Understanding the various components of the immune system and the complex signaling that takes place between immune cells is key to understanding HIV. Both non-specific and specific lines of defense help thwart the invasion of pathogens. Non-specific defenses act quickly and indiscriminately to exclude microbes from the body or actively kill intruders. Mechanical barriers - such as the mucus, hairs, and cilia in the respiratory tract, and the flow of urine through the urinary tract - are among these non-specific defenses. Skin oils and chemicals in perspiration and gastric juices also serve as non-specific barriers. Mechanisms involving complex chemical signals such as fever and inflammation also act against a wide variety of pathogens. One non-specific defense involves phagocytes, a particular type of leukocyte (white blood cell), which act as cellular "Pac-Men," engulfing and digesting microbes or other irritants like dust and pollen.
Table 1: Types of Leukocytes
If invaders have breached the non-specific defenses, the immune system will use a variety of leukocytes to mount directed defenses against specific invaders. Lymphocytes bind and respond to specific foreign molecules (antigens). One subset of lymphocytes, the B cells, matures into antibody-secreting cells. Another subset of lymphocytes, the T cells, includes immune cells that directly kill cancerous or virally infected cells. Some subtypes of T cells serve a regulatory function, releasing chemical signals that can stimulate or suppress a variety of immune functions. Because HIV preferentially infects one of these regulatory T cells, the so-called helper T (TH) cell, it can subvert and decimate the immune system, leading to AIDS.
The Central Role of Helper T Cells
Helper T (TH) cells are critical to coordinating the activity of the immune response. The chemical messages they secrete (cytokines) stimulate the non-specific immune response to continue, and strengthen and boost appropriate specific responses. Helper T cells have sometimes been called the "conductors" of the immune system because they coordinate activity like the conductor of a symphony. They have also been called the "generals" of the immune system because they call up troops of B cells, cytotoxic T cells, and other helper T cells to go into battle against invading pathogens (Fig. 1).
Figure 1. Helper T cells regulate both humoral and cellular immunity
Macrophages alert helper T cells to the presence of pathogens. These phagocytic macrophages engulf bacteria and viruses, and can display foreign antigens - the identifying proteins of the bacteria or viruses - on the surface of their cell membrane. Embedded within the macrophage cell membrane is a molecule produced by the human leukocyte antigen (HLA) complex. (See the Human Evolution unit.) The helper T cells bind simultaneously to the foreign antigen and the HLA molecule. Only TH cells with receptors that match those of the foreign antigen on the activated macrophage are able to bind and respond to the call to action. Once bound, the helper T cell proliferates to form a clone of cells, each capable of recognizing the same antigen. The members of the helper T clone, the generals, generate the chemical signals that call up the troops.
Some signals sent by helper T cells stimulate cytotoxic T cells (TC). Cytotoxic T cells (also known as killer T cells) bind cells that have been altered, such as by viral infection; they avoid healthy cells. Surface antigens on the altered cell perform the binding. These antigens are specific to the offending agent, and match receptors in the membrane of the specific TC cell. In addition, the TC cell simultaneously binds an MHC molecule on the surface of the infected cell. Once bound by both the foreign antigen and the HLA molecule, the cytotoxic T cell secretes a chemical called "perforin," which destroys the offending cell (Fig. 2).
Figure 2. A cytotoxic T cell attacking a host cell that is expressing foreign antigens
Helper T cells also stimulate the production of antibodies. Chemical signals from helper T cells stimulate the production of B cells specific to an infecting pathogen, and then stimulate the B cells to differentiate into plasma cells. The plasma cells are factories for the production of antibodies, which are specific to given pathogens circulating in blood or lymph. Antibodies work by blocking the receptors that allow pathogens to attach to target cells, or by creating clumps of bacteria. Clumping makes the job of phagocytes easier, as they will more readily engulf bacteria in clumps. Bound antibodies sometimes serve as tags, called opsonins, enhancing phagocytosis. Antibody binding can also initiate a cascade of biochemical reactions, activating a set of chemicals known as complement. Activated complement components can form holes in bacterial membranes and enhance inflammation.
Helper T cells are clearly critical to the operation of the immune system. If they are destroyed because of an HIV infection, the whole system is crippled. The immune system is described as having two "arms": the cellular arm, which depends on T cells to mediate attacks on virally infected or cancerous cells; and the humoral arm, which depends on antibodies to clear antigens circulating in blood and lymph. As an HIV infection progresses, destroying helper T cells, both arms of immunity are impaired.
The Structure and Life Cycle of HIV How does HIV evade the immune system so efficiently? Why are so many variants of the virus found in a single patient? Understanding the structure and life cycle of the virus is key to answering these questions and essential to the design of effective treatments.
Figure 3. The structure of HIV
HIV is an enveloped RNA virus: As HIV buds out of the host cell during replication, it acquires a phospholipid envelope. Protruding from the envelope are peg-like structures that the viral RNA encodes. Each peg consists of three or four gp41 glycoproteins (the stem), capped with three or four gp120glycoproteins. Inside the envelope the bullet-shaped nucleocapsid of the virus is composed of protein, and surrounds two single strands of RNA. Three enzymes important to the virus's life cycle - reverse transcriptase,integrase, and protease - are also within the nucleocapsid (Fig. 3).
Although helper T cells seem to be the main target for HIV, other cells can become infected as well. These include monocytes and macrophages, which can hold large numbers of viruses within themselves without being killed. Some T cells harbor similar reservoirs of the virus.
Entry of HIV into the host cell requires the binding of one or more gp120 molecules on the virus to CD4 molecules on the host cell's surface. Binding to a second receptor is also required. Ed Berger helped identify this coreceptor. As he compared his results with those of other researchers, it became clear that two different coreceptors are involved in the binding. One, CCR5, a chemokine receptor, serves as a coreceptor early in an infection. Another chemokine receptor (CXCR4) later serves as a coreceptor. That two coreceptors are involved is consistent with previous observations. Viruses isolated from individuals early in an infection, during the asymptomatic phase, will typically infect macrophages in the laboratory, but not T cells (the viruses are M-tropic). Virus isolated from patients later in the infection in the symptomatic phase, will infect T cells (the viruses are T-tropic). It seems that a shift takes place in the viral population during the progression of the infection, so that new cellular receptors are used and different cells become infected.
Figure 4. The replication cycle of HIV
HIV is a member of the group of viruses known as retroviruses, which share a unique life cycle (Fig. 4). Once HIV binds to a host cell, the viral envelope fuses with the cell membrane, and the virus's RNA and enzymes enter the cytoplasm. HIV, like other retroviruses, contains an enzyme called reverse transcriptase. This allows the single-stranded RNA of the virus to be copied and double-stranded DNA (dsDNA) to be generated. The enzyme integrase then facilitates the integration of this viral DNA into the cellular chromosome.Provirus (HIV DNA) is replicated along with the chromosome when the cell divides. The integration of provirus into the host DNA provides the latency that enables the virus to evade host responses so effectively.
Production of viral proteins and RNA takes place when the provirus is transcribed. Viral proteins are then assembled using the host cell's protein-making machinery. The virus's protease enzyme allows for the processing of newly translated polypeptides into the proteins, which are then ultimately assembled into viral particles. The virus eventually buds out of the cell. A cell infected with a retrovirus does not necessarily lyse the cell when viral replication takes place; rather, many viral particles can bud out of a cell over the course of time.
HIV Transmission HIV is transmitted principally in three ways: by sexual contact, by blood (through transfusion, blood products, or contaminated needles), or by passage from mother to child. Although homosexual contact remains a major source of HIV within the United States, "heterosexual transmission is the most important means of HIV spread worldwide today." 2 Treatment of blood products and donor screening has essentially eliminated the risk of HIV from contaminated blood products in developed countries, but its spread continues among intravenous drug users who share needles. In developing countries, contaminated blood and contaminated needles remain important means of infection. Thirteen to thirty-five percent of pregnant women infected with HIV will pass the infection on to their babies; transmission occurs in utero, as well as during birth. Breast milk from infected mothers has been shown to contain high levels of the virus also. HIV is not spread by the fecal-oral route; aerosols; insects; or casual contact, such as sharing household items or hugging. The risk to health care workers is primarily from direct inoculation by needle sticks. Although saliva can contain small quantities of the virus, the virus cannot be spread by kissing.
Progression of HIV Infection
Characteristically, an HIV infection can progress for eight to ten years before the clinical syndrome (AIDS) occurs. The long latent period of the virus has contributed to many of the problems relating to diagnosis and control. The basketball player Magic Johnson was still relatively healthy twelve years after he announced he had HIV. On the other hand, not all cases exhibit the long latent period, and abrupt progression to AIDS occurs. Many factors, including genetics, determine the speed at which the disease will progress in a given individual.
Figure 5. Typical progression of HIV infection and AIDS
The Centers for Disease Control and Prevention (CDC) has identified the stages of a typical HIV infection: Categories A, B, and C. In the first stage, Category A, it can be difficult to determine whether an individual is infected without performing a blood test. While at least half of infected individuals will develop a mononucleosis-like illness (headache, muscle ache, sore throat, fever, and swollen lymph nodes) within three weeks of exposure, some Category A individuals are asymptomatic. Moreover, the symptoms themselves can be the result of many different infections. The presence of a rash may help differentiate an HIV infection from other infections, but not all HIV-infected individuals get a rash. Most of these signs and symptoms subside, but swollen lymph glands and malaise can persist for years through Category A HIV.
The number of virus particles circulating in the bloodstream is usually highest soon after exposure. At this point the CD4 cell population plunges (helper T cells are among the immune cells that express the CD4 receptor, which can be used as a marker for counting cell types). As antibodies to HIV appear the numbers of CD4 cells rise; however, CD4 cell levels drop again as the infection progresses. This lowering of CD4 cell levels typically happens slowly, over the course of years. Category C HIV (clinical AIDS) occurs once CD4 numbers have fallen substantially (to 200/mm3 from the normal level of 800-1200 cells/ mm3).
In the Category B stage indications of immune system failure begin. Persistent infections - such as yeast infections, shingles, diarrhea, and certain cancerous conditions of the cervix - are apparent.
Category C is synonymous with AIDS. In this stage the opportunistic infections associated with AIDS appear. According to the CDC, twenty-six known clinical conditions affect people with AIDS; most are infections that do not usually affect healthy individuals. These include yeast infections of the esophagus, bronchi, and lungs; Pneumocystis pneumonia (a fungal infection); toxoplasmosis (caused by a protozoan that is spread by cats); Kaposi's sarcoma (a rare cancer of the skin caused by a virus); cytomegalovirus (CMV) infections; and tuberculosis. In addition, individuals who have been affected by HIV are more likely to become seriously ill or die than other members of the population during outbreaks of infections such as cryptosporidium (a water-borne parasite) and coccidiomycosis (a dust-borne fungus).
Cytomegalovirus (CMV) causes another opportunistic infection prevalent in AIDS patients. About eighty percent of people in the U.S. have antibodies to this virus, but infections in normal individuals often go undetected or seem like a mild case of mononucleosis. In the immunocompromised, however, CMV can cause life-threatening pneumonia or encephalitis. In AIDS patients CMV that has been latent can reactivate and sometimes cause retinitis, affecting eyesight.
Tuberculosis (caused by Mycobacterium tuberculosis) has been on the rise in the wake of AIDS, such that some call it a co-epidemic. M. tuberculosis causes a respiratory infection (formerly called consumption) that is spread by inhalation. As a result, unlike HIV, behavior modification is less likely to reduce one's chances of exposure. The bacteria, which have an unusually waxy cell wall, survive well in the environment. M. tuberculosis reproduces inside macrophages found in the lung, and stimulates the production of aggregates of immune cells and connective tissue, called tubercles. Viable organisms can be walled off within such structures for decades, only to become reactivated when a person becomes compromised. Most tuberculosis in AIDS patients results from reactivated infections. AIDS patients suffer not only from respiratory infection but also from disseminated tuberculosis, which can involve the lymphatic system, peritoneum, meninges, urogenital system, or digestive tract. Antibiotic-resistant mycobacteria are also contributing to the rise of tuberculosis, so that second- and third-line drugs must often be used. And because treatments are prolonged, lasting as long as a year, patients sometimes do not complete therapy appropriately. Mycobacteria other than M. tuberculosis, particularly M. avium-intracellulare (MAC), also affect AIDS patients.
Why Do Some Individuals Never Get AIDS? Despite repeated exposure, some individuals never become infected with HIV. These individuals often have unusual helper T cells with a less-efficient variant of the coreceptor CCR5, which is necessary for viral entry into helper T cells. (See the Human Evolution unit.)
There are also individuals who become infected, but do not progress to AIDS. These long-term survivors, or long-term non-progressors, include individuals who have been AIDS-free as long as eighteen years after infection. A variety of factors may be responsible; for example, infection with less-virulent viruses. Some long-term non-progressors seem to have CD8 cells, which are particularly adept at curtailing HIV infection. (In most AIDS patients CD8 cells become less active.) Several investigators, including Jay Levy (University of California, San Francisco), are evaluating the CD8 cells of long-term survivors to see of they secrete an antiviral protein or proteins that may act against HIV.
Genetic Variation Among HIV There are five major subtypes of HIV, designated A through E. Different subtypes predominate in different geographical areas. For example, subtype B is more common in North America. In contrast, subtype C predominates in sub-Saharan Africa. Considerable variation within a given subtype also exists. In fact, any given individual infected with HIV will harbor multiple variants of the virus. HIV makes many mistakes as is copies its viral RNA to the DNA that integrates into the host's chromosome. Because of its sloppy copying of reverse transcriptase, HIV's mutation rate is high, causing great variability. This large number of variants makes the virus more difficult to treat and hinders vaccine development. In addition, because of its rapid rate of evolution, even within a single individual, HIV can quickly evolve resistance to the drugs the individual is taking to combat the virus.
