Chapter 1
The Nature of HIV/AIDS

Acquired immune deficiency syndrome (AIDS) is the late stage of an infection that is generally acknowledged to be caused by the human immunodeficiency virus (HIV). HIV is a retrovirus that attacks and destroys certain white blood cells. The targeted destruction weakens the body's immune system and makes the infected person susceptible to infections and diseases that ordinarily would not be life threatening. AIDS is considered a blood-borne, sexually transmitted disease because HIV is spread through contact with blood, semen, or vaginal fluids from an infected person.

Before 1981 AIDS was virtually unknown in the United States. In that year, testing of blood and other samples for HIV began, and reporting of the disease became mandatory. Awareness grew as the annual number of diagnosed cases and deaths steadily increased. By October 1995 the number of U.S. AIDS cases reported since 1981 reached the half-million mark. Indeed, in 1995 HIV infection was the leading cause of death among Americans age twenty-five to forty-four.

By 1998, however, HIV/AIDS deaths among this age group had fallen dramatically, and HIV infection was the fifth most common cause of death among people in the United States between twenty-five and forty-four years old. HIV/AIDS deaths fell to sixth place in the 2001 summary. This rank was maintained in the 2003 summary, with the disease claiming a reported 6,879 lives of the 33,022 total cases of infection. (See Table 1.1.)

On the other hand, HIV as a cause of death increased in those age fifteen to twenty-four between 2000 (178 deaths) and 2001 (227 deaths). But in the 2003 summary the number of deaths in this age group had declined to 171. Reflecting this decline, HIV infection was the seventh most common cause of death in this age group in 2001 and the tenth in 2003. (See Table 1.1.)

Overall, HIV death rates began to decline in 1996, even prior to the widespread use of new and effective drug treatments such as protease inhibitors. In 1997 HIV infection was the fourteenth-leading cause of death overall in the United States. By 1999 HIV infection no longer ranked among the fifteen leading causes of death in the United States. This trend continued in 2000, 2001, and 2003. (See Table 1.2.)

When examined at a general level, the decline in HIV/AIDS deaths between 1995 and 2000 seemed to indicate a positive trend for sufferers of the disease. But the reality was that the actual number of people living with HIV/AIDS increased between 1995 and 2000. In other words, while not as many people were dying of AIDS, more people were living with the disease, due to the success of new therapies. These people will eventually need additional treatment and care.

The observed decline in HIV/AIDS deaths is no reassurance to the estimated forty thousand people who acquire an HIV infection each year in the United States. Furthermore, the Centers for Disease Control and Prevention (CDC), headquartered in Atlanta, Georgia, estimates that one-quarter of the 850,000 to 950,000 people living with HIV in the United States are unaware of their infection.

Despite the overall decline in the death rate, in 1997 HIV remained a leading cause of death for African-Americans age twenty-five to forty-four. By 1999 this death rate was nearly eleven times higher than for white Americans, according to the CDC. African-Americans accounted for 49% of AIDS deaths in 1999 and 51% in 2000, despite representing only 13% of the U.S. population in both years.

The dramatic 42% decline in AIDS deaths between 1996 and 1997 was the result of the introduction and use of effective antiretroviral drugs that slow the progression of HIV infection. This decline continued but slowed to 20% between 1997 and 1998, and only 8% between 1998 and 1999. This may be due to a combination of several factors: resistance to the drug treatments has developed in some patients, the complicated drug treatment regimens can be difficult for patients to maintain, and there can be a lack of access to prompt testing or treatment. According to the CDC, an estimated 929,566 people in the United States had been diagnosed with AIDS up to December 2003. Of these, 524,060 had died ("Basic Statistics," http://www.cdc.gov/hiv/stats.htm).

The AIDS epidemic is by no means strictly a U.S. phenomenon. Researchers for the Joint United Nations Program on HIV/AIDS and the World Health Organization report that AIDS has become a global epidemic that exceeds predictions made in the mid-1990s by 50%. According to the December 2004 AIDS Epidemic Update (http://www.unaids.org/wad2004/EPIupdate2004_html_en/epi04_00_en.htm), 39.4 million people worldwide were then living with HIV/AIDS. In 2004 alone, an estimated 4.9 million people became infected and 3.1 million people worldwide died of AIDS. The countries of sub-Saharan Africa continued to have the world's highest annual rates of HIV infection and deaths in 2004.

THE HUMAN IMMUNODEFICIENCY VIRUS

A virus is a tiny infectious agent composed of genes surrounded by a protective coating. Until a virus contacts a host cell, it is essentially an inert bag of genetic material. Viruses are parasites. They must invade other cells and commandeer the host cell's replication machinery in order to reproduce. A frequent outcome of viral infection is the destruction of the host cell, as the newly made virus particles burst out of the cell. The host cell destruction can harm the host (in the case of HIV, a human). The common cold, influenza (flu), and some forms of pneumonia are also caused by specific, non-HIV viruses.

HIV belongs to a group of viruses known as retroviruses. The name arises from the presence of a special enzyme—reverse transcriptase—that reverses the usual pattern of translating the genetic message. (See Figure 1.1.) In animals the genetic units of information that are called genes are made up of deoxyribonucleic acid (DNA). DNA is the blueprint from which another type of genetic material called ribonucleic acid (RNA) is made, in a process called transcription. The RNA in turn serves as the blueprint for the various proteins that are the structural building blocks of the virus. In contrast to animals, retroviruses have their genes stored in RNA. After HIV infects a human cell, the viral reverse transcriptase works to transcribe HIV RNA into DNA. The viral DNA then becomes part of the host DNA—a process called integration—and is replicated along with the host DNA to produce new HIV particles.

Prior to 1980 retroviruses had been found in some animals. Indeed, as far back as 1911 Peyton Rous isolated an infectious and debilitating virus from a chicken. The Rous sarcoma virus was later shown to be both an oncogenic (cancer-causing) virus and the first known retrovirus. The first human retroviruses, human T cell leukemia virus (HTLV-I) and the very closely related human T cell lymphotropic virus (HTLV-II), were discovered in 1980 by Robert Gallo and his colleagues at the U.S. National Cancer Institute (NCI). This breakthrough provided the groundwork for the discovery of the virus that would eventually be known as HIV.

Identifying the Virus

In September 1983 Luc Montagnier and researchers at the Pasteur Institute in Paris, France, isolated and identified a retrovirus they named lymphadenopathy-associated virus (LAV). Eight months later Gallo's group at NCI isolated the same virus in AIDS patients, which they called HTLV-III. LAV and HTLV-III were found to be identical and are now referred to as HIV. A conflict arose about which researcher should be credited with the discovery. In 1991, in an intense, politically charged atmosphere, Gallo dropped his claim to the discovery of HIV.

The Origins of the Virus

It has long been speculated that HIV evolved from simian immunodeficiency virus (SIV), a retrovirus that infects monkeys. The theory is that HIV evolved from a human infection with a mutated form of SIV that was infectious to humans. Consistent with this theory is the finding that HIV is a part of the lentivirus family, which includes SIV.

In 1982 Isao Miyoshi of Kochi University in Japan identified an HTLV-related virus in Japanese macaque monkeys. Genetically similar to HTLV, it was designated as the simian T-lymphotropic virus (STLV). Further studies identified STLV in both Asian and

African monkeys and in apes, with an infection rate ranging from 1 to 40%.

Max Essex and Phyllis T. Kanki of the Harvard School of Public Health in Boston, Massachusetts, discovered that the simian virus found in the African chimpanzee and the African green monkey was more homologous (related in primitive origin) to the human virus than to the simian virus in the Asian macaque. This discovery provided strong support for an evolved version of African STLV as being the origin of human HTLV.

In 1999 researchers from the University of Alabama announced their determination that the genetic sequence of a simian virus isolated from a tissue sample obtained from a chimpanzee was virtually identical to the HIV discovered by Montagnier. Interestingly, chimpanzees are only rarely infected with SIV. This implies that the chimpanzee may be a temporary "carrier" of the virus, which normally resides in some other, as yet unidentified, primate species.

The original HIV is now known as HIV-1. This is because of the 1986 discovery by scientists at the Pasteur Institute in Paris of a new AIDS-causing virus in West Africans. They labeled the virus HIV-2. The two forms of HIV have similar modes of transmission. But the symptoms of HIV-2 were found to be milder than those of HIV-1. Furthermore, HIV-2 was shown to differ in molecular structure from HIV-1 in a way that ties it more closely to a virus that causes AIDS in macaque monkeys. The CDC estimates that as of 1998, seventy-nine people in the United States had been infected with HIV-2. (Unless otherwise specified, the term "HIV" in the remainder of this publication refers to HIV-1.)

Along with the majority of investigators, Montagnier and Gallo believe that HIV has been present in Central Africa and other regions for some time. Presumably, at some point the virus crossed the species barrier from primates to humans. Currently, the most accepted theory is that this crossover resulted from a human eating meat from a chimpanzee or other primate. The rural nature of these societies and the limited access to the outside world by those infected with the virus may have confined the spread of HIV for many decades. But once migration of tribal Central Africans to urban areas began, the more liberated sexual practices there promoted the spread of HIV. Within a comparatively short time, the once rare and remote disease was spread by globe-trotting HIV-infected people.

Some other, more controversial theories propose that HIV was created in the laboratory, only to escape into the natural world. One theory is that the creation of one of the versions of the polio vaccine—which used primate tissue samples—was the source of the human infection. But examination of some of the original tissue samples stored at the Wistar Institute in Philadelphia in April 2001 failed to detect evidence of either HIV or SIV.

ATTACKING THE IMMUNE SYSTEM

As with other infections, HIV must evade the immune system, which functions to detect and destroy invaders. To learn how HIV first attacks healthy cells while evading attack by the immune system, it is important to understand the complex structure of HIV and how normal white blood cells work.

Healthy White Blood Cells at Work

White blood cells are major components of the complicated, coordinated system of organs and cells that make up the human immune system. These organs and cells work together to prevent invasion by foreign substances. There are five types of white blood cells: macrophages (scavenger cells of the immune system), T4 or helper T cells, T8 or killer T cells, plasma B cells, and memory B cells. T and B white blood cells are also called lymphocytes. It is these lymphocytes that bear the major responsibility for carrying out immune system activities.

Each type of white blood cell has a specific function. The macrophage, which begins as a smaller monocyte (single cell), readies the T4 cells to respond to particular invaders such as viruses. At the time of viral attack, the macrophage, sometimes referred to as the vacuum cleaner of the immune system, swallows the virus, but leaves a portion displayed so that the T4 cell can make contact. The macrophage also stimulates the production of thousands of T4 cells, which are all programmed to battle the invader.

When T4 lymphocytes attack an invading virus, they also send out chemical messages that cause the multiplication of B cells and T8 killer cells. These cells, along with the help of some T4 cells, destroy the infected cell. Other T4 cells, which are not actively involved in destroying the infected cells, send chemical messages to B cells, causing them to reproduce and divide into groups of either plasma cells or memory cells. Plasma cells make antibodies that cripple the invading virus, while memory cells increase the immune response in the event that the invader ever attacks again.

HIV's Molecular Structure

HIV has nine genes. Three of these—designated env, gag, and pol code—form the structural components of the virus, such as the "coats" that surround the genetic material and form the outer surface of the virus particle. The remaining genes—tat, nef, rev, vpr, vpu, and vif—are involved in regulating the genetic activities that are necessary to create copies of the infecting virus.

HIV's compliment of nine genes is miniscule compared to the some thirty thousand genes that are in human DNA. Nevertheless, HIV is more complex than most other retroviruses, which have only three or four genes. Scientists believe that these genes direct the production of proteins that make up parts of the virus and regulate its reproduction. The HIV core contains genes that are protected by a protein shell, while the entire virus is surrounded by a fatty membrane dotted with glycoproteins (proteins with sugar units attached), adding to its protection. Figure 1.2, Figure 1.3, and Figure 1.4 show microscopic views of HIV in various stages of development.

Once HIV enters the human body, its primary target is a subset of immune cells that contain a molecule called CD4. In particular, the virus attaches itself to CD4+ T cells and, to a lesser extent, to macrophages.

A New Discovery

In 1995 researchers at Oxford University in England proposed that HIV defuses the killer cells that are supposed to destroy virus-stricken cells. The researchers isolated HIV from AIDS patients and demonstrated that the virus had undergone a mutation, or change, in its genetic structure. When killer T cells approached cells infected with the mutated virus, the T cells failed to kill the stricken cells, perhaps because they no longer recognized them. The T cells were in fact unable to kill even cells infected with the original, unmutated virus. The mutations not only allowed the altered strains to multiply, but also allowed unaltered strains to flourish.

ANOTHER THEORY: "FRIENDLY FIRE"

Not all researchers agree that the alteration of killer T cells is the underlying basis for the establishment of an HIV infection. Some researchers believe instead that other cells in the immune system attack and kill CD4-containing cells in what has been termed an "autoimmune response." The CD4-containing cells that have not been invaded by the virus, but display fragments of it, become targets for other cells—in addition to the killer cells—which see the infected cells as a camouflaged virus and kill them. In addition, HIV-infected cells may send out protein signals that weaken or destroy other healthy cells in the immune system.

Whatever the basis of the beginning of an HIV infection, it is agreed that HIV subsequently exhibits various behaviors, depending on the kind of cell it has invaded and how the cell behaves. The virus can remain dormant in T cells for two to twenty years, hidden from the immune system. When the cells are stimulated, however, the viral genes that have been incorporated into the DNA of the T4 cells can be replicated and the gene products assembled into new virus particles that then break free of the T4 cells and attack other cells. Once a T4 cell has been infected, it cannot respond adequately and may reproduce to form as few as ten cells. An uninfected T4 cell usually reproduces a thousand or more times to form the army needed to fight the HIV invader. When these crippled T4 cells do encounter the invader, the virus inside them reproduces and the cells are destroyed. To make the situation even worse, HIV reproduces itself at a rate far greater than any other known virus. The T4 cells essentially become factories for the invading enemy soldiers, ultimately producing them in overwhelming numbers.

The Attack

The immune system is unable to produce sufficient antibodies to fight off the complex HIV. The battle between HIV and the immune system begins when the virus slips into the bloodstream via a CD4 receptor enzyme on a T4 cell, to which it preferentially attaches itself. A CD4 receptor alone, however, is not enough to cause infection, and for years scientists searched for some other protein on the cell surface that HIV can exploit to gain entry.

This protein was discovered in May 1996 by a team of scientists at the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland. The scientists named the protein "fusin" because it helps the virus fuse with a healthy cell membrane and inject genetic material into the cell. The CD4-containing cell signals to killer T cells that it is infected by displaying fragments of HIV proteins on its surface. This triggers the killer cells to spring into action, which multiply and seek out the infected CD4-containing cells in order to pierce them open and destroy them.

CONFIRMING A HIDING PLACE

Typically, an HIV infection begins with a sudden, flu-like illness. Shortly after this first episode, the virus virtually disappears and symptoms may not materialize for as long as twenty years. Over time, the immune system eventually collapses and the virus appears in ever-increasing amounts of CD4-containing cells floating free in the patient's blood. While previous studies focused on the presence of the virus in the blood, two independently conducted studies in 1993 confirmed suspicions long held by scientists that HIV hides in a patient's lymph nodes and similar tissue during the quiescent (first or early) stage of infection. In March 1993 Anthony S. Fauci et al. from NIAID and Ashley T. Haase et al. from the University of Minnesota published papers describing the hiding places of HIV (Science, Vol. 262, November 12, 1993).

Searching for an Active Virus

Research by Fauci and his colleagues focused on the search for the virus in the blood and lymphoid tissue (the lymph nodes, spleen, tonsils, and adenoids) of twelve HIV-infected patients whose infections had progressed to varying severities. Initially, the virus is concentrated almost entirely in the lymphoid tissues. Fauci et al. believe that the virus infiltrates the lymph nodes within weeks of the initial infection. Particles of the virus, coated with antibodies, adhere to the follicular dendritic cells, a group of filtering cells that trap foreign material. CD4-containing cells nearby "see" the trapped material and are stimulated to attack the invaders. The stronger virus counterattacks and reproduces itself on some of these CD4-containing cells.

After this infiltration, the performance of the immune system declines. This decline, which ultimately is dramatically debilitating, occurs over an extended period of time—up to twenty years in some AIDS sufferers. During this decline the follicular dendritic cells also begin to deteriorate, and the quantity of HIV in the CD4-containing cells floating free in the blood increases significantly. In the final stage of the disease there is an almost complete dissolution of the follicular dendritic cell network. At this point the amount of HIV in the blood and in the CD4-containing cells has grown to equal the amount in the lymph nodes.

NOT JUST THE IMMUNE SYSTEM

For some time scientists and researchers believed HIV attacked and affected only the immune system. Many early AIDS cases that provided evidence of the involvement of other regions of the body were not counted because of the narrower definitions of AIDS that existed before 1993. But after 1993 clear evidence showed that the free virus (not attached to any other cells) could appear in the fluid surrounding the brain and the spinal cord and in the bloodstream. HIV can be found not only in T4 lymphocytes but also in other immune system cells, as well as in cells in the nervous system, intestine, and bone marrow.

Researchers at the CDC proposed another reason why HIV infections are so difficult to eliminate and why the immune system appears to be so susceptible to them. Their research shows that HIV can infect and grow in very immature bone marrow cells, offering no clues about what the mature HIV-infected cells would become. The virus reproduces without revealing itself to the immune system, which under normal circumstances would destroy it. By developing in immature bone marrow cells, a great quantity of virus can be produced before the body ever attempts to resist it.

As they mature, the cells change, becoming infected monocytes and macrophages that may not only fail to fight infections, but may also spread the virus to other immune system cells. Infected marrow cells may seed the virus into other parts of the body, including the brain. The infected cells that develop in the marrow are carried through the bloodstream to the rest of the body.

SEARCHING FOR ANSWERS

Researchers have long been puzzled by the fact that AIDS is virtually always fatal, even though relatively small amounts of the virus are found in patients, compared to other lethal viral infections. How the virus acts to kill the cells has been hotly debated. Certainly, this behavior is inconsistent with other retroviruses, which do not kill all the infected host cells. Although HIV is considered a slow virus (a virus that exerts its effect over a long period of time), some AIDS activity occurs more quickly and may be associated with the coincidental presence of infectious mycoplasma (bacteria that lack a cell wall).

Restoring Immune Response

In December 1993 the NCI reported that the immune function had been restored to HIV-infected cells grown in a laboratory through the addition of interleukin-12 (IL-12). IL-12 is a member of a group of natural blood proteins called cytokines that were discovered in 1991 by scientists at the Wistar Institute in Philadelphia, Pennsylvania, and Hoffman-LaRoche Inc. in Nutley, New Jersey. Despite this promising result, the Food and Drug Administration (FDA) halted human testing of IL-12 in June 1995 when two patients died. After testing the protein on animals, researchers concluded that the problem was not in IL-12 itself, but in the timing of the doses. Consequently, human testing resumed in November 1995.

In December 1995 a new class of drugs called protease inhibitors received FDA approval. These drugs block the ability of HIV to mature and to infect new cells by suppressing the protein-degrading activity of a viral enzyme. Enzymes with this activity are classified as proteases, hence the designation of the enzyme blocker as a protease inhibitor. If protease inhibitors can block the spread of HIV in the immune system, then AIDS will not develop. Though patients may be HIV-positive the rest of their lives, they may never die from HIV infection.

Theories of HIV/AIDS Progression

Even after more than two decades of research, there is still no consensus among HIV experts as to the pathogenesis (the origination and development) of AIDS. Despite this, there is agreement that the latent period between the establishment of an HIV infection and the appearance of the symptoms of AIDS averages from about two to eleven years. But some people remain symptom-free for as long as twenty years. Furthermore, a select group of between 5 and 10% of all HIV-infected people does not appear to develop AIDS. Called "long-term nonprogressors," these individuals are believed to have genetic and immune response characteristics that slow, or may even halt, the course of disease progression. Much research interest centers on these people, since an understanding of their physiological characteristics that allow them to suppress the infection could be invaluable to the treatment of the disease in other patients.

After HIV infection is established, the immune system regenerates cells only up to a certain point, which would explain a gradual progression to AIDS. The early regulatory functions of the immune system limit viral replication until a certain threshold is reached. When the number of different viral mutants becomes too large, the regulatory system is overwhelmed and shuts down, opening the door to opportunistic infections and eventual total decline.

When the total CD4+ T cell count falls from the normal 800 to 1,000 per cubic millimeter of blood to 200 per cubic millimeter, the rate of immune decline speeds up and the HIV-positive patient becomes prone to the opportunistic infections and other illnesses that are characteristic of AIDS. In searching for an antiretroviral therapy, researchers find that rather than boosting the CD4+ T cell count, interruption of the viral replication may be the way to reverse immune deficiency in HIV infection, though the nature of a reversing mechanism remains unknown.

SOME INCONSISTENCIES WITH CURRENT THEORIES

Most scientists agree that there are major gaps and inconsistencies in the knowledge of how HIV causes AIDS. One inconsistency deals with the infection and killing of the helper T cells. Initially, researchers thought that the main tactic of HIV was to infect and destroy the T cells. As these cells died, the numerical strength of the helper T cell force must be depleted, causing the immune deficiency associated with AIDS patients.

Other scientists, however, consider this theory too simplistic, since so few T cells—no more than one infected cell in 500—are infected. Rather, two studies published in 2001 in the Journal of Experimental Medicine (vol. 194) support the idea that HIV does not block the production of T cells but instead accelerates the division of existing T cells. This causes the existing T cells to die off more quickly than normal.

Another inconsistency involves the observation that the rapid decline in the number of T cells comes relatively late in the infection, even though there are clear indications that the immune system has been impaired much earlier.

NON-HIV THEORY OF AIDS: PETER DUESBERG

Finally, a theory championed by Peter Duesberg of the University of California, Berkeley, proposes that HIV is in fact not the cause of AIDS. Instead, Duesberg (Journal of Bioscience, vol. 28, no. 4, 2003) argues that AIDS in the United States "is a collection of chemical epidemics" resulting from the long-term consumption of recreational drugs, anti-HIV/AIDS drugs, and malnutrition. According to this hypothesis, AIDS is not contagious and HIV is a coincidental "passenger." This theory is extremely provocative and contentious and has not been accepted by the HIV/AIDS research community. Nonetheless, the theory does highlight some inconsistencies that have not been satisfactorily addressed to date.

CIGARETTES AND ALCOHOL SPEED DEVELOPMENT OF AIDS

Evidence that heavy cigarette smokers and chronic alcoholics can display a suppressed immune response has led some experts to believe that cigarette and alcohol use accelerates the development of AIDS symptoms. Accordingly, they counsel HIV-positive patients to abandon smoking and drinking alcohol.

OPPORTUNISTIC INFECTIONS

Once HIV has destroyed the immune system, the body can no longer protect itself against bacterial, fungal, protozoal, and other viral agents that take advantage of the compromised condition and cause infections. These infections, which would not otherwise occur but for an impaired immune system, are known as opportunistic infections (OIs). In the non-AIDS community, OIs are problematic in hospitals, where ill, newborn, or elderly patients also display a less than adequately functioning immune system. Because the patient is considered to have AIDS if at least one OI appears, OIs are also referred to as "AIDS-defining events," though OIs are not the only AIDS-defining events.

By 1997 the leading OI for Americans suffering from HIV/AIDS was Pneumocystis carinii pneumonia (PCP), a lung disease caused by a fungus. This dominance has continued through 2005. Prior to the discovery of HIV/AIDS, PCP was found almost exclusively in cancer and transplant patients with weakened immune systems. PCP has been declining since 1987, most likely due to better treatment and earlier diagnosis. Esophageal candidiasis, an infection of the esophagus, and extrapulmonary cryptococcosis, a systemic fungus that enters the body through the lungs and may invade any organ of the body, are also OIs frequently diagnosed in AIDS patients.

Other illnesses such as Burkitt's lymphoma, invasive cervical cancer, and primary brain lymphoma are also considered AIDS-defining events. Wasting syndrome (which includes sudden weight loss and lethargy) is another illness that may be considered an AIDS-defining event. Other examples of AIDS-defining events include diagnosis of Mycobacterium avium complex (MAC), a serious bacterial infection that may occur in one part of the body such as the liver, bone marrow, and spleen or spread throughout the body; cytomegalovirus disease, a member of the herpesvirus group; Kaposi's sarcoma, a once-rare cancer of the blood vessel walls that causes conspicuous purple lesions on the skin (see Figure 1.5 and Figure 1.6); and toxoplasmic encephalitis, an inflammation of the brain. Patients may experience more than one OI or AIDS-defining event.

HIV and Tuberculosis

Tuberculosis (TB) is a communicable infection caused by the bacterium Mycobacterium tuberculosis. TB was a widespread epidemic in North America in the late nineteenth and early twentieth centuries. Subsequently, it faded from prominence. But TB regained a foothold in the 1990s, with the number of cases increasing in the United States. Part of this increase is the parallel increase in the occurrence of the infection in HIV-positive individuals. Indeed, HIV infection has become one of the strongest known risk factors for the progression of TB from infection to disease.

An important 1996 report from the Conference on Retroviruses and Opportunistic Infections first concluded that the decline in CD4+ T cells is greater in HIV-infected patients who develop TB than in those who remain free of TB. In some geographic areas up to 58% of those diagnosed with TB were also HIV-positive. Of the many diseases associated with HIV infection, TB is one of the few that is transmissible, treatable, and preventable.

TB is spread from person to person through the inhalation of airborne particles containing M. tuberculosis. The particles, called droplet nuclei, are produced when a person with infectious TB of the lung or larynx forcefully exhales, such as when coughing, sneezing, speaking, or singing. These infectious particles remain suspended in the air and may be inhaled by someone sharing the same air. Risk of transmission is increased where ventilation is poor and when susceptible people share air for prolonged periods with a person who has untreated pulmonary TB.

Approximately 85% of TB infections occur in the lungs. This infection is termed "pulmonary TB." But TB may occur at any site of the body, such as the larynx, the lymph nodes, the brain, the kidneys, or the bones. These cases are termed extrapulmonary TB. With the exception of laryngeal TB, people with extrapulmonary TB are usually not considered infectious to others. It is important to note that, as mentioned earlier in this chapter, HIV is a blood-borne infection and cannot be spread through air. An HIV-positive person who has TB can spread TB nuclei through the air, but not HIV.

TB does not develop in everyone who is infected with the bacteria. In the United States about 90% of the infections are lifelong, yet those infected never develop symptoms of TB. But in about 5% of people, the disease develops in the first or second year after infection, and in another 5% it develops later in life. The risk that TB symptoms will develop in people with both TB and HIV is about 8% per year. In contrast, the risk that TB will develop in those infected only with M. tuberculosis is 5 to 10% within their lifetime.

HIV and Cancer

People with AIDS are susceptible to cancer. Some malignant tumors, such as Kaposi's sarcoma and cancers of the lymph system, have been common among AIDS patients since the disease was first discovered in 1981. More recently, however, physicians and researchers are beginning to find that certain forms of cancer are becoming prevalent among HIV/AIDS patients who are living longer.

Most AIDS-related cancers are believed to be caused by viruses. These cancers are more common among HIV-infected people because HIV suppresses the immune system, enabling cancer-causing viruses to attack more successfully. These cancers include non-Hodgkin's lymphoma (found in lymph tissues) and primary lymphoma of the brain. People infected with HIV are also at greater risk of myeloma (malignant tumors of the bone marrow), brain tumors, testicular cancers, and leukemia.

Since newer anti-HIV combination drug therapies, such as highly active antiretroviral therapy (HAART), have become available, researchers have reported a decline in Kaposi's sarcoma and primary lymphoma of the brain. One possible explanation for the decline may be that the combination drug therapies enable the body to recover partial immunity, which in turn controls the cancer. While the decline appears real, investigators believe it is too early to accept these findings until a longer-term follow-up has been completed.

TOWARD A VACCINE: THE HOPE AND THE REALITIES

The different routes of attack of HIV on the immune system and the ability of the virus to mutate has prompted the suggestion by some researchers that the development of an effective vaccine will be difficult to achieve. This admission is very different from the day in 1984 when Margaret Heckler, the secretary of the Department of Health and Human Services under President Ronald Reagan, announced that the identification of HIV would lead to a vaccine within two years.

The intervening years have made many AIDS researchers realize that the chances of developing a vaccine that would prevent AIDS (confer immunity on the person receiving the vaccine) are remote. Testing the effectiveness of an AIDS vaccine is also difficult, since the deliberate contamination of people with HIV is both unethical and illegal. The focus of research has shifted to vaccines that do not prevent infections but rather lessen their effects and delay the progress of the disease.

Such vaccine efforts continue. At the end of 2001 NIAID and the international HIV Vaccine Trials Network announced an agreement with Merck & Co., a leading manufacturer of anti-HIV compounds, to support the evaluation of promising HIV vaccines. The agreement with Merck was expected to spur evaluation of still more candidate vaccines. According to the HIV Vaccine Trials Network, as of May 2005 sixteen vaccine trials are underway on 3,639 enrolled participants.

In the mid-1990s a "hit-hard-early" strategy gained favor. In this strategy a cocktail of anti-HIV drugs was given to patients soon after diagnosis of the presence of the virus. The idea of HAART is to suppress the reproduction of the virus as much as possible. HAART shows promise. Some of the drugs target the virus's reverse transcriptase. By inhibiting the enzyme's activity, the ability of HIV to reproduce is thwarted. But HAART has a downside. The therapy is expensive and hard to maintain, and its long-term use is associated with a number of serious side effects. A "seven-day-on, seven-day-off" pattern of HAART (structured treatment interruptions) produces promising results. While it is still too early to say whether these structured interruptions will be incorporated into the normal course of therapy, it is conceivable that, in the future, the side effects of HAART may be lessened by the use of intermittent therapy.