It comes acquainted with different antigens.
And recall that what we were talking
about was the following, that there were several kinds of
phagocytic cells. Phagocytic cells are cells that
chew up other things, both macrophages and even more
frequently, dendritic cells, many of which hang around lymph
nodes by the way. They process antigens into
oligopeptides. The oligopeptides get presented on
the surface of these cells. Let's say, here's a macrophage,
in the form of through the class 2 MHC molecules which are displayed on
the surfaces of the cells. And, here's a typical oligopeptide
that has been chewed up from one of the antigens that was previously
internalized, eaten up by the macrophage, a dendritic cell,
and then presented on the surface. Recall, then, we have an itinerant
macrophage or dendritic cell. Could we turn up the sound just a
little, just a notch? Thank you. And this dendritic cell
or macrophage, I'll just call it a macrophage for
the moment, is then moving largely through the lymph nodes,
but wherever it moves, it's carrying along this oligopeptide.
And recall that we liken this voyage of it to a Middle Eastern market
where there's a lot of bazaar stalls on either side of the road,
and where instead of the usual male merchants, there's a lot of female
merchants hanging out. And these females are called T
helper cells. They're a kind of T lymphocyte or T
cell. TH refers to their function. And here, all of these T helper
cells, I'll indicate each of them here as a pink circle.
And these T helper cells display on their surface to blow them up to a
large size a T cell receptor that is organized much the way
immunoglobulin molecule and antibody molecule's organized.
That is to say, it has variable and constant regions.
It's generated through the rearrangement of antibody-like genes.
But it only functions, this T cell receptor or as it's
called in the trade the TCR, only functions to sense the presence
of antigens in the extracellular space. In fact,
it senses antigens in the context of the MHC class 2.
So here's an MHC class 2 molecule. We can think of the MHC class 2 as
being a hand, which is presenting this oligopeptide.
I haven't drawn a hand, but you can pretend it's a hand.
And this MHC class 2 is being presented by either a macrophage or
a dendritic cell. And recall, we talked about the
voyage of this macrophage or dendritic cell through this street
here, and all these T helper cells are kind of lazily waiting along on
the sidelines looking at what this phagocytic cell is hocking.
Most of the T helper cells are totally uninterested in what he's
hocking. But one of them is struck. It's love at first sight, this one
over here, let's say, because her T cell receptor
precisely recognizes this oligopeptide in the context of the
MHC class 2 molecule. And, obviously I would like to draw
thousands of these T helper cells here, each of which bears a
different T cell receptor on her surface. I'm only showing one.
And recall that after they make this encounter,
the T helper cell gets all excited because she says,
oh, I can't believe it, you have exactly the oligopeptide
that's recognized by my receptor. And so, she gets all excited, and
what she does is she proliferates because that's about all that
excited cells can do. Well, they can do other things,
but again, we don't want to talk about it. Anyhow,
so this particular T helper cell undergoes a clonal expansion,
and is now activated, i.e. activated not only psychologically but
physiologically by having encountered the antigen-presenting
cell. The MHC class 2, the macrophage is called an
antigen-presenting cell. It's using its MHC class 2 molecules
to do so. Macrophages and dendritic cells are pretty much similar in
this respect. Macrophages go all over the body in the tissues.
Dendritic cells tend to inhabit the lymph nodes. But from the point of
view of our discussion today, we can imagine that they're
functionally essentially equivalent. And having said that, now these T
helper cells go looking for a congenial B cell.
So, now we have a third actor in the drama, and the congenial B cell
looks like this. And, the B cell has the following
thing. The B cell has also on its surface, MHC class 2 molecules,
which can be used in antigen presentation. But the B cell has an
addition as we said last time, already, on its surface, IGM
molecules. An IGM is a brand of antibody.
Keep in mind that really one of the paradoxes that we haven't really
fully settled on is the following question or the following issue.
How is it that when a B cell sees a cognate antigen,
why does it get stimulated? In other words, what is it that
induces the B cell to start proliferating?
Here's another version of what I showed you last time,
where a B cell which makes the right antibody gets stimulated,
but a B cell that doesn't does not get stimulated.
And that's the issue we're wrestling with right now.
So here on the surface of this B cell is an IGM molecule.
Keep in mind an IGM molecule is an antibody molecule.
Immunoglobulin means IG. It's the earliest form of antibody
that's made. Once again, it is antigen specific.
Its variable region has been rearranged through the fusion of
different VDJ segments and somatic hypermutation.
And, this B cell has a very interesting property.
This is a naïve cell, and what this B cell does is as
follows. It moves around the body, and if this B cell happens to find
an antigen, which is recognized by its antibody, the IGM antibody.
Then the B cell will bind this antigen using its IGM molecule to do
so. More importantly, it will then internalize this
antigen and chew it up into little pieces, and then present it on it
surface via the MHC class 2 molecule. So, let's just review what
we've been saying. Before, we were talking about
macrophages and dendritic cells, which gobbled up whatever they could,
processed whatever they gobbled up, and put it on the surface again as
MHC class 2, and therefore the macrophages and the dendritic cells
are really like sewer rates. They'll just chew on anything and
they'll put it on their surface. They're totally promiscuous in what
they present on their surface. But here, the B cell is doing
something rather similar. But the B cell isn't presenting
whatever it happens to stumble across on its surface.
The B cell is extraordinarily selective at what it presents on its
surface. It only presents on its surface those antigens which are
recognized by its IGM molecule. So here, it uses its IGM molecule
to grab hold of this antigen. It internalizes the antigen, and
then presents it back on the surface as an MHC class 2 molecule.
So, there's a profound contrast in the behavior of these two kinds of
antigen-presenting cells. The macrophages and dendritic cells,
they just gobble up everything, and whatever they find,
they put on their surface. They don't care with MHC class 2.
The B cell is extraordinarily selective and specific.
It will pull in not through regular phagocytosis. It will pull in using
its IGM receptor, specific antigens that are
recognized by its IGM molecule, and then externalize it using its
MHC class 2 molecule to do so. Let's go back to the drama of the
activated T helper cell, and here's the activated T helper
cell. We'll draw her in pink. The T helper cell has just had an
encounter with a macrophage, or dendritic cell. And, she's just
left this marketplace. And now, she's very excited.
So here is her T cell receptor. And she's very excited. She's
putting out all kinds of growth factors and multiplying
all over the place. And she starts looking again now for
a B cell with which he can react. Now, most of the B cells in the
body will not have an epitope that she recognizes.
Most of the B cells in the body will have picked up other kinds of
things that happen to recognize by their T cell receptor,
and will present it on the surface. A rare B cell will happen to
internalize an antigen, and put on the surface, which is the
same antigen that was recognized previously in the previous
encounter. And so, now this T helper cell goes
around looking for an attractive male. What's an attractive male for
her? An attractive male for her is one whose MHC class 2 molecule is
recognized directly in the context, and this oligopeptide is recognized
by her T cell receptor. And so, she'll come over here and
she'll say excitedly to the B cell, you can't believe what just happened.
She will say, I was just there. I just went through the market.
I was sitting there in the marketplace, and along came a
macrophage, and presented me with an oligopeptide that exactly fit in my
T cell receptor. And now, she says excitedly,
here I find a B cell has exactly the same oligopeptide presenting it to
me. Isn't that a coincidence? And the B cell says, come on lady,
get to the point. And she says, I just had an encounter with a
macrophage dendritic cell. I recognized the same oligopeptide
in the macrophage dendritic cell that you have.
And, the B cell says, well, I guess this must be some kind
of meaningful encounter, and so these two cells get together.
And what happens now is that the T cell, having recognized the
oligopeptide, presented on the surface of the B cell now begins to
send out signals to stimulate the B cell to proliferate.
And this B cell now begins to proliferate. And this B cell now
begins to proliferate, as is indicated on this overhead,
and eventually it starts making IGM molecules. It makes more of them,
and then through the class switching that we talked about last time,
it'll make eventually IGG secreted antibody gamma globulin molecules.
So you see here the three essential cell types that participate in this.
And why is it so complicated? Because it's extraordinarily
important that the immune system doesn't inadvertently make
antibodies that are inappropriate to express, because as we said before,
if a certain of those antibodies and indeed possibly many of them could
be autoreactive. And what do I mean by autoreactive?
I mean reactive with self. They could be antibodies that react with
one's own tissues. And in so doing, they could create
series kinds of autoimmune diseases. So, we have this sequence of
failsafe reactions. So, when finally the decision for
the B cell to get activated depends on a previous encounter with the
same oligopeptide by a macrophage or dendritic cell,
the T helper cell acting as an intermediary and now activating the
B cell, once the T cell tells the B cell that the T cell has had a
previous encounter with exactly the same oligopeptide,
on that occasion being presented by a macrophage or dendritic cell.
And that is actually the mechanism by which we get this clonal
expansion of B cells in the immune system, and ultimately how we get
the productive antibody molecules. I mean, this is the image I showed
you earlier, but I never really explained to you what the biology
behind that is. I just said that antigen encounter
on the part of the B cell causes that B cell to enjoy clonal
expansion. And now, we've gone through the detail of
deciding how three different cell types interact,
collaborate with one another to create the antibody response because
this B cell then goes on to produce IGM as it already is doing,
and then eventually IGG, and possibly a series of other
immunoglobulins, IGE and IGA which have other
purposes. Now, all of this actually is an important
prelude to our main topic of discussion today, which is
the disease of AIDS. And, let me just add one other
detail to this because the ability of a T helper cell to recognize MHC
class 2 molecules depends on another cell surface molecule expressed by
the T helper cell. And this other T cell surface
molecule is called CD4. CD4, we don't have to worry of what
it stands for. CD4 is not an antigen specific
receptor. CD4, instead, only recognizes MHC class 2
molecules no matter what they're carrying.
So, there are MHC class 2 molecules which I've implied to you can carry
thousands of different oligopeptides. CD4 doesn't care what's being
carried by the MHC class 2. It just binds to MHC class 2
molecules, thereby telling the T helper cell that an encounter has
been made with an antigen-presenting cell.
So, the ligand for CD4 is part of the MHC class 2 molecule.
Now, that all leaves us in a very nice segue to the whole disease of
AIDS. Let's just remember how the disease of AIDS was discovered.
In 1981, there were a group of five young men who were all subsequently
determined to be gay, be homosexual, who were discovered
in San Francisco to have a very unusual kind of immunodeficiency.
They all had night sweats. They got different kinds of
otherwise unusual diseases. For example one of the things they
got was a disease called Kaposi's sarcoma, which was otherwise known
only in old southern Italian and Jewish men, Kaposi's sarcoma.
But these were young men, and they were neither southern Italian
nor Jewish. They got pneumocystis carinii,
which is a microbial infection of the lung. And,
in fact, they got all kinds of herpes virus infections.
And they were all seen in a cluster by an alert physician who saw
something very unusual, and therefore said, perhaps
correctly, that they had acquired immunodeficiency.
Now, this acquired immunodeficiency is a syndrome.
A syndrome, by the way, for your information, is a whole
collection of symptoms that appear together. That's what a syndrome
means. So, this term AIDS came from the fact that they had a whole
series of symptoms. And, this was an acquired
immunodeficiency rather than a congenital immunodeficiency rather
than a congenital immunodeficiency because given the complexity of the
immune system, you can imagine correctly that there
are a lot of people in the world who were born with congenitally
defective immune systems that are immunodeficient from birth because
there's so many different proteins involved in regulating all of these
different immune responses. But this was really different.
It was an acquired immunodeficiency. It was seen in a very special
subgroup, and so the race was on over the next two years to figure
out what was going on.
Now, by coincidence, starting in 1970-'71,
retrovirus research had begun. And as it turned out, retrovirus
search, President Nixon's war on cancer, retrovirus research was
motivated largely by the notion that human cancers are caused by
retrovirus infections. And, that led to the war on cancer.
And the notion behind the war on cancer was totally wrong because it
turns out that only a minute fraction of human cancers have
anything to do with retrovirus infections, although as we've said
earlier, retroviruses proved to be very important tools experimentally
for discovering proto-oncogenes and oncogenes in the genome.
But if you ask, what fraction of human cancers are
actually due to a human being infected by a retrovirus?
It's almost zero. It's a small fraction of a percent.
Nonetheless, in the 1970s, there was an enormous effort made in
trying to figure out all of the biology of retroviruses.
And by the late 1970s, people concluded this was very
interesting science. Indeed, proto-oncogenes and
oncogenes were discovered, but that it was pretty irrelevant to
understanding directly how human cancer arose, which human cancers
could be explained rather by somatic mutations in the genome.
In 1981, the AIDS infection arose. And, what happened subsequently is
that there was a race on to try to find out what the infectious agent
was because it seemed to be an infectious agent.
It was being spread from one gay young man to another that was used
to induce this. And within two years,
by 1983, the culprit retrovirus had been found. I'm telling you this
long song and dance to give you the following insight.
If there had not been a decade of earlier retrovirus research,
it could have taken the scientific community many,
many years to figure out what was causing AIDS. But through
happenstance, through a sheer stroke of luck, by the time the first
individuals suffering from AIDS were encountered in '81,
there was already a backlog of a decade's worth of detailed
retrovirus research, which made it possible to discover,
to discern almost within months what was causing it.
And, the agent that was causing it was a retrovirus.
The retrovirus here has indicated, very schematically, these artists'
drawings never have any resemblance of what things really look like.
And if they do, it's only by coincidence. Let me borrow your
laser pointer here for a second. So here, and this is what a
retrovirus looks like just to give you a feeling.
In the center, there are two single stranded RNA
molecules. The virus is diploid. There's two copies of the genome
for reasons we still don't understand.
Surrounding it is a so-called nucleocapsid, which is responsible
for protecting the RNA molecules. These two pink dots are
reverse-transcriptase molecules because as you'll recall,
when retroviruses infect a cell, they carry the enzyme with them into
the cell. You could say, why don't they make it after they
get into the cell? And it's not totally obvious why,
but this is what they do. There's another shell of proteins out here.
And then, beyond that is a lipid bilayer. And this lipid bilayer is,
as you may recall, stolen from cell from which the
virus is protruding because if you look at retrovirus-infected cells,
here's the plasma membrane of a retrovirus-infected cell.
Here you can see a nucleo-capsid forming with the RNA molecules.
And this shoves its way, protrudes its way through the plasma membrane,
stealing a patch of plasma membrane from the infected cell,
and at the same time this part of the plasma membrane carries with it
viral glycoproteins. And viral glycoproteins,
they're obviously glycosylated, as are many other extracellular
proteins. And in this case, they're indicated with these yellow
ovals, and these viral glycoproteins are used to attach to subsequently
infected cells so what happens is that when the retrovirus gets out of
the cell, I'll draw it again schematically here,
it has this glycoproteins coat on it with the plasma membrane,
and it uses these glycoproteins spikes.
I just won't put the yellow ovals on them, to attach to cells which need
to be infected. So, here's a target cell that needs
to be infected. So, the target cell,
and how does this virus know how to attach to this cell and not to other
cells? Because on the surface of the target cell are certain cellular
proteins, which are used for normal cell physiology,
which are there, and which the virus has opportunistically developed
an affinity for. So here on the surface of a target
cell might be a normal cellular protein to which the viral
glycoprotein combined. Or, if you want to get technical,
this enables the virus particle to adsorb, to attach to.
Notice the D here rather than the B, to adsorb to the surface of the
target cell. Importantly, what's the cell surface protein of
the target cell to which HIV virus adsorbs? It's our old friend CD4.
I.e. the HIV particle likes to adsorb, preferentially adsorbs to
the surface of cells that express the CD4 molecule on the surface.
Note, by the way, that just five minutes ago, we described a totally
different function of CD4. CD4 over here was said to represent
the means by which the T helper cell can recognize MHC molecules being
displayed on the surface of either of these dendritic
cells or B cells. But here we see CD4 in a totally
different context. Here, the CD4 represents the
docking site to which the viral glycoprotein can attach,
enabling the virus, which came to be called human immunodeficiency
virus. In fact, the virus was discovered by
two groups simultaneously, one of them called HDLV-3, the other
called lymphadenopathy virus. The first group was American.
The second group was French, and they allowed Herald Varmus,
one of the co-discoverers of the proto-oncogene to act as sort of the
judge to see what it would be called because there was great political
tension. Would it get the American or the French name depending on
which of the two warring scientists, and they were warring, could claim
discovery? So, he had a Solomonic decision.
He decided to name it human immunodeficiency virus.
That was a compromise. And by the way, some people in less than
charitable mood say, well, of course he named it human
immunodeficiency virus because those are almost his own initials.
But, I think that's unfair. These were his initials.
Here's human immunodeficiency virus. He named it for a perfectly good
reason. Anyhow, that broke the Franco-American
diplomatic tension, and now one began to realize that
HIV or human immunodeficiency virus attacked T helper cells and
preferentially infected T helper cells by virtue of the ability of
the virus particle to dock itself to the CD4 molecules presented on the
surface of these cells. By the way, what happens afterwards,
after the virus becomes adsorbed to the surface of an infectable cell
such as a T helper cell. So, here's the virus particle.
Here's the surface of a T helper cell. What happens then is these
two lipid bilayers fuse with one another so that now they became one,
and now the internal contents, the nucleocapsid which contains the RNA
and the reverse transcriptase now has direct topological access into
the cytoplasm of the cell. In fact, the glycoprotein,
the yellow ovals there of human immunodeficiency virus actually had
two functions. First, it specifically recognizes
the CD4 molecules to which it then anchors or adsorbs the virus
particle. And secondly, it also has fusing functions,
i.e. it's capable of causing the lipid bilayer of the virion,
or the virus particle, to fuse with that of the plasma membrane of the
infected target cell. And, once it's in there,
then the virus can begin to do its replication. Now,
the replication of the HIV virus was already pretty well understood by
the time that HIV was discovered in 1982-'83 because of this backlog of
retrovirus research. And just to review for you how
retroviruses replicate, RNA is put into the cell,
single stranded RNA. It's called plus strand RNA because
it is of the same polarity of the same strandedness as messenger RNA.
If it were complementary to messenger RNA,
then it would be called minus strand RNA. This is reverse transcribed by
the reverse transcriptase, which is carried into the cell.
RT stands for reverse transcriptase. And now, one gets a double stranded
DNA molecule, a copy of the virus. And this DNA copy is sometimes
called a provirus. And just to review,
this provirus is then subsequently integrated into the chromosomal DNA
of the cell. So, here's the provirus.
Here's the chromosomal DNA. And then, this integrated provirus
then serves as a template for making progeny plus-stranded RNA.
And this progeny plus-stranded RNA, which is, by the way, forward
transcribed by RNA polymerase too, which does the bulk of the heavy
lifting in terms of making RNA in the nucleus, this plus-stranded RNA
can have two functions recall. One, it can serve as a template on
ribosomes for making viral proteins such as the viral capsid proteins.
And two, the plus stranded RNA can in turn be encapsidated,
i.e. it can become packaged. Encapsidate equals,
it can become packaged by the viral proteins to make progeny virus
particles, which can then bud, as I've indicated here, from the
surface of the infected cell. And in fact, we can imagine three
classes of viral proteins that are required for replication.
First is the reverse transcriptase, which is encoded by the viral RNA.
Second are the capsid proteins which carry the RNA,
and third are the viral glycoproteins up here which these
glycoprotein spikes which are trans-membrane proteins that
protrude from the virion, and allow the virion to adsorb to
the surface of infected cells. It turns out that this virus has
become an extremely difficult virus to deal with. For most viruses that
we have encountered over the last 100 years, one has had great success
in making vaccines against these viruses including,
as we discussed in great detail, poliovirus.
In fact, for smallpox, another virus, the vaccine effort
was so successful that about 20 years ago, the last case of smallpox
finally occurred in Eritrea in northeast African when some herdsmen
had the last documented case. And since that time, there have
been no documented cases of smallpox in the wild, and there's only two or
three stocks of smallpox virus surviving.
One of them is in some type of research center is Moscow,
and the other is probably in the Communicable Disease Center in
Atlanta, Georgia. And, there's been great debate,
by the way. Should one get rid of those surviving stalks,
or should one keep them for research? By now, you guys aren't vaccinated
against smallpox because nobody gets it anymore, and there's a certain
risk of getting a small pox vaccine.
I am, so I'm not worried, but maybe you should be because
starting about 20-25 years ago, one stopped vaccinating people
against smallpox because it just doesn't seem to be necessary.
Why give them the risk of having some disease which happens in one
out of a million vaccinees (sic) instead of just leaving them
unvaccinated? Well, I digress. Back to HIV,
the fact is we've had enormous lack of success in making a good kind of
vaccine against HIV, and why is that?
Well, one of the critical things is that HIV is attacking and
replicating in the T helper cells, and the T helper cells it turns out
are the lynch pains of the immune response. Keep in mind that the T
helper cells that I've shown you in this diagram over here represent
these critical cellular messengers between the dendritic cells and the
macrophages on the one hand, and the B cells on the other.
You wipe them out, and the ability to make new antibodies is
totally compromised. It turns out the T helper cells can
also help to make another class of cells which are called cytotoxic T
cells, another kind of T cell, cytotoxic, and these cytotoxic T
cells have on their surfaces T cell receptors, which they can use to
recognize infected cells, and kill infected cells.
So, the cytotoxic T cells aren't involved in making antibody
responses at all. The cytotoxic T cells are involved
in recognizing cells that are expressing unusual or foreign
antigens on their surface, and killing those cells. That's the
function of the cytotoxic T cells. Obviously, it's quite different
from the helper T cells. But once again, the activation of
the cytotoxic T cells, and empowering them to make these
attacks on abnormal cells depends on the helper T cells.
Once again, the helper T cells represent the lynch pins,
the keystones, of the immune response. But,
because of this tropism, and when I use the word tropism,
I mean because of the desire of the virus to phase towards and infect a
certain subset of cells in the body, this tropism of HIV for infecting
and killing helper T cells, the production of antibodies is
strongly compromised on the one hand, and the production of cytotoxic T
cells is compromised on the other.
There's another aspect of HIV infection which is also very
insidious, and that's the following. It turns out that the body can
initially make an immune response against an infecting HIV particle.
And here's kind of what things look like. I hope this shows up here.
Who could lend me a laser pointer again?
Excellent, thank you. OK, so here's what happens.
And, there's two graphs here. On one hand are the cytotoxic T
cells, and their level is shown on the solid line here.
So, look at the course of infection. It's plotted here in weeks and
years. If you see what happens in a primary HIV infection,
and here on the right on this ordinate here is the viral titer
indicated on a log scale. So, this is a semi-log graph for the
viral titer. And what you see over here is that when you initially
infected it, there's an enormous burst of viral titer.
It goes up by four or five orders of magnitude, and then it falls down
dramatically by two or three orders of magnitude. And it goes on,
and it remains depressed by two or three orders of magnitude below its
initial height for a number of years.
What's going on then? The immune system has come to grips
with the presence of the HIV virus, and begins successfully to try to
eliminate it. How does the immune system eliminate HIV?
By two mechanisms. First of all, the immune system makes neutralizing
antibodies of the sort that float through the serum,
and are able to glom onto the virus particle, attach to the virus
particle, and thereby prevent it from being infectious.
And secondly, as I mentioned last time, the immune system also can
recognize virus-infected cells and kill them. And by killing a
virus-infected cell, the immune system prevents that cell
from continuing to function as a factory for putting out new virus
particles. So, there's two ways by which virus
particles are eliminated, but note here that the virus
infected cell which is critically important among all the cell types
in the body are the T helper cells.
So, certain components of the immune system are killing the T helper
cells that are involved in harboring and producing HIV virus.
So, there's an auto destruction on the part of the immune system.
Look, at the same time, at the titer, at the number of CD4 cells,
and they're indicated here on the left ordinate,
in this case, cells per microliter. CD4 cells originally started up
here. They go down by a factor of two or
three for the first weeks, and then over a period of years
there's this ongoing struggle between the HIV particle and the
immune system as the number of CD4 cells, and the CD4 cells we've said
before, the CD4 positive cells are these T helper cells as the number
of these cells per microliter of blood progressively declines further
and further and further. And finally, the number of CD4
positive cells, i.e. T helper cells,
gets so low that the body is totally overwhelmed, and the patient then
dies of an opportunistic infection.
What do I mean by an opportunistic infection? Well,
what I mean is that we are surrounded all the time by all kinds
of microbes, which given the chance will kill us within a couple days.
Keep in mind, I told you that there are in your gut,
as many bacterial cells as there are the rest of your body.
And some of these bacteria are really nasty. I remember,
my grandfather got kicked in the belly by a horse,
and three days later he was dead. Why? Because some of the bacteria
got out of his gut, got into his peritoneal fluid cavity,
and gone. This was the pre-antibiotic era,
by the way, never new him very well because he died in 1916.
I'm just telling you that your gut is full of all kinds of nasty thing
on your skin. Not just on my skin, but on your skin there are billions
of staph aureus bacteria. They're just waiting to cause you
problems. Don't look. It's OK.
Don't look too closely. They're just waiting to cause a
nasty infection as well. Everyday we breathe in all kinds of
awful microbes, fungi, and all these kinds of things
including pneumocystis. And, rarely do we get sick because
of the extraordinary competence of the immune system to respond to such
a diversity of infectious agents, and to hold them at bay.
In the 20th century, the percentage of people who die of
infectious diseases has plummeted both because of the immune system
and because we're eating healthier up to a point,
and because of antibiotics and antifungals. But if the immune
system is defective, all the antibiotics in the world,
and all the antifungal agents can't save a patient if their CD4 cells
get down very, very low because these antifungals
always worked as collaborators with the immune system.
They get rid of a bulk of the infection, but the immune system has
to wipe out the residue. And what you see here is a struggle
going on for a period of three, four, five, six years where the
viral titer is successfully held low, and then all of a sudden as the
immune system weakens the viral titer goes up to high levels,
wipes out the residual T helper cells, and death invariably
ensues. Now, I've given you one reason why
the immune system can't deal with this virus, because virtually all
other viruses attack various tissues throughout our body,
but they don't attack the immune system itself.
Here, we're having a virus which is attacking the defense of the body,
that is to say, the immune system. So, one reason is the continuing
depletion of the T helper cells. They can regenerate themselves for
a period of time, very impressively long period of
time, four, five, six, seven years. But ultimately,
they get worn out, they die. Another reason is this is antigenic
variation. Now, if you look at the retrovirus
particle, what you see is on the surface the glycoprotein.
It's right here. And, the glycoprotein is used by antibodies
to recognize and bind to the virus particle and neutralize it,
same as with poliovirus. But let's imagine,
as happens to be the case, that the virus is highly error prone
in replicating its genome. When I say error prone, I mean that
instead of the host cell, polymerase, which makes ultimately
one mistake out of a billion, the viral replication machinery
makes mistakes all the time. It's quite defective in the
fidelity and the faithfulness with which it replicates nucleic acid.
That means that after each cycle of replication, there are in effect
mutant viruses that have been produced, mutant progeny viruses,
and where the mutation rate instead of being one in 10-9 might be one in
10-2 or one in 10-3. And that means that there are
continually novel variants of HIV being produced in a person's body.
Let's imagine that that person has developed antibodies against the
viral glycoprotein of the virus that initially infected him or her.
Let's imagine that. And those antibodies are successful
in eliminating most of the virus particles of the sort that initially
infected that individual. But now we can imagine the
possibility that in the imperative weeks or months,
a new strain of HIV will arise within that individual's body a
mutant strain in which the sequences that code the viral glycoprotein had
been changed slightly. And now, the viral glycoprotein has
changed slightly its epitopes. And the initially developed
neutralizing antibody that recognized the initial cohort of
virus coming into the cell in the individual no longer works because
the virus has undertaken a strategy of immune evasion,
sometimes it's called immunoevasion, in which now the viral glycoprotein,
although it's still competent to affect a replication cycle to adsorb
and fuse to the surface of an affected cell.
Many of the epitopes, many of the oligopeptide antigens on
the surface of the glycoprotein have been changed slightly through amino
acid substitutions, through point mutations.
And hence, the initially developed antibody, which previously was
successful in glomming on and neutralizing this virus particle is
rendered ineffective. And now, this second wave,
this new strain of HIV will grow up and expand in that individual,
and once again provoke a new immune response.
And, the same cycle will repeat it. The second strain will now soon be
eliminated, but while the elimination is going on,
there's strong Darwinian selective pressure favoring the outgrowth of
yet another mutant strain which is not recognized by either of the two
initial antibody responses. And so, over this period of many
years, what's happening is that the virus in the immune system are
playing continual cat and mouse games with one another.
The immune system goes after the virus; the virus moves over here;
the immune system goes after that; and so you have a succession of
antigenic variance. Here's one variant.
Here's another variant. Here's another variant, and so
forth. By the time the immune system succeeds in getting rid of
the first variant, a new variant has appeared,
and then the immune system ramps up its defenses and tries to get rid of
that. And, it succeeds almost. But by the time that has happened,
yet a third variant has appeared. And so, there are these continual
clonal successions. A clonal succession represents a
time where one clonal virus explodes, expands. It's soon eliminated,
collapses, and then another clone comes up and expands.
And this goes on. This works OK for about four,
five, six years. But ultimately, the ability of the
T helper cells to replenish themselves and to continue to mount
an effective immune response fails.
There's yet another aspect of HIV infection which is so insidious,
and that's the following. Let's look at the viral life cycle right
here, and the provirus, remember the provirus is this thing
right here, which is integrated into the chromosomal DNA.
And, we can assume that this provirus is transcribed by RNA
polymerase too, and I will tell you that the
promoter of the provirus is carried in by the proviral DNA,
and actually depends on transcription factors that are
present in the T helper cell. In fact, you'll recall that the T
helper cell gets excited sometimes, and other times it's not excited.
And she gets excited if I can attach gender to a T helper cell,
when she encounters macrophages and dendritic cells,
and/or when she encounters B cells. Other times, the T helper cell is
kind of quiet and unactivated (sic). And, what happens when a T helper
cell gets activated through these encounters?
The T helper cell starts making her own transcription factors,
which are used in order to facilitate these complex biological
interactions with both antigen-presenting cells,
macrophages and dendritic cells, and later on, B cells. And those
same transcription factors that the T helper cell uses to turn on its
own expression program are used by the provirus to transcribe
its own DNA, i.e. HIV has evolved a proviral
promoter sequence here which takes advantage of transcription factors
that are present uniquely in an activated T cell.
And when those transcription factors are available,
not only does the T cell become activated, but the provirus becomes
transcribed because these transcription factors now enable RNA
polymerase 2 of the host to transcribe the provirus.
But let's imagine now, if we follow that scenario to its conclusion,
what happens when the T cell is not activated?
When the T cell is quiescent, when it's quiet, these transcription
factors are unavailable to attach to the promoter of the integrated
provirus, and as a consequence the provirus will not be transcribed.
It won't make RNA, and in that situation, how will anybody know
that there's an integrated provirus in there? Well,
the provirus is not being transcribed. The transcripts aren't
being used to make viral protein. So in effect, the only evidence for
the existence of HIV in the cell is this segment of DNA.
In other words, this provirus can hide out in an unactivated quiescent
T cell indefinitely. And, the immune system can't know
that there's a provirus hiding out in this T helper cell because it's
not being transcribed. And therefore, one can have a
quiescent T helper cell, and several other cell types in the
body, macrophages also, which aren't transcribing their
proviruses. Well, you'll say,
so what? It doesn't make any difference. If it's not being
transcribed, it's not going to hurt the individual.
But, keep in mind that the idea of getting rid of a viral infection is
to eliminate all traces of a viral genome from an infected individual,
and that's what happens with smallpox and with poliovirus,
and with measles and virtually all the other infections we have.
But here, we have a situation where the viral genome can hide out in a
latent or inapparent (sic) configuration.
There's no way to know it's there, and it may reemerge days, weeks,
months, even years later because this previously transcriptionally
silent provirus may suddenly be present in a cell which suddenly
becomes activated. And now, an individual who
"thought" quote unquote that he or she had gotten rid of HIV infection
all of a sudden realizes there are viral genomes still hiding
out in the body. And what that means is that in
effect, it's absolutely impossible to rid the body of HIV infection
ever. Once an individual is infected, in fact,
that individual is infected for life. There's no way on Earth what we
have at present of getting rid of the viral infection because the
viral genome is always hiding out here or there in different
interstices of the immune system, hiding out in transcriptionally
silent state. Of course, we have very effective
drugs against HIV now. Some drugs inhibit the reverse
transcriptase. Others inhibit the processing of
the capsid proteins, that is, the proteins which these
capsid proteins happen to be cleaved from a large, high molecular-weight
protein precursor into individual proteins, and there's an inhibitor
of the protease that cleaves these proteins to the mature size.
And, those drugs together hold the viral infection at bay for maybe 10,
15, 20 years. But keep in mind that even though
the viral infection is being stopped by these drugs,
first of all, the virus is always hiding out in the bodies of such
individuals in this latent, hidden form, and secondly, there may
be a slow depletion of their T helper cells in spite of the
effectiveness of these drugs. On that cheerful note, I wish you a
good day.