --> 00:27:05,000
infected target cell.
And, once it's in there,

361
00:27:05,000 --> 00:27:10,000
then the virus can begin
to do its replication. Now,

362
00:27:10,000 --> 00:27:15,000
the replication of the HIV virus
was already pretty well understood by

363
00:27:15,000 --> 00:27:20,000
the time that HIV was discovered in
1982-'83 because of this backlog of

364
00:27:20,000 --> 00:27:25,000
retrovirus research. And
just to review for you how

365
00:27:25,000 --> 00:27:30,000
retroviruses replicate,
RNA is put into the cell,

366
00:27:30,000 --> 00:27:35,000
single stranded RNA. It's
called plus strand RNA because

367
00:27:35,000 --> 00:27:40,000
it is of the same polarity of the
same strandedness as messenger RNA.

368
00:27:40,000 --> 00:27:45,000
If it were complementary
to messenger RNA,

369
00:27:45,000 --> 00:27:51,000
then it would be called minus strand
RNA. This is reverse transcribed by

370
00:27:51,000 --> 00:27:56,000
the reverse transcriptase,
which is carried into the cell.

371
00:27:56,000 --> 00:28:01,000
RT stands for reverse transcriptase.
And now, one gets a double stranded

372
00:28:01,000 --> 00:28:06,000
DNA molecule, a copy of the virus.
And this DNA copy is sometimes

373
00:28:06,000 --> 00:28:11,000
called a provirus.
And just to review,

374
00:28:11,000 --> 00:28:15,000
this provirus is then subsequently
integrated into the chromosomal DNA

375
00:28:15,000 --> 00:28:20,000
of the cell. So,
here's the provirus.

376
00:28:20,000 --> 00:28:25,000
Here's the chromosomal DNA. And
then, this integrated provirus

377
00:28:25,000 --> 00:28:30,000
then serves as a template for
making progeny plus-stranded RNA.

378
00:28:30,000 --> 00:28:34,000
And this progeny plus-stranded
RNA, which is, by the way, forward

379
00:28:34,000 --> 00:28:39,000
transcribed by RNA polymerase too,
which does the bulk of the heavy

380
00:28:39,000 --> 00:28:43,000
lifting in terms of making RNA in
the nucleus, this plus-stranded RNA

381
00:28:43,000 --> 00:28:48,000
can have two functions recall.
One, it can serve as a template on

382
00:28:48,000 --> 00:28:53,000
ribosomes for making viral proteins
such as the viral capsid proteins.

383
00:28:53,000 --> 00:28:57,000
And two, the plus stranded RNA
can in turn be encapsidated,

384
00:28:57,000 --> 00:29:02,000
i.e. it can become
packaged. Encapsidate equals,

385
00:29:02,000 --> 00:29:06,000
it can become packaged by the
viral proteins to make progeny virus

386
00:29:06,000 --> 00:29:10,000
particles, which can then bud,
as I've indicated here, from the

387
00:29:10,000 --> 00:29:14,000
surface of the infected cell.
And in fact, we can imagine three

388
00:29:14,000 --> 00:29:18,000
classes of viral proteins that
are required for replication.

389
00:29:18,000 --> 00:29:23,000
First is the reverse transcriptase,
which is encoded by the viral RNA.

390
00:29:23,000 --> 00:29:27,000
Second are the capsid
proteins which carry the RNA,

391
00:29:27,000 --> 00:29:31,000
and third are the viral
glycoproteins up here which these

392
00:29:31,000 --> 00:29:35,000
glycoprotein spikes which are
trans-membrane proteins that

393
00:29:35,000 --> 00:29:39,000
protrude from the virion, and
allow the virion to adsorb to

394
00:29:39,000 --> 00:29:44,000
the surface of infected cells.
It turns out that this virus has

395
00:29:44,000 --> 00:29:49,000
become an extremely difficult virus
to deal with. For most viruses that

396
00:29:49,000 --> 00:29:54,000
we have encountered over the last
100 years, one has had great success

397
00:29:54,000 --> 00:29:59,000
in making vaccines against
these viruses including,

398
00:29:59,000 --> 00:30:04,000
as we discussed in
great detail, poliovirus.

399
00:30:04,000 --> 00:30:09,000
In fact, for smallpox, another
virus, the vaccine effort

400
00:30:09,000 --> 00:30:14,000
was so successful that about 20
years ago, the last case of smallpox

401
00:30:14,000 --> 00:30:19,000
finally occurred in Eritrea in
northeast African when some herdsmen

402
00:30:19,000 --> 00:30:24,000
had the last documented case.
And since that time, there have

403
00:30:24,000 --> 00:30:29,000
been no documented cases of smallpox
in the wild, and there's only two or

404
00:30:29,000 --> 00:30:34,000
three stocks of
smallpox virus surviving.

405
00:30:34,000 --> 00:30:37,000
One of them is in some type
of research center is Moscow,

406
00:30:37,000 --> 00:30:41,000
and the other is probably in the
Communicable Disease Center in

407
00:30:41,000 --> 00:30:44,000
Atlanta, Georgia. And,
there's been great debate,

408
00:30:44,000 --> 00:30:48,000
by the way. Should one get
rid of those surviving stalks,

409
00:30:48,000 --> 00:30:51,000
or should one keep them for research?
By now, you guys aren't vaccinated

410
00:30:51,000 --> 00:30:55,000
against smallpox because nobody gets
it anymore, and there's a certain

411
00:30:55,000 --> 00:30:59,000
risk of getting a
small pox vaccine.

412
00:30:59,000 --> 00:31:02,000
I am, so I'm not worried, but
maybe you should be because

413
00:31:02,000 --> 00:31:06,000
starting about 20-25 years ago,
one stopped vaccinating people

414
00:31:06,000 --> 00:31:10,000
against smallpox because it just
doesn't seem to be necessary.

415
00:31:10,000 --> 00:31:14,000
Why give them the risk of having
some disease which happens in one

416
00:31:14,000 --> 00:31:18,000
out of a million vaccinees (sic)
instead of just leaving them

417
00:31:18,000 --> 00:31:22,000
unvaccinated? Well, I
digress. Back to HIV,

418
00:31:22,000 --> 00:31:26,000
the fact is we've had enormous lack
of success in making a good kind of

419
00:31:26,000 --> 00:31:30,000
vaccine against
HIV, and why is that?

420
00:31:30,000 --> 00:31:34,000
Well, one of the critical things
is that HIV is attacking and

421
00:31:34,000 --> 00:31:38,000
replicating in the T helper cells,
and the T helper cells it turns out

422
00:31:38,000 --> 00:31:42,000
are the lynch pains of the immune
response. Keep in mind that the T

423
00:31:42,000 --> 00:31:46,000
helper cells that I've shown you
in this diagram over here represent

424
00:31:46,000 --> 00:31:50,000
these critical cellular messengers
between the dendritic cells and the

425
00:31:50,000 --> 00:31:54,000
macrophages on the one hand,
and the B cells on the other.

426
00:31:54,000 --> 00:31:58,000
You wipe them out, and the
ability to make new antibodies is

427
00:31:58,000 --> 00:32:03,000
totally compromised. It turns
out the T helper cells can

428
00:32:03,000 --> 00:32:09,000
also help to make another class of
cells which are called cytotoxic T

429
00:32:09,000 --> 00:32:16,000
cells, another kind of T cell,
cytotoxic, and these cytotoxic T

430
00:32:16,000 --> 00:32:23,000
cells have on their surfaces T cell
receptors, which they can use to

431
00:32:23,000 --> 00:32:30,000
recognize infected cells,
and kill infected cells.

432
00:32:30,000 --> 00:32:34,000
So, the cytotoxic T cells aren't
involved in making antibody

433
00:32:34,000 --> 00:32:38,000
responses at all. The
cytotoxic T cells are involved

434
00:32:38,000 --> 00:32:42,000
in recognizing cells that are
expressing unusual or foreign

435
00:32:42,000 --> 00:32:46,000
antigens on their surface, and
killing those cells. That's the

436
00:32:46,000 --> 00:32:50,000
function of the cytotoxic T cells.
Obviously, it's quite different

437
00:32:50,000 --> 00:32:54,000
from the helper T cells. But
once again, the activation of

438
00:32:54,000 --> 00:32:58,000
the cytotoxic T cells, and
empowering them to make these

439
00:32:58,000 --> 00:33:02,000
attacks on abnormal cells
depends on the helper T cells.

440
00:33:02,000 --> 00:33:06,000
Once again, the helper T
cells represent the lynch pins,

441
00:33:06,000 --> 00:33:10,000
the keystones, of the
immune response. But,

442
00:33:10,000 --> 00:33:14,000
because of this tropism, and
when I use the word tropism,

443
00:33:14,000 --> 00:33:19,000
I mean because of the desire of the
virus to phase towards and infect a

444
00:33:19,000 --> 00:33:23,000
certain subset of cells in the body,
this tropism of HIV for infecting

445
00:33:23,000 --> 00:33:27,000
and killing helper T cells,
the production of antibodies is

446
00:33:27,000 --> 00:33:31,000
strongly compromised on the one hand,
and the production of cytotoxic T

447
00:33:31,000 --> 00:33:36,000
cells is compromised
on the other.

448
00:33:36,000 --> 00:33:40,000
There's another aspect of HIV
infection which is also very

449
00:33:40,000 --> 00:33:45,000
insidious, and that's the following.
It turns out that the body can

450
00:33:45,000 --> 00:33:50,000
initially make an immune response
against an infecting HIV particle.

451
00:33:50,000 --> 00:33:55,000
And here's kind of what things look
like. I hope this shows up here.

452
00:33:55,000 --> 00:34:00,000
Who could lend me a
laser pointer again?

453
00:34:00,000 --> 00:34:05,000
Excellent, thank you. OK,
so here's what happens.

454
00:34:05,000 --> 00:34:10,000
And, there's two graphs here.
On one hand are the cytotoxic T

455
00:34:10,000 --> 00:34:16,000
cells, and their level is
shown on the solid line here.

456
00:34:16,000 --> 00:34:21,000
So, look at the course of infection.
It's plotted here in weeks and

457
00:34:21,000 --> 00:34:26,000
years. If you see what happens
in a primary HIV infection,

458
00:34:26,000 --> 00:34:32,000
and here on the right on this
ordinate here is the viral titer

459
00:34:32,000 --> 00:34:37,000
indicated on a log scale. So,
this is a semi-log graph for the

460
00:34:37,000 --> 00:34:41,000
viral titer. And what you see over
here is that when you initially

461
00:34:41,000 --> 00:34:45,000
infected it, there's an
enormous burst of viral titer.

462
00:34:45,000 --> 00:34:49,000
It goes up by four or five orders
of magnitude, and then it falls down

463
00:34:49,000 --> 00:34:53,000
dramatically by two or three
orders of magnitude. And it goes on,

464
00:34:53,000 --> 00:34:57,000
and it remains depressed by two or
three orders of magnitude below its

465
00:34:57,000 --> 00:35:02,000
initial height for
a number of years.

466
00:35:02,000 --> 00:35:06,000
What's going on then? The
immune system has come to grips

467
00:35:06,000 --> 00:35:10,000
with the presence of the HIV virus,
and begins successfully to try to

468
00:35:10,000 --> 00:35:14,000
eliminate it. How does the
immune system eliminate HIV?

469
00:35:14,000 --> 00:35:18,000
By two mechanisms. First of all,
the immune system makes neutralizing

470
00:35:18,000 --> 00:35:22,000
antibodies of the sort that
float through the serum,

471
00:35:22,000 --> 00:35:26,000
and are able to glom onto the
virus particle, attach to the virus

472
00:35:26,000 --> 00:35:30,000
particle, and thereby prevent
it from being infectious.

473
00:35:30,000 --> 00:35:34,000
And secondly, as I mentioned last
time, the immune system also can

474
00:35:34,000 --> 00:35:38,000
recognize virus-infected cells
and kill them. And by killing a

475
00:35:38,000 --> 00:35:42,000
virus-infected cell, the
immune system prevents that cell

476
00:35:42,000 --> 00:35:46,000
from continuing to function as a
factory for putting out new virus

477
00:35:46,000 --> 00:35:50,000
particles. So, there's
two ways by which virus

478
00:35:50,000 --> 00:35:54,000
particles are eliminated,
but note here that the virus

479
00:35:54,000 --> 00:35:58,000
infected cell which is critically
important among all the cell types

480
00:35:58,000 --> 00:36:02,000
in the body are
the T helper cells.

481
00:36:02,000 --> 00:36:06,000
So, certain components of the immune
system are killing the T helper

482
00:36:06,000 --> 00:36:10,000
cells that are involved in
harboring and producing HIV virus.

483
00:36:10,000 --> 00:36:14,000
So, there's an auto destruction
on the part of the immune system.

484
00:36:14,000 --> 00:36:19,000
Look, at the same time, at the
titer, at the number of CD4 cells,

485
00:36:19,000 --> 00:36:23,000
and they're indicated
here on the left ordinate,

486
00:36:23,000 --> 00:36:27,000
in this case, cells per microliter.
CD4 cells originally started up

487
00:36:27,000 --> 00:36:32,000
here. They go down
by a factor of two or

488
00:36:32,000 --> 00:36:36,000
three for the first weeks,
and then over a period of years

489
00:36:36,000 --> 00:36:40,000
there's this ongoing struggle
between the HIV particle and the

490
00:36:40,000 --> 00:36:44,000
immune system as the number of CD4
cells, and the CD4 cells we've said

491
00:36:44,000 --> 00:36:48,000
before, the CD4 positive cells are
these T helper cells as the number

492
00:36:48,000 --> 00:36:52,000
of these cells per microliter of
blood progressively declines further

493
00:36:52,000 --> 00:36:56,000
and further and further. And
finally, the number of CD4

494
00:36:56,000 --> 00:37:00,000
positive cells,
i.e. T helper cells,

495
00:37:00,000 --> 00:37:04,000
gets so low that the body is totally
overwhelmed, and the patient then

496
00:37:04,000 --> 00:37:08,000
dies of an
opportunistic infection.

497
00:37:08,000 --> 00:37:12,000
What do I mean by an
opportunistic infection? Well,

498
00:37:12,000 --> 00:37:16,000
what I mean is that we are
surrounded all the time by all kinds

499
00:37:16,000 --> 00:37:21,000
of microbes, which given the chance
will kill us within a couple days.

500
00:37:21,000 --> 00:37:25,000
Keep in mind, I told you
that there are in your gut,

501
00:37:25,000 --> 00:37:30,000
as many bacterial cells as
there are the rest of your body.

502
00:37:30,000 --> 00:37:33,000
And some of these bacteria
are really nasty. I remember,

503
00:37:33,000 --> 00:37:36,000
my grandfather got kicked
in the belly by a horse,

504
00:37:36,000 --> 00:37:40,000
and three days later he was dead.
Why? Because some of the bacteria

505
00:37:40,000 --> 00:37:43,000
got out of his gut, got into
his peritoneal fluid cavity,

506
00:37:43,000 --> 00:37:47,000
and gone. This was
the pre-antibiotic era,

507
00:37:47,000 --> 00:37:50,000
by the way, never new him very
well because he died in 1916.

508
00:37:50,000 --> 00:37:54,000
I'm just telling you that your gut
is full of all kinds of nasty thing

509
00:37:54,000 --> 00:37:57,000
on your skin. Not just on my skin,
but on your skin there are billions

510
00:37:57,000 --> 00:38:01,000
of staph aureus bacteria.
They're just waiting to cause you

511
00:38:01,000 --> 00:38:05,000
problems. Don't
look. It's OK.

512
00:38:05,000 --> 00:38:09,000
Don't look too closely.
They're just waiting to cause a

513
00:38:09,000 --> 00:38:13,000
nasty infection as well. Everyday
we breathe in all kinds of

514
00:38:13,000 --> 00:38:17,000
awful microbes, fungi, and
all these kinds of things

515
00:38:17,000 --> 00:38:21,000
including pneumocystis. And,
rarely do we get sick because

516
00:38:21,000 --> 00:38:25,000
of the extraordinary competence of
the immune system to respond to such

517
00:38:25,000 --> 00:38:30,000
a diversity of infectious
agents, and to hold them at bay.

518
00:38:30,000 --> 00:38:34,000
In the 20th century, the
percentage of people who die of

519
00:38:34,000 --> 00:38:38,000
infectious diseases has plummeted
both because of the immune system

520
00:38:38,000 --> 00:38:42,000
and because we're eating
healthier up to a point,

521
00:38:42,000 --> 00:38:46,000
and because of antibiotics and
antifungals. But if the immune

522
00:38:46,000 --> 00:38:50,000
system is defective, all
the antibiotics in the world,

523
00:38:50,000 --> 00:38:54,000
and all the antifungal agents can't
save a patient if their CD4 cells

524
00:38:54,000 --> 00:38:58,000
get down very, very low
because these antifungals

525
00:38:58,000 --> 00:39:03,000
always worked as collaborators
with the immune system.

526
00:39:03,000 --> 00:39:07,000
They get rid of a bulk of the
infection, but the immune system has

527
00:39:07,000 --> 00:39:11,000
to wipe out the residue. And
what you see here is a struggle

528
00:39:11,000 --> 00:39:15,000
going on for a period of three,
four, five, six years where the

529
00:39:15,000 --> 00:39:19,000
viral titer is successfully held
low, and then all of a sudden as the

530
00:39:19,000 --> 00:39:23,000
immune system weakens the viral
titer goes up to high levels,

531
00:39:23,000 --> 00:39:27,000
wipes out the residual T helper
cells, and death invariably

532
00:39:27,000 --> 00:39:31,000
ensues. Now, I've
given you one reason why

533
00:39:31,000 --> 00:39:34,000
the immune system can't deal with
this virus, because virtually all

534
00:39:34,000 --> 00:39:38,000
other viruses attack various
tissues throughout our body,

535
00:39:38,000 --> 00:39:41,000
but they don't attack
the immune system itself.

536
00:39:41,000 --> 00:39:44,000
Here, we're having a virus which is
attacking the defense of the body,

537
00:39:44,000 --> 00:39:48,000
that is to say, the immune system.
So, one reason is the continuing

538
00:39:48,000 --> 00:39:51,000
depletion of the T helper cells.
They can regenerate themselves for

539
00:39:51,000 --> 00:39:54,000
a period of time, very
impressively long period of

540
00:39:54,000 --> 00:39:58,000
time, four, five, six,
seven years. But ultimately,

541
00:39:58,000 --> 00:40:02,000
they get worn out, they die.
Another reason is this is antigenic

542
00:40:02,000 --> 00:40:08,000
variation. Now, if you
look at the retrovirus

543
00:40:08,000 --> 00:40:14,000
particle, what you see is on
the surface the glycoprotein.

544
00:40:14,000 --> 00:40:19,000
It's right here. And, the
glycoprotein is used by antibodies

545
00:40:19,000 --> 00:40:25,000
to recognize and bind to the
virus particle and neutralize it,

546
00:40:25,000 --> 00:40:30,000
same as with poliovirus.
But let's imagine,

547
00:40:30,000 --> 00:40:34,000
as happens to be the case, that
the virus is highly error prone

548
00:40:34,000 --> 00:40:39,000
in replicating its genome. When
I say error prone, I mean that

549
00:40:39,000 --> 00:40:44,000
instead of the host cell,
polymerase, which makes ultimately

550
00:40:44,000 --> 00:40:48,000
one mistake out of a billion,
the viral replication machinery

551
00:40:48,000 --> 00:40:53,000
makes mistakes all the time.
It's quite defective in the

552
00:40:53,000 --> 00:40:58,000
fidelity and the faithfulness with
which it replicates nucleic acid.

553
00:40:58,000 --> 00:41:02,000
That means that after each cycle
of replication, there are in effect

554
00:41:02,000 --> 00:41:07,000
mutant viruses that have been
produced, mutant progeny viruses,

555
00:41:07,000 --> 00:41:11,000
and where the mutation rate instead
of being one in 10-9 might be one in

556
00:41:11,000 --> 00:41:16,000
10-2 or one in 10-3. And
that means that there are

557
00:41:16,000 --> 00:41:20,000
continually novel variants of HIV
being produced in a person's body.

558
00:41:20,000 --> 00:41:25,000
Let's imagine that that person has
developed antibodies against the

559
00:41:25,000 --> 00:41:30,000
viral glycoprotein of the virus
that initially infected him or her.

560
00:41:30,000 --> 00:41:34,000
Let's imagine that. And those
antibodies are successful

561
00:41:34,000 --> 00:41:38,000
in eliminating most of the virus
particles of the sort that initially

562
00:41:38,000 --> 00:41:42,000
infected that individual.
But now we can imagine the

563
00:41:42,000 --> 00:41:46,000
possibility that in the
imperative weeks or months,

564
00:41:46,000 --> 00:41:50,000
a new strain of HIV will arise
within that individual's body a

565
00:41:50,000 --> 00:41:54,000
mutant strain in which the sequences
that code the viral glycoprotein had

566
00:41:54,000 --> 00:41:58,000
been changed slightly. And
now, the viral glycoprotein has

567
00:41:58,000 --> 00:42:02,000
changed slightly its epitopes.
And the initially developed

568
00:42:02,000 --> 00:42:07,000
neutralizing antibody that
recognized the initial cohort of

569
00:42:07,000 --> 00:42:12,000
virus coming into the cell in the
individual no longer works because

570
00:42:12,000 --> 00:42:17,000
the virus has undertaken a
strategy of immune evasion,

571
00:42:17,000 --> 00:42:22,000
sometimes it's called immunoevasion,
in which now the viral glycoprotein,

572
00:42:22,000 --> 00:42:27,000
although it's still competent to
affect a replication cycle to adsorb

573
00:42:27,000 --> 00:42:32,000
and fuse to the surface
of an affected cell.

574
00:42:32,000 --> 00:42:36,000
Many of the epitopes, many of
the oligopeptide antigens on

575
00:42:36,000 --> 00:42:40,000
the surface of the glycoprotein have
been changed slightly through amino

576
00:42:40,000 --> 00:42:44,000
acid substitutions,
through point mutations.

577
00:42:44,000 --> 00:42:48,000
And hence, the initially developed
antibody, which previously was

578
00:42:48,000 --> 00:42:52,000
successful in glomming on and
neutralizing this virus particle is

579
00:42:52,000 --> 00:42:56,000
rendered ineffective.
And now, this second wave,

580
00:42:56,000 --> 00:43:00,000
this new strain of HIV will grow
up and expand in that individual,

581
00:43:00,000 --> 00:43:04,000
and once again provoke
a new immune response.

582
00:43:04,000 --> 00:43:07,000
And, the same cycle will repeat it.
The second strain will now soon be

583
00:43:07,000 --> 00:43:11,000
eliminated, but while the
elimination is going on,

584
00:43:11,000 --> 00:43:15,000
there's strong Darwinian selective
pressure favoring the outgrowth of

585
00:43:15,000 --> 00:43:19,000
yet another mutant strain which is
not recognized by either of the two

586
00:43:19,000 --> 00:43:23,000
initial antibody responses.
And so, over this period of many

587
00:43:23,000 --> 00:43:27,000
years, what's happening is that
the virus in the immune system are

588
00:43:27,000 --> 00:43:31,000
playing continual cat and
mouse games with one another.

589
00:43:31,000 --> 00:43:34,000
The immune system goes after the
virus; the virus moves over here;

590
00:43:34,000 --> 00:43:38,000
the immune system goes after that;
and so you have a succession of

591
00:43:38,000 --> 00:43:42,000
antigenic variance.
Here's one variant.

592
00:43:42,000 --> 00:43:45,000
Here's another variant.
Here's another variant, and so

593
00:43:45,000 --> 00:43:49,000
forth. By the time the immune
system succeeds in getting rid of

594
00:43:49,000 --> 00:43:53,000
the first variant, a
new variant has appeared,

595
00:43:53,000 --> 00:43:57,000
and then the immune system ramps up
its defenses and tries to get rid of

596
00:43:57,000 --> 00:44:00,000
that. And, it succeeds almost.
But by the time that has happened,

597
00:44:00,000 --> 00:44:04,000
yet a third variant has appeared.
And so, there are these continual

598
00:44:04,000 --> 00:44:08,000
clonal successions. A clonal
succession represents a

599
00:44:08,000 --> 00:44:11,000
time where one clonal virus explodes,
expands. It's soon eliminated,

600
00:44:11,000 --> 00:44:15,000
collapses, and then another
clone comes up and expands.

601
00:44:15,000 --> 00:44:19,000
And this goes on. This
works OK for about four,

602
00:44:19,000 --> 00:44:22,000
five, six years. But
ultimately, the ability of the

603
00:44:22,000 --> 00:44:26,000
T helper cells to replenish
themselves and to continue to mount

604
00:44:26,000 --> 00:44:30,000
an effective immune
response fails.

605
00:44:30,000 --> 00:44:34,000
There's yet another aspect of HIV
infection which is so insidious,

606
00:44:34,000 --> 00:44:38,000
and that's the following. Let's
look at the viral life cycle right

607
00:44:38,000 --> 00:44:42,000
here, and the provirus, remember
the provirus is this thing

608
00:44:42,000 --> 00:44:46,000
right here, which is integrated
into the chromosomal DNA.

609
00:44:46,000 --> 00:44:50,000
And, we can assume that this
provirus is transcribed by RNA

610
00:44:50,000 --> 00:44:54,000
polymerase too, and I
will tell you that the

611
00:44:54,000 --> 00:44:58,000
promoter of the provirus is
carried in by the proviral DNA,

612
00:44:58,000 --> 00:45:02,000
and actually depends on
transcription factors that are

613
00:45:02,000 --> 00:45:07,000
present in the T helper cell.
In fact, you'll recall that the T

614
00:45:07,000 --> 00:45:11,000
helper cell gets excited sometimes,
and other times it's not excited.

615
00:45:11,000 --> 00:45:15,000
And she gets excited if I can
attach gender to a T helper cell,

616
00:45:15,000 --> 00:45:20,000
when she encounters
macrophages and dendritic cells,

617
00:45:20,000 --> 00:45:24,000
and/or when she encounters B cells.
Other times, the T helper cell is

618
00:45:24,000 --> 00:45:28,000
kind of quiet and unactivated (sic).
And, what happens when a T helper

619
00:45:28,000 --> 00:45:33,000
cell gets activated
through these encounters?

620
00:45:33,000 --> 00:45:37,000
The T helper cell starts making
her own transcription factors,

621
00:45:37,000 --> 00:45:41,000
which are used in order to
facilitate these complex biological

622
00:45:41,000 --> 00:45:45,000
interactions with both
antigen-presenting cells,

623
00:45:45,000 --> 00:45:49,000
macrophages and dendritic cells,
and later on, B cells. And those

624
00:45:49,000 --> 00:45:53,000
same transcription factors that the
T helper cell uses to turn on its

625
00:45:53,000 --> 00:45:57,000
own expression program are used
by the provirus to transcribe

626
00:45:57,000 --> 00:46:01,000
its own DNA, i.e. HIV
has evolved a proviral

627
00:46:01,000 --> 00:46:05,000
promoter sequence here which takes
advantage of transcription factors

628
00:46:05,000 --> 00:46:09,000
that are present uniquely
in an activated T cell.

629
00:46:09,000 --> 00:46:13,000
And when those transcription
factors are available,

630
00:46:13,000 --> 00:46:17,000
not only does the T cell become
activated, but the provirus becomes

631
00:46:17,000 --> 00:46:21,000
transcribed because these
transcription factors now enable RNA

632
00:46:21,000 --> 00:46:25,000
polymerase 2 of the host
to transcribe the provirus.

633
00:46:25,000 --> 00:46:29,000
But let's imagine now, if we follow
that scenario to its conclusion,

634
00:46:29,000 --> 00:46:33,000
what happens when the
T cell is not activated?

635
00:46:33,000 --> 00:46:37,000
When the T cell is quiescent, when
it's quiet, these transcription

636
00:46:37,000 --> 00:46:41,000
factors are unavailable to attach
to the promoter of the integrated

637
00:46:41,000 --> 00:46:45,000
provirus, and as a consequence the
provirus will not be transcribed.

638
00:46:45,000 --> 00:46:49,000
It won't make RNA, and in that
situation, how will anybody know

639
00:46:49,000 --> 00:46:53,000
that there's an integrated
provirus in there? Well,

640
00:46:53,000 --> 00:46:57,000
the provirus is not being
transcribed. The transcripts aren't

641
00:46:57,000 --> 00:47:02,000
being used to make viral protein.
So in effect, the only evidence for

642
00:47:02,000 --> 00:47:06,000
the existence of HIV in the
cell is this segment of DNA.

643
00:47:06,000 --> 00:47:10,000
In other words, this provirus can
hide out in an unactivated quiescent

644
00:47:10,000 --> 00:47:14,000
T cell indefinitely. And,
the immune system can't know

645
00:47:14,000 --> 00:47:18,000
that there's a provirus hiding out
in this T helper cell because it's

646
00:47:18,000 --> 00:47:22,000
not being transcribed. And
therefore, one can have a

647
00:47:22,000 --> 00:47:26,000
quiescent T helper cell, and
several other cell types in the

648
00:47:26,000 --> 00:47:30,000
body, macrophages also, which
aren't transcribing their

649
00:47:30,000 --> 00:47:34,000
proviruses.
Well, you'll say,

650
00:47:34,000 --> 00:47:38,000
so what? It doesn't make any
difference. If it's not being

651
00:47:38,000 --> 00:47:42,000
transcribed, it's not going
to hurt the individual.

652
00:47:42,000 --> 00:47:46,000
But, keep in mind that the idea of
getting rid of a viral infection is

653
00:47:46,000 --> 00:47:49,000
to eliminate all traces of a viral
genome from an infected individual,

654
00:47:49,000 --> 00:47:53,000
and that's what happens with
smallpox and with poliovirus,

655
00:47:53,000 --> 00:47:57,000
and with measles and virtually
all the other infections we have.

656
00:47:57,000 --> 00:48:01,000
But here, we have a situation where
the viral genome can hide out in a

657
00:48:01,000 --> 00:48:05,000
latent or inapparent
(sic) configuration.

658
00:48:05,000 --> 00:48:09,000
There's no way to know it's there,
and it may reemerge days, weeks,

659
00:48:09,000 --> 00:48:13,000
months, even years later because
this previously transcriptionally

660
00:48:13,000 --> 00:48:17,000
silent provirus may suddenly be
present in a cell which suddenly

661
00:48:17,000 --> 00:48:22,000
becomes activated. And
now, an individual who

662
00:48:22,000 --> 00:48:26,000
"thought" quote unquote that he or
she had gotten rid of HIV infection

663
00:48:26,000 --> 00:48:30,000
all of a sudden realizes there
are viral genomes still hiding

664
00:48:30,000 --> 00:48:34,000
out in the body. And
what that means is that in

665
00:48:34,000 --> 00:48:38,000
effect, it's absolutely impossible
to rid the body of HIV infection

666
00:48:38,000 --> 00:48:42,000
ever. Once an individual
is infected, in fact,

667
00:48:42,000 --> 00:48:46,000
that individual is infected for
life. There's no way on Earth what we

668
00:48:46,000 --> 00:48:50,000
have at present of getting rid
of the viral infection because the

669
00:48:50,000 --> 00:48:54,000
viral genome is always hiding
out here or there in different

670
00:48:54,000 --> 00:48:58,000
interstices of the immune system,
hiding out in transcriptionally

671
00:48:58,000 --> 00:49:02,000
silent state. Of course,
we have very effective

672
00:49:02,000 --> 00:49:06,000
drugs against HIV now. Some
drugs inhibit the reverse

673
00:49:06,000 --> 00:49:10,000
transcriptase. Others
inhibit the processing of

674
00:49:10,000 --> 00:49:14,000
the capsid proteins, that
is, the proteins which these

675
00:49:14,000 --> 00:49:19,000
capsid proteins happen to be cleaved
from a large, high molecular-weight

676
00:49:19,000 --> 00:49:23,000
protein precursor into individual
proteins, and there's an inhibitor

677
00:49:23,000 --> 00:49:27,000
of the protease that cleaves
these proteins to the mature size.

678
00:49:27,000 --> 00:49:31,000
And, those drugs together hold the
viral infection at bay for maybe 10,

679
00:49:31,000 --> 00:49:36,000
15, 20 years. But keep
in mind that even though

680
00:49:36,000 --> 00:49:40,000
the viral infection is
being stopped by these drugs,

681
00:49:40,000 --> 00:49:45,000
first of all, the virus is always
hiding out in the bodies of such

682
00:49:45,000 --> 00:49:49,000
individuals in this latent, hidden
form, and secondly, there may

683
00:49:49,000 --> 00:49:54,000
be a slow depletion of their
T helper cells in spite of the

684
00:49:54,000 --> 00:49:58,000
effectiveness of these drugs. On
that cheerful note, I wish you a

685
00:49:58,000 --> 00:50:03,000
good day.