AIDS
Main
disease
byname of acquired immunodeficiency syndrome
transmissible disease of the immune system caused by the human
immunodeficiency virus (HIV). HIV is a lentivirus (literally meaning
“slow virus”; a member of the retrovirus family) that slowly attacks and
destroys the immune system, the body’s defense against infection,
leaving an individual vulnerable to a variety of other infections and
certain malignancies that eventually cause death. AIDS is the final
stage of HIV infection, during which time fatal infections and cancers
frequently arise.
The emergence of HIV/AIDS
Details of the origin of HIV remain unclear. However, a lentivirus
that is genetically similar to HIV has been found in chimpanzees and
gorillas in western equatorial Africa. This virus is known as simian
immunodeficiency virus (SIV), and it was once widely thought to be
harmless in chimpanzees. However, in 2009 a team of researchers
investigating chimpanzee populations in Africa found that SIV in fact
causes AIDS-like illness in the animals. SIV-infected chimpanzees have a
death rate that is 10 to 16 times higher than their uninfected
counterparts. The practice of hunting, butchering, and eating the meat
of chimpanzees may have allowed transmission of the virus to humans,
probably in the late 19th or early 20th century. The strain of SIV found
in gorillas is known as SIVgor, and it is distinct from the strain found
in chimpanzees. Because primates are suspected to be the source of HIV,
AIDS is considered a zoonosis, an infection that is shared by humans and
other vertebrate animals.
Genetic studies of a pandemic strain of HIV, known as HIV-1 group M,
have indicated that the virus emerged between 1884 and 1924 in central
and western Africa. Researchers estimate that this strain of the virus
began spreading throughout these areas in the late 1950s. Later, in the
mid-1960s, an evolved strain called HIV-1 group M subtype B spread from
Africa to Haiti. In Haiti this subtype acquired unique characteristics,
presumably through the process of genetic recombination. Sometime
between 1969 and 1972, the virus migrated from Haiti to the United
States. The virus spread within the United States for about a decade
before it was discovered in the early 1980s. The worldwide spread of
HIV-1 was likely facilitated by several factors, including increasing
urbanization and long-distance travel in Africa, international travel,
changing sexual mores, and intravenous drug use.
In 1981 investigators in New York and California reported the first
official case of AIDS. Initially, most cases of AIDS in the United
States were diagnosed in homosexual men, who contracted the virus
primarily through sexual contact, and in intravenous drug users, who
became infected mainly by sharing contaminated hypodermic needles. In
1983 French and American researchers isolated the causative agent, HIV.
(In 2008 French virologists Françoise Barré-Sinoussi and Luc Montagnier
were awarded the Nobel Prize for Physiology or Medicine for their
discovery of HIV.) By 1985 serological tests to detect the virus had
been developed. According to the 2007 United Nations report on AIDS, an
estimated 33.2 million people were living with HIV, approximately 2.5
million people were newly infected with HIV, and about 2.1 million
people died of AIDS. Relative to previous years, the statistics for 2007
reflect a decrease in the annual number of new infections and deaths
from AIDS and an increase in the overall number of people living with
AIDS. Some 25 million people have died of the disease since 1981.
People living in sub-Saharan Africa account for about 70 percent of
all infections, and in some countries of the region the prevalence of
HIV infection of inhabitants exceeded 10 percent of the population.
Rates of infection are lower in other parts of the world, but different
subtypes of the virus have spread to Europe, India, South and Southeast
Asia, Latin America, and the Caribbean. Rates of infection have leveled
off somewhat in the United States and Europe. In the United States
nearly one million people are living with HIV/AIDS, and half of all new
infections are among African Americans. In Asia the sharpest increases
in HIV infections are found in China, Indonesia, and Vietnam. Access to
retroviral treatment for AIDS remains limited in some areas of the
world, although more people are receiving treatment today than in the
past.
Groups and subtypes of HIV
Genetic studies have led to a general classification system for HIV
that is primarily based on the degree of similarity in viral gene
sequence. The two major classes of HIV are HIV-1 and HIV-2. HIV-1 is
divided into three groups, known as group M (main group), group O
(outlier group), and group N (new group). Worldwide, HIV-1 group M
causes the majority of HIV infections, and it is further subdivided into
subtypes A through K, which differ in expression of viral genes,
virulence, and mechanisms of transmission. In addition, some subtypes
combine with one another to create recombinant subtypes. HIV-1 group M
subtype B is the virus that spread from Africa to Haiti and eventually
to the United States. Pandemic forms of subtype B are found in North and
South America, Europe, Japan, and Australia. Subtypes A, C, and D are
found in sub-Saharan Africa, although subtypes A and C are also found in
Asia and some other parts of the world. Most other subtypes of group M
are generally located in specific regions of Africa, South America, or
Central America.
In 2009 a new strain of HIV-1 was discovered in a woman from
Cameroon. The virus was closely related to a strain of SIV found in wild
gorillas. Researchers placed the new virus into its own group, HIV-1
group P, because it was unique from all other types of HIV-1. It was
unclear whether the newly identified virus causes disease in humans.
HIV-2 is divided into groups A through E, with subtypes A and B being
the most relevant to human infection. HIV-2, which is found primarily in
western Africa, can cause AIDS, but it does so more slowly than HIV-1.
There is some evidence that HIV-2 may have arisen from a form of SIV
that infects African green monkeys.
Transmission
HIV is transmitted by the direct transfer of bodily fluids, such as
blood and blood products, semen and other genital secretions, or breast
milk, from an infected person to an uninfected person. The primary means
of transmission worldwide is sexual contact with an infected individual.
HIV frequently is spread among intravenous drug users who share needles
or syringes. Prior to the development of screening procedures and
heat-treating techniques that destroy HIV in blood products,
transmission also occurred through contaminated blood products; many
people with hemophilia contracted HIV in this way. Today the risk of
contracting HIV from a blood transfusion is extremely small. In rare
cases transmission to health care workers may occur by an accidental
stick with a needle used to obtain blood from an infected person. The
virus also can be transmitted across the placenta or through the breast
milk from mother to infant; administration of antiretroviral medications
to both the mother and infant around the time of birth reduces the
chance that the child will be infected with HIV. HIV is not spread by
coughing, sneezing, or casual contact (e.g., shaking hands). HIV is
fragile and cannot survive long outside of the body. Therefore, direct
transfer of bodily fluids is required for transmission. Other sexually
transmitted diseases, such as syphilis, genital herpes, gonorrhea, and
chlamydia, increase the risk of contracting HIV through sexual contact,
probably through the genital lesions that they cause.
Life cycle of HIV
The main cellular target of HIV is a special class of white blood
cells critical to the immune system known as helper T lymphocytes, or
helper T cells. Helper T cells are also called CD4+ T cells because they
have on their surfaces a protein called CD4. Helper T cells play a
central role in normal immune responses by producing factors that
activate virtually all the other immune system cells. These include B
lymphocytes, which produce antibodies needed to fight infection;
cytotoxic T lymphocytes, which kill cells infected with a virus; and
macrophages and other effector cells, which attack invading pathogens.
AIDS results from the loss of most of the helper T cells in the body.
HIV is a retrovirus, one of a unique family of viruses that consist
of genetic material in the form of RNA (instead of DNA) surrounded by a
lipoprotein envelope. HIV cannot replicate on its own and instead relies
on the mechanisms of the host cell to produce new viral particles. HIV
infects helper T cells by means of a protein embedded in its envelope
called gp120. The gp120 protein binds to a molecule called CD4 on the
surface of the helper T cell, an event that initiates a complex set of
reactions that allow the HIV genetic information into the cell. Entry of
HIV into the host cell also requires the participation of a set of cell
surface proteins that normally serve as receptors for chemokines
(hormone-like mediators that attract immune system cells to particular
sites in the body). It appears that the binding of gp120 to CD4 exposes
a region of gp120 that interacts with the chemokine receptors. This
interaction triggers a conformational change that exposes a region of
the viral envelope protein gp41, which inserts itself into the membrane
of the host cell so that it bridges the viral envelope and the cell
membrane. An additional conformational change in gp41 pulls these two
membranes together, allowing fusion to occur. After fusion the viral
genetic information can enter the host cell.
Once the virus has infected a T cell, HIV copies its RNA into a
double-stranded DNA copy by means of the viral enzyme reverse
transcriptase; this process is called reverse transcription because it
violates the usual way in which genetic information is transcribed.
Because reverse transcriptase lacks the “proofreading” function that
most DNA synthesizing enzymes have, many mutations arise as the virus
replicates, further hindering the ability of the immune system to combat
the virus. These mutations allow the virus to evolve very rapidly,
approximately one million times faster than the human genome evolves.
This rapid evolution allows the virus to escape from antiviral immune
responses and antiretroviral drugs. The next step in the virus life
cycle is the integration of the viral genome into the host cell DNA.
Integration occurs at essentially any accessible site in the host genome
and results in the permanent acquisition of viral genes by the host
cell. Under appropriate conditions these genes are transcribed into
viral RNA molecules. Some viral RNA molecules are incorporated into new
virus particles, while others are used as messenger RNA for the
production of new viral proteins. Viral proteins assemble at the plasma
membrane together with the genomic viral RNA to form a virus particle
that buds from the surface of the infected cell, taking with it some of
the host cell membrane that serves as the viral envelope. Embedded in
this envelope are the gp120/gp41 complexes that allow attachment of the
helper T cells in the next round of infection. Most infected cells die
quickly (in about one day). The number of helper T cells that are lost
through direct infection or other mechanisms exceeds the number of new
cells produced by the immune system, eventually resulting in a decline
in the number of helper T cells. Physicians follow the course of the
disease by determining the number of helper T cells (CD4+ cells) in the
blood. This measurement, called the CD4 count, provides a good
indication of the status of the immune system. Physicians also measure
the amount of virus in the bloodstream—i.e., the viral load—which
provides an indication of how fast the virus is replicating and
destroying helper T cells.
Genome of HIV
The genome of HIV mutates at a very high rate, and thus the virus in
each infected individual is slightly different. The genetic mechanisms
that underlie this individual variation have been investigated through
approaches based on genome sequencing. The HIV-1 genome in 2009 was the
first HIV genome to be sequenced in its entirety. Prior to this
achievement, the ability of HIV RNA to fold into highly intricate
structures had complicated attempts to elucidate the genomic sequence,
and scientists could sequence only small segments of the genome. The
HIV-1 genome is composed of 9,173 nucleotides of RNA (nucleotides are
the building blocks of nucleic acids).
Sequencing revealed that variation occurs throughout the HIV genome
but is especially pronounced in the gene encoding the gp120 protein. By
constantly changing the structure of its predominant surface protein,
the virus can avoid recognition by antibodies produced by the immune
system. Sequencing also has provided useful insight into genetic factors
that influence viral activity. Knowledge of these factors is expected to
contribute to the development of new drugs for the treatment of AIDS.
Course of infection
The course of HIV infection involves three stages: primary HIV
infection, the asymptomatic phase, and AIDS. During the first stage the
transmitted HIV replicates rapidly, and some persons may experience an
acute flulike illness that usually persists for one to two weeks. During
this time a variety of symptoms may occur, such as fever, enlarged lymph
nodes, sore throat, muscle and joint pain, rash, and malaise. Standard
HIV tests, which measure antibodies to the virus, are initially negative
because HIV antibodies generally do not reach detectable levels in the
blood until a few weeks after the onset of the acute illness. As the
immune response to the virus develops, the level of HIV in the blood
decreases.
The second phase of HIV infection, the asymptomatic period, lasts an
average of 10 years. During this period the virus continues to
replicate, and there is a slow decrease in the CD4 count (the number of
helper T cells). When the CD4 count falls to about 200 cells per
microlitre of blood (in an uninfected adult it is typically about 1,000
cells per microlitre), patients begin to experience opportunistic
infections—i.e., infections that arise only in individuals with a
defective immune system. This is AIDS, the final stage of HIV infection.
The most common opportunistic infections are Pneumocystis carinii
pneumonia, tuberculosis, Mycobacterium avium infection, herpes simplex
infection, bacterial pneumonia, toxoplasmosis, and cytomegalovirus
infection. In addition, patients can develop dementia and certain
cancers, including Kaposi sarcoma and lymphomas. Death ultimately
results from the relentless attack of opportunistic pathogens or from
the body’s inability to fight off malignancies.
A small proportion of individuals infected with HIV have survived
longer than 10 years without developing AIDS. It was suspected for many
years that such individuals mount a more vigorous immune response to the
virus, but scientists could not explain why. Then, in 2006, a variation
called a single nucleotide polymorphism, or SNP, in the HLA-G gene—human
leukocyte antigen G, a gene that codes for a molecule that stimulates
immune response—was identified in a subset of female prostitutes who had
remained HIV-negative despite having had sexual contact with more than
500 HIV-positive men. In 2007 scientists identified three additional
SNPs responsible for an estimated 15 percent of the variability in viral
load and disease progression between HIV-infected individuals. Two of
these SNPs are located in genes that code for HLA-B and HLA-C, molecules
that are similar to HLA-G in that they specialize in pathogen
recognition and immune system activation. The third SNP is located in a
gene called HCP5 (HLA complex P5), an inactive retrovirus first
incorporated into the human genome millions of years ago that shares
similarities in DNA sequence with HIV and is thought to interfere with
viral replication.
In 2009 scientists discovered that HIV is capable of rapidly mutating
to escape recognition by certain HLA immune molecules. In particular,
researchers identified two forms of the HLA-B gene, known as HLA-B*51
and HLA-B*27, that produced immune molecules particularly susceptible to
escape by HIV. The mutation of HIV to avoid these molecules is directly
correlated to the frequency at which the HLA-B*51 and HLA-B*27 genes
occur within populations. For example, the percentage of HIV-infected
individuals that carried mutant virus capable of escaping immune
detection by HLA-B*51 and HLA-B*27 molecules was high in populations
with the highest frequencies of the HLA-B*51 and HLA-B*27 genes. In
contrast, in populations with the lowest frequencies of these genes,
only a small percentage of HIV-infected individuals were infected with
mutant virus. The ability of HIV to mutate and hence rapidly evolve to
escape immune detection by the most prevalent HLA molecules is similar
to the rapid adaptation and mutation of other infectious viruses such as
influenza.
Diagnosis, treatment, and prevention
Tests for the disease check for antibodies to HIV, which appear from
four weeks to six months after exposure. The most common test for HIV is
the enzyme-linked immunosorbent assay (ELISA). If the result is
positive, the test is repeated on the same blood sample. Another
positive result is confirmed using a more specific test such as the
Western blot. A problem with ELISA is that it produces false positive
results in people who have been exposed to parasitic diseases such as
malaria; this is particularly troublesome in Africa, where both AIDS and
malaria are rampant. Polymerase chain reaction (PCR) tests, which screen
for viral RNA and therefore allow detection of the virus after very
recent exposure, and Single Use Diagnostic Screening (SUDS) are other
options. Because these tests are very expensive, they are often out of
reach for the majority of the population at risk for the disease.
Pharmaceutical companies are developing new tests that are less
expensive and that do not need refrigeration, allowing for a greater
testing of the at-risk population around the world.
There is no cure for HIV infection. Efforts at prevention have
focused primarily on changes in sexual behaviour such as the practice of
abstinence and the use of condoms. Attempts to reduce intravenous drug
use and to discourage the sharing of needles also led to a reduction in
infection rates in some areas. The first vaccine to demonstrate some
level of effectiveness in preventing HIV infection was RV144, which
actually consisted of two different vaccines given in succession, a
strategy known as “prime boost.” Each vaccine was designed to work
against strains of HIV circulating in Southeast Asia. In 2009, results
from a clinical trial involving more than 16,000 volunteers in Thailand
revealed that RV144 reduced the risk of HIV infection by 31.2 percent in
healthy men and women between ages 18 and 30.
HIV infection is treated with three classes of antiretroviral
medications. Protease inhibitors, which inhibit the action of an HIV
enzyme called protease, include ritonavir, saquinivir, indinavir,
amprenivir, nelfinavir, and lopinavir. Nucleoside reverse transcriptase
(RT) inhibitors (e.g., abacavir [ABC], zidovudine [AZT], zalcitabine [ddC],
didanosine [ddI], stavudine [d4T], and lamivudine [3TC]) and
non-nucleoside RT inhibitors (e.g., efavirenz, delavirdine, and
nevirapine) both inhibit the action of reverse transcriptase. Each drug
has unique side effects, and, in addition, treatment with combinations
of these drugs leads to additional side effects including a
fat-redistribution condition called lipodystrophy.
Because HIV rapidly becomes resistant to any single antiretroviral
drug, combination treatment is necessary for effective suppression of
the virus. Highly active antiretroviral therapy (HAART), a combination
of three or more RT and protease inhibitors, has resulted in a marked
drop in the mortality rate from HIV infection in the United States and
other industrialized states since its introduction in 1996. Because of
its high cost, HAART is generally not available in regions of the world
hit hardest by the AIDS epidemic. Although HAART does not appear to
eradicate HIV, it largely halts viral replication, thereby allowing the
immune system to reconstitute itself. Levels of free virus in the blood
become undetectable; however, the virus is still present in reservoirs,
the best-known of which is a latent reservoir in a subset of helper T
cells called resting memory T cells. The virus can persist in a latent
state in these cells, which have a long life span due to their role in
allowing the immune system to respond readily to previously encountered
infections. These latently infected cells represent a major barrier to
curing the infection. Patients successfully treated with HAART no longer
suffer from the AIDS-associated conditions mentioned above, although
severe side effects may accompany the treatment. Patients must continue
to take all of the drugs without missing doses in the prescribed
combination or risk developing a drug-resistant virus; viral replication
resumes if HAART is discontinued.
Antiretroviral therapy is typically initiated once CD4 levels have
fallen to 200 cells per microlitre of blood, which generally coincides
with the establishment of symptomatic disease. In most patients,
initiating treatment at this point provides maximal therapeutic
effectiveness, in that it minimizes the severity of drug toxicities and
thus the risk for discontinuance of treatment and development of drug
resistance. However, studies have indicated that in patients with
morbidity-increasing factors, such as coinfection with a hepatitis virus
or unusually rapid CD4 decline or high viral load, initiating treatment
earlier, when CD4 levels have declined to 350 cells per microlitre, can
improve survival and delay the onset of AIDS-related diseases
significantly. Other studies have indicated that beginning
antiretroviral treatment in infants immediately following diagnosis,
rather than waiting until symptoms appear, can reduce infant mortality
and disease progression dramatically. Such studies have resulted in the
consideration of treatment recommendations that are more dynamic today
than in the past, thereby improving treatment outcomes for certain
subsets of patients with HIV.
The identification of gene variations in HLA-B, HLA-C, HLA-G, and
HCP5 has opened avenues of drug and vaccine development that had not
been previously explored for HIV infection. Scientists anticipate that
therapies aimed at these genes will serve as ways to boost immune
response.
Robert Siliciano
Social, legal, and cultural aspects
As with any epidemic for which there is no cure, tragedy shadows
the disease’s advance. From wreaking havoc on certain populations (such
as the gay community in San Francisco in the 1980s) to infecting more
than one-third of adults in sub-Saharan African countries such as
Botswana, Swaziland, and Zimbabwe at the turn of the 21st century, AIDS
has had a devastating social impact. Its collateral cultural effect has
been no less far-reaching, sparking new research in medicine and complex
legal debates, as well as intense competition among scientists,
pharmaceutical companies, and research institutions. Since the
mid-1980s, the International AIDS Society has held regular conferences
at which new research and medical advances were discussed.
In order to raise public awareness, advocates promote the wearing of
a loop of red ribbon to indicate their concern. Activist groups lobby
governments for funding for education, research, and treatment, and
support groups provide a wide range of services including medical,
nursing, and hospice care, housing, psychological counseling, meals, and
legal services. Those who have died of AIDS have been memorialized in
the more than 44,000 panels of the AIDS Memorial Quilt, which has been
displayed worldwide both to raise funds and to emphasize the human
dimension of the tragedy. The United Nations designated December 1 as
World AIDS Day.
Regarding access to the latest medical treatments for AIDS, the
determining factors tend often to be geographic and economic. Simply
put, developing nations often lack the means and funding to support the
advanced treatments available in industrialized countries. On the other
hand, in many developed countries specialized health care has caused the
disease to be perceived as treatable or even manageable. This perception
has fostered a lax attitude toward HIV prevention (such as safe sex
practices or sterile needle distribution programs), which in turn has
led to new increases in HIV infection rates.
Because of the magnitude of the disease in Africa, and in sub-Saharan
Africa in particular, the governments of this region have tried to fight
the disease in a variety of ways. Some countries have made arrangements
with multinational pharmaceutical companies to make HIV drugs available
in Africa at lower costs. Other countries, such as South Africa, have
begun manufacturing these drugs themselves instead of importing them.
Plants indigenous to Africa are also being scrutinized for their
usefulness in developing various HIV treatments.
In the absence of financial resources to pay for new drug therapies,
many African countries have found education to be the best defense
against the disease. In Uganda, for example, songs about the disease,
nationally distributed posters, and public awareness campaigns starting
as early as kindergarten have all helped to stem the spread of AIDS.
Prostitutes in Senegal are licensed and regularly tested for HIV, and
the clergy, including Islamic religious leaders, work to inform the
public about the disease. Other parts of Africa, however, have seen
little progress. For example, the practice of sexually violating very
young girls has developed among some HIV-positive African men because of
the misguided belief that such acts will somehow cure them of the
disease. In sub-Saharan Africa the stigma associated with homosexuality
and the illegal nature of this sexual orientation in some countries
there have discouraged gay men from seeking treatment for the disease
and have severely hindered the extension of AIDS outreach programs to
this population. In 2009 the incidence of AIDS among homosexual males in
certain African countries was found to be alarmingly high—some 10 times
higher than in the male population at large. Furthermore, many
homosexual men in those areas were reportedly unaware that the disease
could be transmitted from male to male. In the opinion of many, only
better education can battle the damaging stereotypes, misinformation,
and disturbing practices associated with AIDS.
Laws concerning HIV and AIDS typically fall into four broad
categories: mandatory reporting, mandatory testing, laws against
transmission, and immigration. The mandatory reporting of newly
discovered HIV infections is meant to encourage early treatment. Many
countries, including Canada, Switzerland, Denmark, and Germany, have
enacted mandatory screening laws for HIV. Some countries, such as
Estonia, require mandatory testing of prison populations (in response to
explosive rates of infection among the incarcerated). Most of the United
States requires some form of testing for convicted sex offenders. Other
legal and international issues concern the criminalization of knowing or
unknowing transmission (more prevalent in the United States and Canada)
and the rights of HIV-positive individuals to immigrate to or even enter
foreign countries.
In the United States some communities have fought the opening of AIDS
clinics or the right of HIV-positive children to attend public schools.
Several countries—notably Thailand, India, and Brazil—have challenged
international drug patent laws, arguing that the societal need for
up-to-date treatments supersedes the rights of pharmaceutical companies.
At the start of the 21st century many Western countries were also
battling the reluctance of some governments to direct public awareness
campaigns at high-risk groups such as homosexuals, prostitutes, and drug
users out of fear of appearing to condone their lifestyles.
For the world of art and popular culture, HIV/AIDS has been
double-edged. On the one hand, AIDS removed from the artistic heritage
many talented photographers, singers, actors, dancers, and writers in
the world. On the other hand, as with the tragedy of war and even the
horror of the Holocaust, AIDS has spurred moving works of art as well as
inspiring stories of perseverance. From Paul Monette’s Love Alone, to
John Corigliano’s Symphony No. 1, to the courage with which American
tennis star Arthur Ashe publicly lived his final days after acquiring
AIDS from a blood transfusion—these, as much as the staggering rates of
infection, constitute the legacy of AIDS.
Keith Dorwick
Encyclopaedia Britannica
