What is acquired immunodeficiency syndrome (AIDS)?

Causes and Symptoms

Acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency
virus (HIV), a member of the lentivirus family of
retroviruses. This virus is thought to have arisen in Africa
in the early to mid-twentieth century from related viruses in the chimpanzee and
the sooty mangabey monkey. The virus cannot survive long in the air and cannot be
transmitted by casual contact. Individuals can be infected only by the exchange of
certain body fluids, including semen, vaginal fluid, blood, and breast milk. Other
body fluids such as sweat, tears, saliva, urine, and feces may contain HIV, but
the virus exists in such low concentrations that these fluids are completely
ineffective in transmitting an infection. The most common mode of transmission is
through vaginal and anal sex; it is also possible to transmit HIV by performing
oral sex, although this is less common than with vaginal or anal sex. The presence
of other sexually
transmitted diseases (STDs), such as gonorrhea, syphilis,
chlamydia, genital herpes, or human papillomavirus, dramatically increases the
risk of acquiring an HIV infection through sexual contact.

The second most common mode of transmission is through the sharing of needles or
syringes contaminated with HIV-positive blood. An HIV-positive pregnant woman may
transmit the virus to her child in utero, or more commonly during childbirth.
Mother-to-child transmission may also occur through breast-feeding in which the virus is present in the milk.
Early in the AIDS epidemic and before a blood test for HIV was available, blood
and blood products from blood banks were sometimes contaminated with HIV that
subsequently infected recipients. Indeed, more than 90 percent of patients with
hemophilia at this time became infected with HIV through injections of
HIV-contaminated clotting factor VIII. Because of the development of a heat
treatment for clotting factor VIII and the screening of the blood supply, patients
with hemophilia and other blood-transfusion recipients are no longer at high risk
for HIV infection. Although the blood supply is relatively safe today, a very low
probability of acquiring HIV through a transfusion of contaminated blood still
exists, as a recently infected donor may not yet test positive for HIV, although
this is phenomenon is extremely rare in developed countries.

Although HIV can infect virtually all cells of the body, it has a strong affinity
for cells of the immune system. The virus uses a cell surface receptor called
CD4 to bind to the membrane of a cell. The CD4 receptor is found on many cells in
the body but is in relatively high concentrations on the surface of a class of
T
lymphocytes called T4 or CD4 cells. The virus uses a
coreceptor called CXCKR4, also found on the membrane, that promotes the fusion of
the membrane of the virus particle with the membrane of the cell, thereby allowing
entry of the virus. Persons who lack the coreceptor on their cells appear to
resist infection by the virus. The T4 cells are also known as T-helper cells, as
they produce a series of chemical signals called lymphokines that are needed for
the development and maintenance of the entire immune system. While the body
constantly makes new T4 cells, HIV has a very small edge in the rate at which
these T4 cells are infected and destroyed. Thus, there is a slow but progressive
decrease in T4 lymphocytes in the body and loss of immune function. This process
may take ten or more years.

The clinical course of infection occurs in three stages. Initially upon infection,
HIV produces an acute retroviral syndrome referred to as the prodromal stage,
beginning about three to four weeks after initial infection and lasting for two to
three weeks. During a retroviral syndrome, the patient experiences flulike or
mononucleosis-like symptoms. The patient will believe that
he or she simply has a moderate-to-severe case of influenza or, if the symptoms
are prolonged, mononucleosis. During this period, HIV is rapidly proliferating,
disseminating throughout the body and infecting lymphoid tissues. Viral load is
high at this stage, and the patient is highly infectious. At the same time, the T4
cell count, which normally is about 1,000 per cubic millimeter, drops by about
half. The patient’s immune system will mount an antibody response against HIV, but
these antibodies are ineffective in stopping the infection. When such antibodies
are detectable, the patient is then said to have seroconverted. Anti-HIV antibody
detection by a simple blood test is the basis for assigning HIV-positive status.
In most cases, seroconversion occurs between six to eighteen weeks after
initial infection, although, in rare cases, antibodies may not be detectable until
later. By three months, 95 percent of patients will have seroconverted; by six
months, more than 99 percent will have detectable circulating antibodies to
HIV.

The second stage is called the clinical latency period or asymptomatic stage.
Without anti-HIV therapy, this period may last ten or more years. It is during
this time that the patient usually has no AIDS symptoms. Early in the latent
period, T4 cell counts usually recover somewhat during the first year of
infection, averaging approximately 700 per cubic millimeter. After that, there is
a very slow decline. In the meantime, viral loads, which were high during the
acute retroviral syndrome stage, drop by several orders of magnitude as the T4
count rises. At about one year into the infection, the viral load very slowly
increases as the latent period progresses.

The third phase of HIV infection is the development of AIDS. This usually occurs
when the T4 count drops below 200 per cubic millimeter. Opportunistic
infections and cancers become common, and patients may have
several infections simultaneously. Many of these diseases are rare in healthy
individuals. Most common is
Pneumocystis jiroveci

pneumonia, a form caused by a fungus that is virtually unseen in individuals with
a normal immune system. Indeed, the fungus is present in a majority of the
population yet almost never causes pneumonia unless the immune system is
compromised or suppressed. As one of the functions of the immune system is to
destroy cancer cells when they arise, patients with AIDS are at a
substantially higher risk of developing some types of cancers compared to
uninfected individuals of the same age. One of these cancers is Kaposi sarcoma, a
normally very rare tumor of blood vessels characterized by pink to purple spots or
slightly raised areas on the skin. These lesions may
also arise on internal organs, where they can impair function. Kaposi’s sarcoma is
caused by human herpes virus 8 (HHV8) and is sexually transmitted. Individuals
with AIDS are several thousand times more likely to develop Kaposi sarcoma than
uninfected individuals. The other cancer commonly associated with AIDS is
non-Hodgkin
lymphoma, often in the brain. Patients with AIDS are nearly
seventy times more likely to be diagnosed with non-Hodgkin lymphoma.

In 1987, the US Centers for Disease Control (CDC) published the criteria for the
diagnosis of AIDS, including the appearance of one or more opportunistic
infections or cancers. Twenty-three different conditions were listed in the
definition: candidiasis of the bronchi, trachea, or lungs; esophageal
candidiasis; disseminated or extrapulmonary coccidiomycosis; extrapulmonary
cryptococcosis; chronic intestinal cryptosporidosis (greater than one month in
duration); cytomegalovirus disease (other than liver, spleen, or lymph
nodes); cytomegalovirus retinitis (with loss of vision); HIV encephalopathy;
herpes simplex causing chronic ulcers (greater than one month in
duration) or bronchitis, pneumonitis, or esophagitis; disseminated or
extrapulmonary histoplasmosis; chronic intestinal isosporiasis
(greater than one month in duration); Kaposi sarcoma; Burkitt
lymphoma; immunoblastic lymphoma; primary lymphoma of the
brain; Mycobacterium avium complex or M.
kansasii; extrapulmonary infection due to Mycobacterium
tuberculosis; other or unidentified Mycobacterium
species; Pneumocystis jiroveci pneumonia; progressive multifocal
leukoencephalopathy (PML); recurrent
Salmonella
septicemia; toxoplasmosis of the brain; and wasting
syndrome caused by HIV. In 1993, three conditions were added to the criteria:
pulmonary tuberculosis, recurrent pneumonia, and invasive cervical carcinoma.
Moreover, the definition was expanded to include any HIV-positive person whose T4
count had dropped to 200 per cubic millimeter or lower or whose level of T4
lymphocytes had fallen to 14 percent or less of total lymphocytes.

For the diagnosis of HIV infection, the CDC recommends laboratory evidence from a
positive HIV antibody screening test, such as a reactive enzyme immunoassay, that
is confirmed by a positive result from a supplemental HIV antibody test or a
positive result from HIV nucleic acid detection test such as polymerase chain
reaction (PCR) or HIV virologic tests such as HIV p24 antigen
test or HIV viral culture. The Infectious Disease Society of America recommends
diagnosing HIV infection by a rapid HIV test or conventional enzyme-linked
immunosorbent assay (ELISA) and confirmed by Western blot or indirect
immunofluorescence assay; if the initial testing is negative or indeterminate it
should be repeated four weeks later.

Treatment and Therapy

As of 2014, no effective vaccine had been developed to prevent HIV infection.
While a number of candidate vaccines have been under development and in clinical
trials, none has proven successful. The usual strategies used with most antiviral
vaccines in the past, immunization with attenuated or inactivated viruses, have so
far proven ineffective for HIV given its significant rate of mutation. Control of
the epidemic has shifted significantly toward preventing exposure and decreasing
infectivity by treating to reduce viral load, a measure of the number of viruses
in blood and in body fluids.

AIDS treatment and therapy fall into two categories: prophylaxis and the
prevention and treatment of opportunistic infections to slow progression to
full-blown AIDS. Treatment of opportunistic infections must follow established
guidelines for the individual disease. Thus, in the treatment of Kaposi sarcoma,
surgery, chemotherapy, and radiation treatment singly or in
combination are utilized. Bacterial and yeast or other fungal infections are
treated with antibiotics or antifungal agents. Although some medications
may reduce the severity of viral infections, such infections are
not easily treated. Because a person with AIDS might suffer from more than one
opportunistic infection and/or cancer at the same time, simultaneous treatments
often take a severe toll on the patient. Without treatment, individuals who
progress to AIDS survive approximately three years. Death typically results from
an opportunistic infection or cancer. However, HIV-positive individuals who
undergo antiretroviral therapy (ART) to maintain a low viral load typically have a
life expectancy similar to HIV-negative individuals and never progress to
AIDS.

This strategy for HIV treatment involves interfering with the viral life cycle
with the aim of slowing viral replication. Anti-HIV drugs target several steps in
the life cycle, primarily at the levels of reverse transcription or assembly. In
1987, the first generation of drugs was developed to treat HIV. The first
effective treatment utilized zidovudine (ZDV), commonly called azidothymidine
(AZT), a drug originally developed for chemotherapy of cancer. ZDV inhibits the
viral encoded enzyme, reverse transcriptase, involved in copying the RNA viral
genome into a DNA copy. As a result, a nucleoside analogue is inserted into the
growing DNA, which stops further synthesis of the DNA copy. Other nucleoside
reverse transcriptase inhibitors (NRTIs) that have a similar effect include
emtricitabine, tenofovir, and abacavir. In a similar manner, the nucleotide
analogue tenofovir blocks DNA replication. Nevirapine and efavirenz are
non-nucleoside drugs that bind directly to and inhibit reverse transcriptase.
Although this group of drugs inhibits reverse transcriptase, their mode of action
is different from nucleoside or nucleotide analogues.

The final step in HIV replication involves the cleavage of a large precursor
protein into smaller structural proteins, an event taking place at the cell
surface and followed by release of the completed virus. The cleaving enzyme is
called a protease and is encoded by the virus. The second generation of anti-HIV
drugs, which were developed in the 1990s, were protease inhibitors, drugs that
interfere with cleavage of the precursor and prevent viral assembly. As a result,
functional virions cannot be made. Atazanavir, darunavir, fosamprenavir,
indinavir, lopinavir, and ritonavir are approved drugs in this class. Other types
of anti-HIV drugs called fusion inhibitors (for example, enfuvirtide) interfere
with entry of the virus into a cell. In addition, integrase inhibitors, such as
raltegravir, may be used. Integrase inhibitors prevent the DNA copy of the virus
from inserting itself into one of the cell’s chromosomes. Thus the anti-HIV
arsenal includes drugs that act at different sites or stages in the HIV life
cycle.

The HIV reverse transcriptase makes numerous mutations during the synthesis of
DNA. Consequently, resistance to individual anti-HIV drugs arises easily and
frequently. Beginning in 1995, a new strategy for anti-HIV therapy called highly
active antiretroviral therapy (HAART), also known as AIDS cocktail therapy, was
developed. HAART consists of using a combination of three or more anti-HIV drugs,
including two reverse transcriptase inhibitors and at least one protease
inhibitor. HAART therapy is very effective, as it has been
estimated that it prolongs the life expectancy of a person with AIDS by three to
ten years. Moreover, many patients with AIDS and in terminal stages of the disease
have made remarkable recoveries when placed on HAART. In many cases, viral loads
were dramatically reduced, T4 cells made some recovery, and the incidence of
opportunistic infections was reduced. Another advantage of multiple drug therapy
is that the probability of HIV developing simultaneous resistance to three or four
different drugs is very low, extending the useful therapeutic life of the
individual drugs.

The long-term effectiveness of HAART is underscored by an examination of the AIDS
deaths in the United States. In 1981, the CDC began to track the number of AIDS
deaths. Each year, the number of deaths climbed steadily, reaching a peak of
50,610 in 1995. In 1996, the first full year of widespread HAART therapy, AIDS
deaths dropped by 25 percent, and they have continued to drop every year since. In
2012, an estimated 1.6 million people died of the disease worldwide, down from
approximately 2.3 million in 2005.

Perspective and Prospects

AIDS was first recognized as a new disease in the United States in late 1980.
Michael Gottlieb at the University of California, Los Angeles (UCLA) diagnosed men
who have had sex with men with Pneumocystis carinii pneumonia and
Kaposi sarcoma, diseases that in the past were extremely rare. In June 1981, the
CDC alerted doctors in a report on this new epidemic for the first time in the
CDC Weekly Morbidity and Mortality Report. Shortly thereafter,
the New York Times reported on the new “gay cancer.” At first,
the disease was called gay-related immunodeficiency (GRID). The name GRID was changed to
acquired immunodeficiency syndrome, or AIDS, in an August 8,
1982, article in the New York Times, representing the first time
that the term was used in a publication. The change reflected the fact that this
new disease was not restricted to men who have had sex with men; cases involving
intravenous drug users, individuals with hemophilia and other blood-transfusion
recipients, and infants were being diagnosed. In January 1983, Luc
Montagnier and colleagues at the Pasteur Institute in Paris
were the first to isolate the virus causing AIDS. It was given the name human
immunodeficiency virus, or HIV, in 1985; previously, the virus had been given
several names by different researchers. With the isolation of the virus, a blood
test could be developed.

Testing of blood and blood products started in March 1985. A test called
enzyme-linked immunosorbent assay (ELISA) screens for the presence of anti-HIV
antibodies. Results once took weeks, but the test is now automated and is
performed within hours.

HIV has been confirmed in the United States since at least 1969. At that time, a
physician in St. Louis, Missouri, had a young male patient with a variety of AIDS
symptoms. After the patient died, the pathologist took samples of his tissues and
froze them. Later, when tests to detect HIV became available, the tissue samples
were tested and found positive for HIV. The oldest positively identified HIV
sample came from blood collected from a male patient by a Belgian physician in
Kinshasa, Democratic Republic of the Congo. The doctor had saved many blood
samples taken between 1959 and 1982; thus, the earliest confirmation of HIV
infection in Africa dates from 1959. The virus has probably been present in the
human population for much longer, but without blood or tissue samples, this cannot
be confirmed.

Two major classes of HIV have been identified: HIV-1, which arose in Central
Africa, and HIV-2, which arose in Western Africa. HIV-1 and HIV-2 have long been
known to be genetically similar to viruses know as simian immunodeficiency viruses
(SIV) in chimpanzees (SIVcmp) and the sooty mangabey monkey (SIVsm). In 2006,
scientists determined that in all likelihood, HIV-1 originated in chimpanzees from
regions of the nation of Cameroon; as many as one-third of chimpanzees from some
colonies were found to carry SIV. The first confirmed human infection was that of
a man from the nearby Congo, who developed AIDS in 1959. However, evidence
suggests that HIV may have emerged in humans as early as 1930.

According to the CDC's HIV Surveillance Supplemental Report, 2011
(2013), an estimated 1.14 million persons aged thirteen and older are living with
HIV infection in the United States, including nearly 181,000 people who are not
aware of the infection; approximately 15,500 persons with an AIDS diagnosis died
in the United States in 2010, although these deaths may or may not be related to
AIDS. Worldwide, the World Health Organization (WHO) estimates that seventy-five
million people have been infected with the HIV virus since the beginning of the
epidemic and approximately thirty-six million people have died of HIV/AIDS.
Worldwide, an estimated 35.5 million people were living with HIV infection at the
end of 2012, and an estimated 1.6 million people died of AIDS-related illnesses in
2012. The WHO estimates that 0.8 percent of people aged fifteen to forty-nine
years worldwide are living with HIV, although the vast majority of people with HIV
live in low- and middle-income countries, where prevention and treatment efforts
are limited. Sub-Saharan Africa is the most severely affected region of the world,
with an estimated 24.9 million adults and children living with HIV in 2012.
However, the number of people dying from AIDS-related causes in sub-Saharan Africa
declined by more than 50 percent from 2004 and 2012, as prevention and treatment
efforts in the region improve.

Several new medications in development will hopefully enlarge the arsenal of
anti-HIV drugs, further extending the life expectancies of individuals with
HIV/AIDS. The success of HAART promises to extend the life of persons with AIDS by
many years, and with adequate treatment many HIV-positive individuals enjoy life
expectancies equal to those of HIV-negative individuals. A significant issue is
the high financial burden of HAART therapy. A typical HAART regimen may cost
$1,500 to $2,000 per month. Although many people in high-income countries can
purchase these drugs through insurance providers or government subsidy, this
financial burden precludes the use of HAART and many anti-HIV drugs in low- and
middle-income countries, where HIV prevalence is highest. Thus, effective
prevention of HIV infections, through vigorous public education about HIV and
AIDS, is absolutely critical. Such a program in Uganda dramatically reduced the
incidence of HIV infections, showing the effectiveness of public education
campaigns. According to the United Nations, although the number of individuals
living with HIV/AIDS has risen between 2005 and 2013, the number of adults and
children newly infected with HIV has declined from 2.9 million in 2005 to 2.1
million in 2013; the number of AIDS-related deaths has also declined from 2.4
million to 1.5 million in the same time period.

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