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

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 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.