So, let's walk ourselves
through the lifecycle of
the human immunodeficiency virus
as it is the best example
for retroviral life.
We start at the top
with the attachment process in which the
virus, through its envelope proteins,
binds to specific receptors, in this case,
CD4 and other cell differentiating
markers, chemokine receptors,
and coreceptors on the surface
of the CD4 T lymphocyte.
The attachment is the first part, and then,
almost like drawing oneself in through
a tow rope by doing waterskiing,
the fusion process occurs.
It brings the virus in
to a further and firm attachment,
allowing the envelope of HIV
to merge with the cell membrane
of the CD4 T lymphocyte.
The next step then is insertion of
the provirus material, the
strands of genetic material,
which then start to undergo
via its own carrier copy of the gene
to create complimentary DNA,
and then an RNA-DNA hybrid construct,
and then ultimately double-
stranded viral DNA.
Then, one starts to get combination
of the viral DNA
between the virus and the host
to create daughter cells. So all this
occurs initially in the cytoplasm,
and then within the nucleus of
the CD4 T lymphocyte.
And you see that occurring in
schematic form in front of you.
Next, we have processing of the
newly created RNA copies
into the genome so that we can have
a full copy to create daughter
cells, or new virions.
And then back in the cytoplasm,
we see assembly with our newly
along with capsid material,
and then creation of an envelope material
from the lymphocyte itself.
And then ultimately, budding which requires
the protease activity of your protease
which had also been synthesized.
So, it's a very complicated structure.
Something like this probably occurs
in many other viruses.
We happen to know so much because HIV has
been a target of extreme scrutiny
with research to discover,
not only how it does what it does,
which is so severe,
but also how to try and prevent it.
And that's the difficult step.
So, transmission of HIV.
Probably quite well known to you, but it
is blood and body fluids. So blood,
semen, vaginal fluid, if there's
breast milk, so transfer from
mother to baby.
The whole 9 yards, unfortunately,
is quite contagious
if the patient has a high viral load, meaning
a high number of HIV viruses,
which are currently circulating
in the bloodstream.
So, let's look at the pathogenesis.
And again, keep in mind that
the principal problem
is that HIV targets the CD4
T lymphocyte, which is the
helper T lymphocyte.
This is the one, in a way, responsible
for controlling, suppressing,
directing, activating the entire
rest of the adaptive immune system,
humoral immunity included.
So, your target cells are the T lymphocytes,
and their interaction with the dendritic
cells, the macrophages,
which initially present HIV to the target.
As one of the downstream effects,
the production of pro-inflammatory cytokines,
such as interleukin-2 is reduced,
because the T lymphocyte, the
CD4 T lymphocyte,
is now being targeted and unable
to interact constructively
with its partner in crime, the
CD8 T lymphocyte,
which is a cell or a cytotoxic T lymphocyte.
This means that patients with HIV
infection are susceptible
to additional viruses, not just HIV.
Similarly, the inhibition of release
of interferon gamma,
another pro-inflammatory cytokine,
compromises macrophage activation,
and there goes yet another phagocytic
part of the immune system.
So patients are now susceptible to
both fungi and bacteria.
As we said before, it's very difficult
for us in medical science
to counteract HIV infection.
But in addition, there are human
factors as well.
For example, the virus replicates itself
within an immune cell, so you can't
just knock out the immune cell
or else we'll accomplish with the virus
has been trying to do in the first place.
In addition, there are known to be
or sequestra where the virus can replicate,
and we can't get access to it even with
very active antiretroviral therapy.
Plus, the virus can go latent in many
of the CD4 T lymphocytes,
and that allows it to be quiet and
evade immune detection
until later in the lifecycle of the virus.
And then finally, as I've mentioned already,
the virus itself has multiple changes
in its antigen expression
via mutations, so it's a shifting target.
So, HIV is incredibly complex and, of course,
incredibly challenging for scientists
and healthcare providers to try and get
a sense of and try and get on top of.
Let's look now at the clinical course
of HIV, and it's best
shown by this graph.
In the green line will be the number
of CD4-positive T lymphocytes,
the target of HIV infection.
The red line, then, is the viral load,
which is the number of HIV
RNA copies expressed per
milliliter in blood.
If one then starts at the beginning of
infection and primary infection
at around 1 to 2 weeks after exposure,
there is an initial precipitous drop
in the number of CD4 cell,
at the same time as the number of HIV
RNA genome particles increases
And that is seen in the shaded green bar
in which acute HIV infection is occurring.
Patients during this time may experience
what's called acute
retrovirus syndrome or acute HIV syndrome.
And this is very much like a nonspecific,
but very severe flu-like illness.
So, fever, malaise, myalgias, arthralgias.
Many times there is an erythematous
Many times, there is a leukopenia, so
a low white blood cell count.
One might not yet see, though,
a lymphopenia, because
until the number of CD4 lymphocytes drops
to a significant amount by maybe 6 weeks in,
there may not be a discernible change
in the number of lymphocytes
circulating in the periphery.
In addition, thrombocytopenia, hepatitis,
the whole body's immune system has
gone wild as its principal modifier
has been targeted.
After this acute process, typically
lasting up to about
9 weeks after initial infection,
there's a stabilization. So, the
number of CD4 cells
starts to increase under production
by the body,
and at the same time, the HIV
virus starts to go latent
to avoid immune detection.
And one can go months to years, in
fact, frequently, many years
before there's a reactivation, if you will.
So, the period of latency or clinical
latency can last for quite some time,
and during this time, the patient may
be completely asymptomatic.
At the worst, they may have some fatigue,
or just a general sense of not well-being.
But after a certain point, activation occurs,
and what triggers that point is yet
unclear to medical science.
It may be a combination of
it may be just finally a time when
production of CD4 lymphocytes
finally is unable to keep up with that slow,
gradual destruction of lymphocytes.
At any point, the number of CD4 cells
finally drops below a critical level.
The patient now is at risk for
and they can be anything which
we'll cover shortly.
And at the same time, the viral load,
the number of HIV RNA copies,
skyrockets, as you see as the red line
just shoots straight upwards.
After a certain point, death occurs,
not from HIV, but from an
which is completely unable to manage in
the absence of an immune response.