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Acquired Immune Deficiency Syndrome (AIDS), a destruction of the immune system resulting from infection with the human immunodeficiency virus (HIV). With the loss of immune function, a clinical syndrome (a group of various illnesses that together characterize a disease) occurs over time and results in death from opportunistic infections or cancers. In HIV-infected individuals, there is a gradual loss of immune cells (called CD4 T-lymphocytes) and immune function so that the patient becomes vulnerable to pneumonia, fungal infections, and other common ailments.

The mechanisms by which HIV causes immune deficiency are still not completely understood. It generally takes six to ten years from the point of infection to develop AIDS. In the early 1980s deaths by opportunistic infections, previously observed mainly in transplant recipients receiving immunosuppressive therapy, were recognized in otherwise healthy homosexual men. In 1983, Luc Montagnier and scientists at the Pasteur Institute in Paris isolated what appeared to be a new human retrovirus from the lymph node of a man at risk of developing AIDS. Nearly simultaneously, both Robert Gallo's group at the National Cancer Institute (NCI) and a group headed by Jay Levy at University College San Francisco isolated a retrovirus from AIDS patients and from people with contact with AIDS patients. All three groups had isolated what is now known as HIV-the aetiological (causative) agent of AIDS.

Detection and Diagnosis

With the identification of HIV in 1983 came the opportunity to develop a method of specific detection. Importantly, in 1984, Robert Gallo's group at the NCI developed a method for continuous production of HIV, providing an abundant source of virus to use in the initial diagnostic test. These tests now have improved specificity. This means the proportion of disease-free people who react negatively to a test: the higher the specificity, the fewer the "false positives". Improved specificity has been achieved through the use of recombinant DNA technology, and the tests detect if an individual has serum antibodies against HIV-an indication of exposure to the virus. An estimated 50 million blood samples are tested each year in the United States alone by blood banks, plasma centres, reference laboratories, private clinics, and health departments. Separate serological tests were developed to detect both HIV-1 and HIV-2, due to the major differences in the protein components of these two related viruses. As new strains of HIV are identified from around the world, they too will need to be evaluated for detection by these tests. There is a brief period (normally four to eight weeks) after exposure to HIV where an individual will remain negative on these serological detection tests because the immune response has not had enough time to make antibodies against HIV. During this period, other methods that detect some component of the virus itself (and not just antibodies against it) can determine if an individual is infected with HIV.

Being HIV infected does not necessarily imply that a person has AIDS, although "having AIDS" is often mistakenly used to mean "HIV-positive". A person can remain HIV-positive for a long period-greater than 10 years-without developing the clinical illness that defines and constitutes a diagnosis of AIDS. /P>

Nature of the Disease

Clinical Progression of AIDS

The progression from the point of HIV infection to the clinical diseases that define AIDS may take six to ten years or more. The progression to disease in HIV-infected individuals can be monitored using surrogate markers, laboratory data that correlate with disease progression, or clinical endpoints, illnesses that are associated with more advanced disease.

A well-recognized progression of disease occurs in HIV-infected individuals. Within one to three weeks after infection with HIV, many individuals experience non-specific flu-like symptoms (fever, headache, skin rash, tender lymph nodes, and malaise) lasting approximately one to two weeks. This phase, termed acute retroviral syndrome, is important because HIV reproduces itself to very high levels, circulates through the blood, and establishes infections throughout the body, especially in the lymph nodes. Patients' CD4 cell counts fall briefly but return to near-normal levels as the immune system responds to the infection and limits HIV replication and spread.

Individuals then enter a prolonged asymptomatic phase that can last ten years or more. During this period, the infected individuals remain in good health, with levels of CD4 cells in the low-normal range (750-500 cells per cu mm). HIV continues to replicate during the asymptomatic phase, although maintained at low levels, to cause a progressive destruction of the immune system. Eventually, the immune system declines and patients enter the early symptomatic phase. This phase can last from only a few months to several years and is characterized by rapidly falling levels of CD4 cells (500-200 cells per cu mm) and non-life-threatening opportunistic infections. From this phase, patients undergo more extensive immune destruction and serious illness that characterize the late symptomatic phase. The late phase again can last from only a few months to years and patients may have CD4 cell levels below 200 along with other AIDS-defining opportunistic infections. A wasting syndrome of progressive weight loss and debilitating fatigue is observed in a large proportion of patients in this stage. The immune system is now in severe failure and patients eventually enter the advanced AIDS phase, where CD4 cell numbers are below 50 and death from severe life-threatening opportunistic infections and cancers is imminent, within one to two years.

Opportunistic Illnesses

Death from AIDS is generally not due to HIV infection itself, but due to opportunistic infections. These infections occur when the immune system can no longer provide protection against agents normally found in the environment. The appearance of any one of more than 20 different opportunistic infections, termed AIDS-defining illnesses, provides the clinical diagnosis of AIDS in HIV-infected individuals.

The most common opportunistic infection seen in AIDS is Pneumocystis carinii pneumonia (PCP) caused by a fungus (P. carinii) that exists in the airways of all individuals. Additional bacterial infections of the gastrointestinal tract (from Salmonella, Campylobacter, Shigella, or other bacteria) commonly cause diarrhoea, weight loss, anorexia, and fever.

Viral opportunistic infections, especially with members of the herpes virus family, are also common in AIDS patients. One herpes family member, cytomegalovirus (CMV), infects the retina and can result in blindness. Another herpes virus, Epstein-Barr virus (EBV) may result in a cancerous transformation of blood cells. Also common are infections with herpes simplex virus (HSV) types 1 and 2 that result in progressive oral, genital, and perianal lesions.

Many AIDS patients develop cancers, the most common being Kaposi's sarcoma (KS) and B-cell lymphoma. KS (a cancer of blood vessels resulting in purple lesions on the skin that can spread to internal organs and cause death) occurs with unusually high frequency among HIV-positive homosexual men but is rare among other HIV-infected persons.

Cause of Aids

Human Immunodeficiency Virus (HIV)

The widely accepted aetiological agent of AIDS is HIV, a human retrovirus. HIV is an enveloped virus, meaning that the viral genetic material is surrounded by a lipid membrane derived from the host cell. Into this lipid membrane, HIV inserts its envelope glycoprotein, called gp120, that specifically recognizes and binds to the CD4 molecule (a cell surface protein important for normal immune interactions) on human cells. The gp120-CD4 interaction allows HIV to fuse with and infect those cells, eventually leading to viral replication and death of the host cell.

Any human cell that expresses the surface CD4 molecule is a potential target for HIV infection. However, it is the specific class of human white blood cells, called helper T-lymphocytes, that are most affected during AIDS because these cells express high levels of the CD4 molecule; they are therefore referred to as "CD4 T-cells". HIV replication in CD4 T-cells can directly kill them or they may be killed or rendered dysfunctional by indirect means without ever being infected with HIV. CD4 T-cells are critical in the normal immune system because they help other types of immune cells respond to invading organisms. Therefore, as CD4 T-cells are specifically targeted and lost during HIV infection (a hallmark feature of AIDS), no help is available for immune responses. General immune system failure occurs and permits the opportunistic infections and cancers that characterize the clinical picture of AIDS.

Modes of Transmission

HIV is spread by either homosexual or heterosexual contact with an infected person and this route represents the majority of transmissions. Present in the sexual secretions of both men and women, HIV gains access to the bloodstream of the uninfected partner by infecting cells in mucous membranes or via small abrasions that occur as a consequence of intercourse. HIV is also spread by sharing needles or syringes, most commonly done by those using intravenous (IV) drugs, that results in a direct exposure to the blood from an infected individual. HIV transmission through medical transfusions or blood-clotting factors is now very rare (less than 1 in 100,000) because of extensive screening of the blood supply. HIV can also be transmitted from an infected mother (either before giving birth, or through breastfeeding), but only about 30 per cent of babies born to HIV-infected mothers actually become infected.

Although these routes of HIV transmission are well established, public fear still exists concerning the potential for transmission by other means. There is no evidence that HIV can be transmitted through the air or by biting insects. If this were the case, the pattern of HIV infections would be dramatically different from what has been observed and cases of AIDS would be reported more frequently in individuals with no identifiable risk for infection (now only a very small percentage of reported cases).

Although HIV is a very fragile virus and does not survive well when exposed to the environment, fear also exists for HIV transmission by casual contact in a household, school, workplace, or food-service setting. No documented cases of HIV transmission by casual contact with, or even kissing an infected individual have been identified. However, practices that increase the likelihood of blood contact, such as sharing toothbrushes or razors, should be avoided.

Public fear has also persisted for HIV transmission from infected health care workers, because of a single case of transmission from a dentist to several patients. This now appears to be an extremely rare and isolated case of transmission and, in general, infected health care workers pose no risk to their patients. There is no risk of HIV transmission while donating blood.

Occurrence

In 1995, HIV was estimated to infect almost 20 million people worldwide with the cumulative estimate of AIDS cases being several million. The epidemiology (incidence and distribution) of AIDS is an evolving picture. Initially in the United States, HIV infection was mainly concentrated in the homosexual community, where widespread transmission occurred because of unprotected anal intercourse, and in haemophiliacs and people receiving other blood products. HIV infection became established among IV drug users, among whom were prostitutes who spread it by heterosexual contact into all groups of society through high-risk sexual practices.

Currently, homosexual behaviour and IV drug use account for about 50 and 25 per cent of transmissions, respectively. Heterosexual spread in the United States, especially male to female, is continuing an alarming increase and now contributes to 10 per cent of the cases. Thanks to effective screening, HIV transmission by blood products is now relatively rare, constituting 1 per cent of cases.

On a global scale, the AIDS epidemic continues a frightful expansion. Although Africa represents less than 10 per cent of the world's population, the continent now contains more than 60 per cent of HIV infections among adults (North America and South America combined account for less than 20 per cent of the adult HIV infections). More than 90 per cent of HIV infection in Africa is thought to be due to heterosexual transmission. AIDS in western Africa is also caused by HIV-2, a closely related "cousin" of HIV-1 (the major AIDS virus in Europe, the United States, and central Africa). An AIDS epidemic is also emerging in Asia, where new HIV infections increased by 100 per cent in the past three years, and estimates from the World Health Organization (WHO) indicate that AIDS in Asia will cause unprecedented rates of infection and death.

Treatment

Although never considered to be a cure for HIV infection, the hope was that drugs would have a significant impact on the progression of AIDS. They were initially used one at a time in sequence, but their effects were disappointingly short-lived. Greater success has been achieved by using them in combination regimens, which can significantly delay the onset of opportunistic infections and prolong life. Nevertheless, they can cause a relatively high rate of side-effects.

The development of antiviral drugs to attack HIV has targeted specific stages in the viral replication cycle. One such target is the requirement for HIV to undergo reverse transcription (the conversion of viral genomic RNA into DNA) at an early stage of infecting a host cell; this is a process unique to retroviruses and performed by the viral enzyme, reverse transcriptase (RT).

More recently, a new class of anti-HIV agents has been developed which specifically interferes with the action of the HIV protease enzyme. Protease is employed at a later stage of the viral replication cycle, when new virus particles are being produced within an HIV-infected cell.

One problem with all anti-HIV drugs produced to date is the development of viral resistance. HIV's replication process is relatively imprecise, resulting in the steady production of mutant variants of the virus, some of which are resistant to the effects of specific anti-HIV agents. The selective pressure exerted by treatment drugs means that within treated people these drug-resistant strains have a survival advantage over "wild-type" drug-sensitive strains. The constant high rate of HIV replication allows resistant strains to become dominant within a matter of weeks.

Clinicians are still developing experience in the optimum use of anti-HIV drugs. Extremely pronounced anti-HIV effects have been seen from the use of two nucleoside analogues and a protease inhibitor in combination therapy regimens. Researchers believe that a regimen that can rapidly suppress viral replication to very low levels should also minimize the chances of drug-resistant HIV mutants emerging.

When to Start Treatment

There has been considerable controversy among AIDS clinicians over the correct time to initiate anti-HIV therapy. It is accepted minimum practice to offer treatment to individuals who have CD4 counts below 200 or who have developed HIV-related symptoms. However, there is a good theoretical basis for starting treatment early in infection. High rates of HIV replication take place even during the years of asymptomatic infection, and over time HIV infection may cause irreversible changes in the immune system if left unchecked. However, studies comparing the efficacy of early-versus-delayed therapy, using nucleoside monotherapy (single drug therapy) or combination therapy regimens, have found no advantage to "early intervention". It remains to be established whether more potent regimens such as those including a protease inhibitor will prove more effective as early therapy.

AIDS activists have campaigned vigorously for early access to experimental therapies for HIV and opportunistic infections. Community-based organizations such as NAM Publications in the United Kingdom or AIDS Treatment News and Project Inform in the United States provide accessible information about new treatments and trials, helping individuals reach informed decisions about their options. Many infected people are willing to participate in clinical trials in the hope that experimental drugs may prove effective. Drug companies often provide pre-approval access to promising therapies through expanded access schemes and, in the United Kingdom, "named patient basis" prescribing. Such schemes are an especially important means of access to treatments outside the United States, since it usually takes considerably longer for anti-HIV agents to be formally approved. Many leading scientists believe that not enough is known about the basic biology of HIV. They recommend a shift in AIDS funding, not necessarily an increase, to place added emphasis on the basic research that could ultimately result in better medicines.

Vaccines

Efforts are underway to develop an effective vaccine for HIV that could be either protective (preventing infection if an immunized person is exposed) or therapeutic (slowing immune destruction or prolonging survival in people who are already infected).

Trials to date have been largely discouraging. Studies of therapeutic vaccines have found that some are immunogenic (they stimulate immune responses) but have not yet shown any evidence of effects on disease progression or survival rates.

Researchers working on preventive vaccines face a range of technical problems, including the difficulty of producing a vaccine that might offer protection against the range of HIV sub-types (or clades) found around the world and the varying strains caused by HIV's high mutation rate. An effective vaccine would need to protect the individual against infection when exposed to either free HIV particles or HIV-infected cells, and to stimulate effective immune responses when the virus enters the body through the blood (such as during injecting drug use or occupational exposure) or across mucous membranes (such as during sexual intercourse).

Prevention

HIV infection and AIDS are considered by many to be completely preventable, because the routes of HIV transmission are so well documented. It is clear that a reliable protective vaccine will not be available for many years. In the absence of a vaccine, the only means of preventing the spread of infection is to avoid personal behaviours that carry a risk of transmission. This has been the focus of AIDS education campaigns throughout the world.

Globally, the most common route of HIV transmission is through unprotected anal or vaginal intercourse. The risk can be eliminated by avoiding intercourse, or minimized by using a condom, since HIV cannot pass through an intact latex barrier. HIV transmission through oral sex is possible but rare, and AIDS organizations in most countries do not routinely recommend condom use for this activity. HIV transmission through drug-injecting equipment can be prevented by avoiding injecting drug use or by only using sterile equipment.

Many safer sex campaigns have been conducted to encourage the general public and the groups most at risk from HIV to avoid unprotected sex. However, research on health promotion repeatedly shows that the simple provision of information is usually not in itself sufficient to lead to behaviour changes. That may require additional factors; for example, campaigns are more likely to succeed if they present acceptable and achievable options, and are reinforced by peer pressure in favour of certain forms of behaviour and against others. The most successful safer sex campaigns were those conducted by and for urban gay communities in the 1980s, where the reduction in unprotected anal intercourse has been identified as the greatest health-related behaviour change ever achieved.

Prevention efforts to promote sexual awareness through open discussion and condom use through distribution in schools have raised opposition from certain groups in society from fear that these efforts promote sexual promiscuity among young adults. Prevention efforts involving identification of HIV-infected individuals and notification (in the United States) of the sexual partners and HIV testing at the time of marriage or pregnancy have been criticised as an invasion of personal privacy. In these cases, the issue of personal privacy has to be weighed against the responsibilities of society to ensure public health and control the spread of HIV.

Needle exchange programmes have been introduced in many countries to minimize HIV transmission among drug users. In the United States such schemes are controversial as some regard them as condoning illegal drug use, but studies consistently show that needle exchanges are effective, leading to a lower incidence of HIV infection among injecting drug users.

In recent years there has been intense debate about the proper allocation of AIDS education funds. In many countries, HIV transmission still occurs primarily among definable population groups and their sexual partners, yet the majority of resources has been spent on campaigns targeted at the general population rather than at the groups most at risk. In the United Kingdom, the Department of Health has recognized these criticisms and in late 1995 published an AIDS strategy stressing the importance of directing campaigns at gay and bisexual men and injecting drug users.

In the early years of the epidemic many cases of HIV transmission occurred through contaminated blood products and transfusions; the introduction of screening and heat treatment procedures means that infection through these routes is now extremely unlikely.

Social Issues

Prevention efforts through public awareness have been propelled by community-based organizations that provide current information to HIV-infected and at-risk individuals. Public figures and celebrities who are themselves HIV-infected or have died from AIDS, including Ervin "Magic" Johnson, Rock Hudson, and Freddie Mercury, have given a recognizable face to AIDS for society to come to terms with the enormity of the epidemic.

In the United States, the government has also attempted to assist HIV-infected individuals through legislation and additional community funding measures. In 1990, HIV-infected individuals were included in the Americans with Disabilities Act so that it became illegal to discriminate against such individuals for jobs, housing, and other social benefits. A community funding programme to major US cities designed to assist the daily lives of individuals living with AIDS was established.