The Effects Of HIV Mutations On The Immune System


The topic of this paper is the human immunodeficiency
virus, HIV, and whether or not mutations undergone by the
virus allow it to survive in the immune system. The cost of
treating all persons with AIDS in 1993 in the United States
was $7.8 billion, and it is estimated that 20,000 new cases
of AIDS are reported every 3 months to the CDC. This
question dealing with how HIV survives in the immune system
is of critical importance, not only in the search for a
cure for the virus and its inevitable syndrome, AIDS
(Acquired Immunodeficiency Syndrome), but also so that over
500,000 Americans already infected with the virus could be
saved. This is possible because if we know that HIV
survives through mutations then we might be able to come up
with a type of drug to retard these mutations allowing the
immune system time to expunge it before the onset of AIDS.
In order to be able to fully comprehend and analyze this
question we must first ascertain what HIV is, how the body
attempts to counter the effects of viruses in general, and
how HIV infects the body. 

HIV is the virus that causes AIDS. HIV is classified as a
RNA Retrovirus. A retrovirus uses RNA templates to produce
DNA. For example, within the core of HIV is a double
molecule of ribonucleic acid, RNA. When the virus invades a
cell, this genetic material is replicated in the form of
DNA . But, in order to do so, HIV must first be able to
produce a particular enzyme that can construct a DNA
molecule using an RNA template. This enzyme, called
RNA-directed DNA polymerase, is also referred to as reverse
transcriptase because it reverses the normal cellular
process of transcription. The DNA molecules produced by
reverse transcription are then inserted into the genetic
material of the host cell, where they are co-replicated
with the host's chromosomes; they are thereby distributed
to all daughter cells during subsequent cell divisions.
Then in one or more of these daughter cells, the virus
produces RNA copies of its genetic material. These new HIV
clones become covered with protein coats and leave the cell
to find other host cells where they can repeat the life

The Body Fights Back
As viruses begin to invade the body, a few are consumed by
macrophages, which seize their antigens and display them on
their own surfaces. Among millions of helper T cells
circulating in the bloodstream, a select few are programmed
to "read" that antigen. Binding the macrophage, the T cell
becomes activated. Once activated, helper T cells begin to
multiply. They then stimulate the multiplication of those
few killer T cells and B cells that are sensitive to the
invading viruses. As the number of B cells increases,
helper T cells signal them to start producing antibodies.
Meanwhile, some of the viruses have entered cells of the
body - the only place they are able to replicate. Killer T
cells will sacrifice these cells by chemically puncturing
their membranes, letting the contents spill out, thus
disrupting the viral replication cycle. Antibodies then
neutralize the viruses by binding directly to their
surfaces, preventing them from attacking other cells.
Additionally, they precipitate chemical reactions that
actually destroy the infected cells. As the infection is
contained, suppresser T cells halt the entire range of
immune responses, preventing them from spiraling out of
control. Memory T and B cells are left in the blood and
lymphatic system, ready to move quickly should the same
virus once again invade the body. 

HIV's Life Cycle
In the initial stage of HIV infection, the virus colonizes
helper T cells, specifically CD4+ cells, and macrophages,
while replicating itself relatively unnoticed. As the
amount of the virus soars, the number of helper cells
falls; macrophages die as well. The infected T cells perish
as thousands of new viral particles erupt from the cell
membrane. Soon, though, cytotoxic T and B lymphocytes kill
many virus-infected cells and viral particles. These
effects limit viral growth and allow the body an
opportunity to temporarily restore its supply of helper
cells to almost normal concentrations. It is at this time
the virus enters its second stage.
Throughout this second phase the immune system functions
well, and the net concentration of measurable virus remains
relatively low. But after a period of time, the viral level
rises gradually, in parallel with a decline in the helper
population. These helper T and B lymphocytes are not lost
because the body's ability to produce new helper cells is
impaired, but because the virus and cytotoxic cells are
destroying them. This idea that HIV is not just evading the
immune system but attacking and disabling it is what
distinguishes HIV from other retroviruses. 

The hypothesis in question is whether or not the mutations
undergone by HIV allow it to survive in the immune system.
This idea was conceived by Martin A. Nowak, an immunologist
at the University of Oxford, and his coworkers when they
considered how HIV is able to avoid being detected by the
immune system after it has infected CD4+ cells. The basis
for this hypothesis was excogitated from the evolutionary
theory and Nowak's own theory on HIV survival. 

The evolutionary theory states that chance mutation in the
genetic material of an individual organism sometimes yields
a trait that gives the organism a survival advantage. That
is, the affected individual is better able than its peers
to overcome obstacles to survival and is also better able
to reproduce prolifically. As time goes by, offspring that
share the same trait become most abundant in the
population, outcompeting other members until another
individual acquires a more adaptive trait or until
environmental conditions change in a way that favors
different characteristics. The pressures exerted by the
environment, then, determine which traits are selected for
spread in a population. 

When Nowak considered HIV's life cycle it seemed evident
that the microbe was particularly well suited to evolve
away from any pressures it confronted (this idea being
derived from the evolutionary theory). For example, its
genetic makeup changes constantly; a high mutation rate
increases the probability that some genetic change will
give rise to an advantageous trait. This great genetic
variability stems from a property of the viral enzyme
reverse transcriptase. As stated above, in a cell, HIV uses
reverse transcriptase to copy its RNA genome into
double-strand DNA. The virus mutates rapidly during this
process because reverse transcriptase is rather error
prone. It has been estimated that each time the enzyme
copies RNA into DNA, the new DNA on average differs from
that of the previous generation in one site. This pattern
makes HIV one of the most variable viruses known.
HIV's high replication rate further increases the odds that
a mutation useful to the virus will arise. To fully
appreciate the extent of HIV multiplication, look at the
numbers published on it; a billion new viral particles are
produced in an infected patient each day, and in the
absence of immune activity, the viral population would on
average double every two days.
With the knowledge of HIV's great evolutionary potential in
mind, Nowak and his colleagues conceived a scenario they
thought could explain how the virus resists complete
eradication and thus causes AIDS, usually after a long time
span. Their proposal assumed that constant mutation in
viral genes would lead to continuous production of viral
variants able to evade the immune defenses operating at any
given time. Those variants would emerge when genetic
mutations led to changes in the structure of viral peptides
recognized by the immune system. Frequently such changes
exert no effect on immune activities, but sometimes they
can cause a peptide to become invisible to the body's
defenses. The affected viral particles, bearing fewer
recognizable peptides, would then become more difficult for
the immune system to detect. 

Using the theory that he had developed on the survival of
HIV, along with the evolutionary theory, Nowak devised a
model to simulate the dynamics and growth of the virus. The
equations that formed the heart of the model reflected
features that Nowak and his colleagues thought were
important in the progression of HIV infection: the virus
impairs immune function mainly by causing the death of CD4+
helper T cells, and higher levels of virus result in more T
cell death. Also, the virus continuously produces escape
mutants that avoid to some degree the current immunologic
attack, and these mutants spread in the viral population.
After awhile, the immune system finds the mutants
efficiently, causing their population to shrink.
The simulation managed to reproduce the typically long
delay between infection by HIV and the eventual sharp rise
in viral levels in the body. It also provided an
explanation for why the cycle of escape and repression does
not go on indefinitely but culminates in uncontrolled viral
replication, the almost complete loss of the helper T cell
population and the onset of AIDS.
After the immune system becomes more active, survival
becomes more complicated for HIV. It is no longer enough to
replicate freely; the virus also has to be able to ward off
immune attacks. Now is when Nowak predicts that selection
pressure will produce increasing diversity in peptides
recognized by immune forces. Once the defensive system has
collapsed and is no longer an obstacle to viral survival,
the pressure to diversify evaporates. In patients with
AIDS, we would again anticipate selection for the
fastest-growing variants and a decrease in viral diversity.
Long-term studies involving a small number of patients have
confirmed some of the modeling predictions. These
investigations, conducted by several researchers--including
Andrew J. Leigh Brown of the University of Edinburgh, et
al.--tracked the evolution of the so-called V3 segment of a
protein in the outer envelop of HIV for several years. V3
is a major target for antibodies and is highly variable. As
the computer simulation predicted, viral samples obtained
within a few weeks after patients become infected were
alike in the V3 region. But during subsequent years, the
region diversified, thus causing a rapid increase in the
amount of V3 variants and a progressive decrease in the
CD4+ cell count.
The model presented by Nowak is extremely difficult to
verify with clinical tests alone, largely because the
diversified interactions between the virus and the immune
system are impossible to monitor in detail. Consequently,
Nowak turned to a computer simulation in which an initially
homogeneous viral population evolved in response to
immunologic pressure. He reasoned that if the mathematical
model produced the known patterns of HIV progression, he
could conclude the evolutionary scenario had some merit. To
verify his model, he turned to the experiments done on the
V3 protein segment in HIV. These experiments demonstrated
that the peptides were mutating and that these mutations
were leading to a decline in helper lymphocytes.
Before we begin to answer the question that this paper is
investigating, an evaluation of our primary experiment
source is necessary, this being a publication of Nowak's
model. Upon evaluation of this source, a problem is
exposed, this being that because there was no experiment
performed to substantiate this model, we have no idea if
the modeling predictions are true. Although there were
previous non-directly related experiments ( i.e., V3
experiment) that Nowak referred to to rationalize his model
there was never an experiment done solely based on the
model. Because the V3 findings were in accord with the
findings of Nowak's model, we can assume that the model has
some merit.
This absence of an experiment is what leads to the
boundaries that one encounters when experimenting with HIV
mutations. These boundaries being that because HIV
replicates and mutates non-linearly, it is impossible to
chronicle all its viral dynamics scrupulously.
The lack of experimental data based on Nowak's model along
with the inadequacy of experiments dealing with HIV
mutations leads to the conclusion that at present, there is
no answer to this question. Although, other questions have
been exposed, including: does the virus mutate at random or
is it systematic? And how does the virus know where to
mutate in order to continue surviving undetected?
These are all questions that must first be answered before
we even begin to try to determine if viral mutations are
what allows HIV to survive in the immune system. 


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