AIDS is a Disease of the Immune System

The increased susceptibility to illness in these men resulted from a decline in their immune-system function. As is discussed in detail in Chapter 11, the role of the immune system is to maintain the integrity of the body. The cells of the immune system constantly patrol the tissues and organs of the body for anything that is not clearly produced by the body—that is, anything that is "non-self." Upon encountering non-self entities, the immune system acts to eliminate it—this is known as an immune response. A non-self substance, object, or organism typically has a unique chemical signature that causes an immune response. This signature is called an antigen. Immune-system cells called lymphocytes respond to antigens. Lymphocytes carry proteins on their cell membranes, called receptors, which recognize and are attracted to particular antigens (Figure 9.1). The binding of an antigen to an antigen receptor on a lymphocyte starts the immune response. Our bodies can make 100 trillion to 1 quintillion different types of antigen receptors, and about 100 million distinct receptors are present on lymphocytes in our bloodstream at any given time. The incredible diversity in antigen receptors is responsible for the immune system's ability to respond to a huge range of non-self objects.

The virus that causes AIDS primarily kills or disables a particular class of lymphocytes called T4 cells. T4 cells are also known as helper T cells because they serve as the directors of the immune system's response to an antigen. Thus, loss of T4 cells causes immune deficiency—that is, affected individuals experience diseases that are normally controlled by healthy immune systems. These include infections by organisms commonly found on our bodies in low levels, such as Pneumocystis carinii, a fungus that is found in nearly everyone's

Figure 9.1 Lymphocytes recognize particular antigens. This lymphocyte has receptors for the antigens that are present on one virus but not on another. When an antigen receptor binds to an antigen, a cascade of events causes an immune-system response and often the elimination of the antigen.

lungs by age 30. In healthy people, P. carinii is held in check by the immune system, but in AIDS patients, this organism often causes pneumonia and extensive lung damage. Diseases like P. carinii pneumonia are called opportunistic infections because they only occur when the opportunity arises due to a weakened immune system.

Because individuals with weakened immune systems may have more than one opportunistic infection, each with its own signs and symptoms, there is no single disease that is always associated with AIDS. This is why the disease is called a syndrome—a group of signs and symptoms indicating that an individual has AIDS. Primary among those signs is the depletion of T4 cells.

HIV Causes AIDS

Within months of the initial reports of this new disease, it became clear that AIDS could be transmitted through both sexual intercourse and contact with the blood of affected individuals. By 1983, scientists in France and the United States had identified the factor causing the transmission and symptoms of AIDS— later named the Human Immunodeficiency Virus, or HIV. (The evidence linking HIV to AIDS is outlined in Essay 9.1.) Worldwide, the majority of HIV transmission is via sexual intercourse without a condom. In the United States, both unprotected sex and the sharing of needles by injection-drug users are primary modes of HIV transmission.

HIV is a simple structure composed of RNA and essential proteins called enzymes, all surrounded by a protein envelope and a membrane coat (Figure 9.2). As with all viruses, HIV can only reproduce by forcing the cells of its host, the organism it is infecting, to make copies. HIV does this by first binding to a protein on the surface of a cell (the CD4 + receptor), and then releasing its RNA and enzymes into the cell. The majority of cells infected with HIV are T4 cells, but other cells that carry the CD4 + receptor are susceptible to HIV as well. Once inside the cell, the viral RNA is reverse transcribed into viral DNA by the action of one of the viral enzymes. Chapter 7 describes that transcription occurs in cells when the information in DNA is rewritten into the language of RNA—re-verse transcription is simply the converse of that process. With the help of another viral enzyme, the viral DNA then inserts itself into the cell's genome, where it commandeers the cellular machinery for copying genetic material and producing proteins. In this way, HIV forces the cell to make copies of the virus. The cell now makes new copies of the viral RNA, translates the genes on the viral DNA into the proteins that make up the coat, enzymes, and membrane surface proteins, and assembles new viruses. The newly made copies of the virus then leave the cell by budding off the cell membrane and go on to infect other cells that possess the CD4 + receptor. Infection with HIV usually either disables or kills the host cell. The life cycle of HIV is summarized in Figure 9.2, and Chapter 11 provides additional details about the biology of viruses.

Media Activity 9.1 Replication of HIV within Helper T Cells

HIV Particle

Viral enzyme Viral RNA

Viral surface proteins (antigen)

1. Attachment and entry.

HIV binds to human T4 cell and their membranes fuse.

Human T4 cell

2. Reverse transcription.

Viral enzyme copies viral RNA into viral DNA.

3. DNA insertion.

Viral DNA inserts itself into human DNA.

4. Transcription.

Viral DNA is transcribed, resulting in many copies of viral RNA.

5. Translation.

Viral mRNA is translated to produce many proteins, some of which are transported to the host-cell membrane.

6. Assembly.

Viral proteins and viral RNA are assembled to make new viral particles.

4. Transcription.

Viral DNA is transcribed, resulting in many copies of viral RNA.

6. Assembly.

Viral proteins and viral RNA are assembled to make new viral particles.

CD4 receptor

Cell membrane

Nucleus

CD4 receptor

Cell membrane

Nucleus a

7. Budding.

Viral particles are wrapped in part of the host-cell membrane.

8. Release.

Many virus particles are released and can attack other host T4 cells.

Figure 9.2 The life cycle of HIV. HIV cannot replicate without infecting a host cell. Once inside, the virus uses the cell's components to make copies. Infection with HIV disables and eventually kills the host cell.

The Evidence Linking HIV to AIDS

Although a small number of scientists have argued that the link between HIV and AIDS is weak, an enormous number of them agree that the statement "HIV causes AIDS" is a fact. Scientists use Koch's postulates, developed by physician Robert Koch in the nineteenth century, as the litmus test for determining the cause of any epidemic disease. They are summarized as follows:

1. Association: The suspected infectious agent is found in all individuals suffering from a particular disease.

2. Isolation: The supposed infectious agent can be grown outside the host in a pure culture (without any other microorganisms).

3. Transmission: Transfer of the suspected pathogen to an uninfected host produces the disease in the new host.

4. Isolation from new victim: The same pathogen must be found in the newly infected host.

Does HIV fulfill Koch's postulates as the cause of AIDS? Let us examine the evidence for each assumption.

Association: Numerous studies from around the world show that virtually all AIDS patients are HIVseropositive; that is, they carry antibodies that indicate HIV infection.

Isolation: Modern laboratory techniques have allowed the isolation of HIV from virtually all AIDS patients, as well as in almost all HIV-seropositive individuals. In addition, researchers have documented the presence of HIV genes in both of these groups of patients.

Transmission: HIV does not appear to cause AIDS in other animals, so transmission is difficult to demonstrate—we cannot expose an animal to the virus and see if it develops AIDS. However, this postulate has been fulfilled by a series of tragic incidents. In one case, three laboratory workers with no other risk factors developed AIDS after accidental exposure to concentrated HIV at work. In another case, transmission of HIV from a Florida dentist to six patients was documented by genetic analysis of the virus isolated from both the dentist and the patients. The dentist and four of the patients developed AIDS and died. Finally, the Centers for Disease Control has received reports of 57 documented, occupationally acquired HIV infections among health-care workers, of whom 26 have developed AIDS in the absence of other risk factors.

Isolation from new victim: In the case of the three laboratory workers described above, HIV was isolated from each infected individual and its RNA sequence was examined; the HIV proved to be the virus the workers had handled. In the case of the Florida dentist, HIV isolated from his infected patients had very similar RNA sequences, indicating that all of them were infected with the same virus strain.

In short, the link between HIV and AIDS has been firmly established using the standard set by Koch's postulates, and this relationship has been accepted by the vast majority of medical scientists.

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