Human Immunodeficiency Virus Essay, Research Paper
Human Immunodeficiency Virus
The content of this paper is whether or not mutations undergone by the Human
Immunodeficiency Virus and 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. The
question dealing with how HIV survives in the immune system is important, not only in
the search for a cure for the virus and its inescapable 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 can survive
through mutations then we might be able to come up with a type of drug to confuse these
mutations allowing the immune system time to erase it before the onset of AIDS. In order
to be able to fully comprehend and analyze this question we must first prove what HIV is,
how the body attempts to counter the effects of viruses in general, and how HIV infects
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 special enzyme that can construct a DNA molecule using an RNA template.
This enzyme, called RNA-directed DNA polymerase, is also known 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 then
distributed to all daughter cells during later 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
catch their antigens and display them on their own surfaces. Among millions of helper T
cells circulating in the bloodstream, a selected few are programmed to ?read? that antigen
Binding the macrophage, the T cell then 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 tell 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 offset the viruses by
binding directly to their surfaces, preventing them from attacking other cells. Also, 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 first stage of the 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 burst 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 stage 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 constantly, 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
defective, 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 generous 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 helpful 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 response 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 capable in mind, Nowak and his
colleagues conceived a plot they thought could explain how the virus resists complete
extermination 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 come out when genetic mutations led to changes in the structure of viral
peptides recognized by the immune system. Frequently such changes put out 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 advance 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 manged 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 pressure 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 change in peptides recognized by immune forces. Once the
defensive system has collapsed and is no longer an obstacle to viral survival, the pressure
to change evaporates. In patients with AIDS, we would again predict 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, He tracked the
evolution of the so-called V3 segment of a protein in the outer cover 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 changed,
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 greatly difficult to resolve with clinical tests
alone, largely because the changed interactions between the virus and the immune system
are impossible to monitor in detail. 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.
Now since all of these tests were performed other questions have risen. 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.