AIDS Immunology Essay, Research Paper

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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