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Immunology of Aids
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.

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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.

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.

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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– Kostirkis LG, Huang Y, Moore JP, et al. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nat Med 1998; 4:350-3.

– Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995; 270:1811-5.

– Pantaleo G, Graziosi C, Demarest JF, et al. HIV infection is active and progressive in lymphoid issue during the clinically latent stage of disease. Nature 1993; 362:355-8.

– Embretson J, Zupancic M, Ribas JL, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993; 362:359-62.

– HIV Pathogenesis and Viral Markers.

HIV Clinical Management – Volume 2. ? 1999 Medscape, Inc.

– Junqueira, Carneiro, and Kelly. Functionele histologie. Utrecht 1996.

– Meer, J van der, et al. Interne Geneeskunde. Bohn Stafleu Van Loghum


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