FREE ESSAY ON IMMUNOLOGY OF AIDS

IMMUNOLOGY OF AIDS

The
Immunology of Aids
Introduction
Although HIV was first identified in 1983, studies of previously stored blood samples
indicate that the virus entered the U.S. population sometime in the late 1970s.
Worldwide, an estimated 27.9 million people had become HIV-infected through mid-1996, and
7.7 million had developed AIDS, according to the World Health Organization (WHO). 
AIDS is a disease of the immune system, and is caused by Human Immuno deficiency Virus
(HIV). HIV targets and infects T-helper cells and macrophages. After infection,
replication of the virus occurs within the T-helper cells. The cells are lysed and the
new viruses are released to infect more T-helper cells. The course of the disease results
in the production of massive numbers of virus (1 billion/day) over the full course of the
disease. The T- helper cells are infected, and rapidly destroyed both by virus and by
cytotoxic T cells. T-helper cells are replaced with nearly a billion produced per day.
Over many years (average may be 10), the T-helper cell population is depleted and the
body loses its ability to mount an immune response against infections. Thus, we mount a
very strong immune response against the virus for a long time, but the virus is produced
at a very high rate and ultimately overcomes the ability of the immune system to respond.

Since HIV belongs to a class of viruses called retroviruses, it has genes composed of
ribonucleic acid (RNA) molecules. Like all viruses, HIV can replicate only inside host
cells, commandeering the cell's machinery to reproduce. However, only HIV and other
retroviruses, once inside a cell, use an enzyme called reverse transcriptase to convert
their RNA into DNA, which can be incorporated into the host cell's genes. HIV belongs to
a subgroup of retroviruses known as lenti-viruses, or slow viruses. The course of
infection with these viruses is characterized by a long interval, up to 12 years or more,
between initial infection and the onset of serious symptoms. Like HIV in humans, there
are animal viruses that primarily infect the immune system cells, often causing
immuno-deficiency and AIDS-like symptoms. Scientists use these and other viruses and
their animal hosts as models of HIV disease. 
The CDC currently defines AIDS when one of 25 conditions indicative of severe
immuno-suppression associated with HIV infection, such as Pneumocystis carinii pneumonia
(PCP) is present, or HIV infection in an individual with a CD4+ T cell count less than
200 cells per cubic millimeter (mm3) of blood. 
However, the question that now remains to be answered is 'How does HIV effectively
overcome the human immune system?'
In this paper I will try to answer this question. In the first chapter I will explain how
HIV is transmitted and what its life cycle looks like. This in order to increase the
understanding of how the virus operates. It can be seen as an introductory chapter to the
main body of the paper, chapter 2. In the second chapter the specific interactions
between the virus and the human immune system will be discussed and shown why its is so
threatening. In the last chapter I will deal with certain promising treatments against
AIDS.
Chapter 1
The Transmission of HIV
Among adults, HIV is spread most commonly during sexual intercourse with an infected
partner. During sex, the virus can enter the body through the mucosal linings of the
vagina, vulva, penis, rectum or, very rarely, via the mouth. The likelihood of
transmission is increased by factors that may damage these linings, especially other
sexually transmitted diseases that cause ulcers or inflammation. 
Research suggests that immune system cells called dendritic cells, which reside in the
mucosa, may begin the infection process after sexual exposure by binding to and carrying
the virus from the site of infection to the lymph nodes where other cells of the immune
system become infected. 
HIV also can be transmitted by contact with infected blood, most often by the sharing of
drug needles or syringes contaminated with minute quantities of blood containing the
virus. The risk of acquiring HIV from blood transfusions is now extremely small in
Western countries, as all blood products in these countries are screened routinely for
evidence of the virus. Almost all HIV-infected children acquire the virus from their
mothers before or during birth. 
The anatomy of HIV
HIV has a diameter of 1/10,000 of a millimeter and is spherical in shape. The outer coat
of the virus, known as the viral envelope, is composed of lipid bi-layer, taken from the
membrane of a human cell when a newly formed virus particle buds from the cell. Embedded
in the viral envelope are proteins from the host cell, as well as 72 copies (on average)
of a complex HIV protein that protrudes from the envelope surface. This protein, known as
Env, consists of a cap made of three or four molecules called glycoprotein (gp) 120, and
a stem consisting of three or four gp41 molecules that anchor the structure in the viral
envelope. 
Within the envelope of a mature HIV particle is a bullet-shaped core or capsid, made of
2000 copies of another viral protein, p24. The capsid surrounds two single strands of HIV
RNA, each of which has a copy of the virus's nine genes. Three of these, gag, pol and
env, contain information needed to make structural proteins for new virus particles. The
env gene, for example, codes for a protein called gp160 that is broken down by a viral
enzyme to form gp120 and gp41, the components of Env. 
Three regulatory genes, tat, rev and nef, and three auxiliary genes, vif, vpr and vpu,
that contain the information necessary for the production of proteins that control the
ability of HIV to infect a cell, produce new copies of virus or cause disease. The
protein encoded by nef, for instance, appears necessary for the virus to replicate
efficiently, and the vpu-encoded protein influences the release of new virus particles
from infected cells. 
The Life Cycle of HIV
When HIV encounters its target cell, the external glycoprotein portion of the viral
envelope (GP120) binds with high affinity to the extra cellular component of the receptor
protein CD 4, present on helper lymphocytes(Helper T cells). 
The membrane portion of the viral envelope fuses to the lymphocyte membrane and the virus
is expelled into the cell. Then the reverse transcriptase of the virus copies the RNA
into DNA. 
Once the DNA is integrated into the host cell genome, the presence of HIV has become a
permanent part of the lymphocyte (Helper T). 
The viral production proceeds through a complex set of highly regulated steps. First,
messenger RNA of the virus and viral proteins are produced. Proteins are then modified by
a viral protease to become mature viral proteins. 
Current efforts at anti-viral therapy involve the use of reverse transcriptase inhibitors
(notably AZT) and newly developed inhibitors of the viral protease. AZT 
Chapter 2
The Immune System and HIV
The body's health is defended by the immune system. Lymphocytes (B cells and T cells)
protect the body from germs such as viruses, bacteria, parasites, and fungi. When germs
are detected, B cells and T cells are activated to defend the body. 
This process is hindered in the case of the acquired immuno-deficiency syndrome (AIDS).
AIDS is a disease in which the body's immune system breaks down. AIDS is caused by the
human immuno-deficiency virus (HIV). When HIV enters the body, it infects the CD4+ T
cells, where the virus grows. The virus kills these cells slowly. As more and more of the
T cells die, the body's ability to fight infection weakens. 
A person with HIV infection may remain healthy for many years. People with HIV infection
are said to have AIDS when they are sick with serious illnesses and infections that can
occur with HIV. The illnesses tend to occur late in HIV infection, when only 200 T cells
per cubic millimeter remain. 
One reason HIV is unique is that despite the body's aggressive immune responses, which
are sufficient to clear most viral infections, some HIV invariably escapes. One
explanation is that the immune system's best soldiers in the fight against HIV-certain
subsets of killer T cells- multiply rapidly following initial HIV infection and kill many
HIV-infected cells, but then appear to exhaust themselves and disappear, allowing HIV to
escape and continue replication. Additionally, in the few weeks that they are detectable,
these specific cells appear to accumulate in the bloodstream rather than in the lymph
nodes, where most HIV is sequestered. 
Viral Variation
Another reason for the uniqueness of HIV are the dynamics of HIV replication. They also
have profound implications for the generation of genetic diversity of HIV quasispecies in
individual patients. Virus isolates obtained from patients at the time of initial
infection show little genetic heterogeneity. Over time, however, the population of
viruses circulating in an individual patient becomes increasingly diverse. The rapid
replication kinetics and high mutation rate of HIV reverse transcriptase drive the
diversification of the HIV quasispecies in response to selective pressure from the host
immune response.
The rapid turnover of HIV also provides the ideal mechanism for producing variants with
mutations that confer drug resistance, or permit escape from immunological control of HIV
infection. When drugs that inhibit HIV-1 replication are partially or
inappropriately administered, the resulting evolutionary pressure selects for the
emergence of resistant strains. In the case of lamivudine (3TC) or nevirapine, a single
nucleotide change in the HIV-1 RT gene is sufficient to produce high-level resistance.
The entire virus population evolves from wild-type to resistant in a matter of weeks when
these drugs are given as single agents. Little or no viral variation emerges in patients
with complete suppression of plasma HIV-1 RNA in response to potent
combination therapy.
The Role of Immune Activation in HIV Disease
During HIV infection, however, the immune system may be chronically activated, with
negative consequences. For HIV replication and spread are much more efficient in
activated CD4+ cells. Chronic immune system activation during HIV disease may also result
in a massive stimulation of a person's B cells, impairing the ability of these cells to
make antibodies against other pathogens. 
Chronic immune activation also can result in apoptosis, and an increased production of
cytokines that may not only increase HIV replication but also have other deleterious
effects. Increased levels of TNF-alpha , for example, may be at least partly responsible
for the severe weight loss or wasting syndrome seen in many HIV-infected individuals. 
The persistence of HIV and HIV replication probably plays an important role in the
chronic state of immune activation seen in HIV-infected people. In addition, researchers
have shown that infections with other organisms activate immune system cells and increase
production of the virus in HIV-infected people. Chronic immune activation due to
persistent infections, or the cumulative effects of multiple episodes of immune
activation and bursts of virus production, likely contribute to the progression of HIV
disease. 
The Role of CD8+ T Cells
CD8+ T cells are important in the immune response to HIV during the acute infection and
the clinically latent stage of disease. These cells attack and kill infected cells that
are producing virus. CD8+ T cells also appear to secrete soluble factors that suppress
HIV replication. Three of these molecules-RANTES, MIP-1alpha and MIP-1beta-apparently
block HIV replication by occupying receptors necessary for the entry of certain strains
of HIV into their target cells. Researchers have hypothesized that an abundance of
RANTES, MIP-1alpha or MIP-1beta, or a relative lack of receptors, notably CCR-5, for
these molecules, block the entry of HIV. This may help explain why some individuals have
not become infected with HIV, despite repeated exposure to the virus. A possible
explanation for that is that some people have a mutation in the allele coding for that
receptor.
Figure 2. New Co-receptors for HIV-1. T-cell-tropic strains of HIV-1, which are
usually syncytium-inducing, require CXCR-4 as co-receptor. This receptor is found on T
lymphocytes, but not monocytes. Mono-cytotropic strains, which are usually
non-syncytium-inducing, require the CCR-5 receptor, which is found on both monocytes and
T lymphocytes. This illustrates why these isolates can infect monocytes and primary
lymphocytes, both of which express CCR-5, but not T-cell lines, which lack this
co-receptor. By contrast, T-cell-tropic strains cannot infect monocytes because they lack
the CXCR-4 co-receptor. 
CD8+ T cells are thought to also secrete other soluble factors-as yet unidentified-that
suppress HIV replication. 
The Loss of Cells of the Immune System
Researchers around the world are studying how HIV destroys or disables CD4+ T cells, and
it is thought that a number of mechanisms may occur simultaneously in an HIV-infected
individual. Recent data suggest that billions of CD4+ T cells may be destroyed every day,
eventually overwhelming the immune system's regenerative capacity. 
Infected CD4+ T cells may be killed directly when large amounts of virus are produced and
bud off from the cell surface, disrupting the cell membrane, or when viral proteins and
nucleic acids collect inside the cell, interfering with cellular machinery. 
Infected CD4+ T cells may be killed when cellular regulation is distorted by HIV
proteins, probably leading to their suicide by a process known as programmed cell death
or apoptosis. Recent reports indicate that apoptosis occurs to a greater extent in
HIV-infected individuals, both in the bloodstream and lymph nodes. 
Normally, when CD4+ T cells mature in the thymus gland, a small proportion of these cells
is unable to distinguish self from non-self. Because these cells would otherwise attack
the body's own tissues, they receive a biochemical signal from other cells that results
in apoptosis. Investigators have shown in cell cultures that gp120 alone or bound to
gp120 antibodies sends a similar but inappropriate signal to CD4+ T cells causing them to
die even if not infected by HIV. 
Uninfected cells may die in an innocent bystander scenario: HIV particles may bind to the
cell surface, giving them the appearance of an infected cell and marking them for
destruction by killer T cells. Killer T cells also may mistakenly destroy uninfected CD4+
T cells that have consumed HIV particles and that display HIV fragments on their
surfaces. Alternatively, because HIV envelope proteins bear some resemblance to certain
molecules that may appear on CD4+ T cells, the body's immune responses may mistakenly
damage such cells as well. 
Studies suggest that HIV also destroys precursor cells that mature to have special immune
functions, as well as the parts of the bone marrow and the thymus needed for the
development of such cells. These organs probably lose the ability to regenerate, further
compounding the suppression of the immune system. 
HIV is Active in the Lymph Nodes
Although HIV-infected individuals often exhibit an extended period of clinical latency
with little evidence of disease, the virus is never truly latent. NIAID researchers have
shown that even early in disease, HIV actively replicates within the lymph nodes and
related organs, where large amounts of virus become trapped in networks of specialized
cells with long, tentacle-like extensions. These cells are called follicular dendritic
cells (FDCs). 
FDCs are located in hot spots of immune activity called germinal centers. They act like
flypaper, trapping invading pathogens (including HIV) and holding them until B cells come
along to initiate an immune response. 
Close on the heels of B cells are CD4+ T cells, which rush into the germinal centers to
help B cells fight the invaders. CD4+ T cells, the primary targets of HIV, probably
become infected in large numbers as they encounter HIV trapped on FDCs. Research suggests
that HIV trapped on FDCs remains infectious, even when coated with antibodies. Once
infected, CD4+ T cells may leave the germinal center and infect other CD4+ cells that
congregate in the region of the lymph node surrounding the germinal center. 
However, over a period of years, even when little virus is readily detectable in the
blood, significant amounts of virus accumulate in the germinal centers, both within
infected cells and bound to FDCs. In and around the germinal centers, numerous CD4+ T
cells are probably activated by the increased production of cytokines such as TNF-alpha
and IL-6, possibly secreted by B cells. Activation allows uninfected cells to be more
easily infected and increases replication of HIV in already infected cells. 
While greater quantities of certain cytokines such as TNF-alpha and IL-6 are secreted
during HIV infection, others with key roles in the regulation of normal immune function
may be secreted in decreased amounts. For example, CD4+ T cells may lose their capacity
to produce interleukin 2 (IL-2), a cytokine that enhances the growth of other T cells and
helps to stimulate other cells' response to invaders. Infected cells also have low levels
of receptors for IL-2, which may reduce their ability to respond to signals from other
cells. 
Ultimately, accumulated HIV overwhelms the FDC networks. As these networks break down,
their trapping capacity is impaired, and large quantities of virus enter the bloodstream.

The destruction of the lymph node structure seen late in HIV disease may prevent a
successful immune response against not only HIV but other pathogens as well. This
devastation heralds the onset of the opportunistic infections and cancers that
characterize AIDS. 
HIV's Strategy
Researchers have discovered a devious strategy used by the human immuno-deficiency virus
(HIV) to undermine the immune system. 
They found that even when HIV does not enter a cell, proteins in the outer envelope of
the virus can bind to CCR5 receptor on the cell's surface and initiate a biochemical
cascade that sends a signal to the cell's interior. This signaling process may activate
the cell, making it more vulnerable to HIV infection. It also may cause cells to migrate
to sites of HIV replication, thereby increasing their vulnerability to infection. If the
cell is already infected with HIV, activation may boost the production of the virus. 
HIV generally requires two receptors (as discussed in 'The Role of CD8+ T Cells') to
enter a target cell: CD4, and either CCR5 or CXCR4, depending on the strain of virus. The
strains of HIV most commonly seen early in HIV disease, known as macrophage-tropic
(M-tropic) viruses, use CD4 and CCR5 for cell entry. Many strains of the simian
immuno-deficiency virus (SIV), a cousin of HIV that infects non-human primates such as
monkeys, also use these receptors for cellular entry. 
Researchers found that envelope proteins from four different M-tropic HIV strains and one
M-tropic SIV strain induced a signal through CCR5 that caused cells to migrate in
culture. In contrast, envelope proteins from other strains of the viruses, known as
T-cell tropic (T-tropic) strains, did not cause signaling. 
Chapter 3
Immunological Treatments for HIV/AIDS
HRG 214:
A joint effort between scientists and industry has resulted in the development of a new
drug to treat patients in the advanced stages of AIDS. Dr. Frank Gelder, director of
Immuno-diagnostic Testing Laboratories, Department of Surgery at Louisiana State
University Medical Center in Shreveport, Louisiana, invented the drug, HRG214. HRG214 is
formulated as an immuno-chemically-engineered group of antibodies that neutralize and
inactivate essential steps in the life cycle of HIV. HRG214 is the first immunology based
pharmaceutical to show successful treatment of HIV infection. When HRG214 is used in
conjunction with two additional drugs, one to initiate and one to control cytokine
pathways, (the chemical signals by which cells communicate). CD8 lymphocytes and other
cells, which fight infection, (present but not functioning normally in AIDS patients),
are rapidly restored to normal function. This drug regime opens new therapeutic options
for the care of HIV patients, including those in advanced stages of AIDS. 
In addition, CD4 and CD8 lymphocyte numbers have statistically increased, and marked
clinical improvements have been observed in all patients receiving treatment with HRG214.
These improvements include increase in appetite and stamina, as well as marked
improvements in AIDS-related conditions such as chronic fatigue syndrome, diarrhea,
malabsorption, and other HIV-related diseases. 
Cytolin 
Unlike current AIDS drugs, which attack HIV directly, Cytolin would help the body's
immune system by correcting the immune system's self-destruct mechanism that is triggered
by an HIV infection. 
Cytolin is a monoclonal antibody designed to prevent one part of the immune system-a
particular type of killer CD8 cells-from attacking another part-CD4 cells, the
destruction of which results in AIDS. Cytolin is designed to protect the immune system's
natural defenses while antiviral drugs take the offensive against HIV. 
Cytolin is to be given in a doctor's office, most often as an adjunct to a combination of
antiviral drugs. Combinations, or cocktails, of antiviral drugs have helped some patients
significantly reduce the level of their HIV infection, improving their health. 
However, the side effects of antiviral drugs can be so significant that at least 15
percent of patients cannot take them. Even some patients who can tolerate antiviral
therapy have continued to face declining health. 
Following injection with Cytolin, the patients demonstrated significantly reduced levels
of HIV infection and clinical signs of immune system recovery, including increased levels
of disease fighting CD4 cells. 
Conclusion
First of all, HIV attacks the very cells that are responsible for the defense of the
human body against invaders, the CD4+ T cells. However, HIV also targets other immune
system cells with CD4 on their surface.
Not only are HIV replication and the spread of the virus more efficient in activated
cells, but chronic immune activation during HIV disease may result in a massive
stimulation of a person's B cells, impairing the ability of these cells to make
antibodies against other pathogens. Chronic immune activation also can result in a form
of cellular suicide known as apoptosis, and in the increased production of signaling
molecules called cytokines that can themselves increase HIV replication. 
This strategy shows that HIV does not to invade the CD4+ cells to inflict damage to the
immune system.
The chronic immune activation not only impairs the ability of B cells to make pathogens
against other cells, but it also results in apoptosis, and an increased production of
cytokines that may not only increase the HIV replication but also have other deleterious
effects, such as the severe weight loss caused by increased levels of TNF-alpha.
Now, finally researchers have found a two potentially successful immunological
treatments, HRG 214 and Cytolin. HRG 214 neutralizes and inactivates essential steps in
the replication cycle of HIV. Cytolin helps the immune system by correcting its
self-destruct mechanism that is triggered by an HIV infection.
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