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 cycle.
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.
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
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
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
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
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