Causes of HIV/AIDS
HIV/AIDS Causes: Book Excerpts
HIV/AIDS as a complication of other conditions:
Other conditions that might have
HIV/AIDS as a complication may,
potentially, be an underlying cause of HIV/AIDS.
Our database lists the following as having
HIV/AIDS as a complication of that condition:
HIV/AIDS as a symptom:
Conditions listing HIV/AIDS
as a symptom may also be potential underlying causes of HIV/AIDS.
Our database lists the following as having
HIV/AIDS as a symptom of that condition:
What causes HIV/AIDS?
Causes: HIV/AIDS:
AIDS is caused by the human immunodeficiency virus (HIV).
By killing or damaging cells of the body's immune system, HIV
progressively destroys the body's ability to fight infections and
certain cancers. People diagnosed with AIDS may get life-threatening
diseases called opportunistic infections, which are caused by
microbes such as viruses or bacteria that usually do not make
healthy people sick. (Source: excerpt from HIV Infection and AIDS, An Overview, NIAID Fact Sheet: NIAID)
Article excerpts about the
causes of HIV/AIDS:
HIV disease is characterized by a gradual deterioration of immune
function. Most notably, crucial immune cells called CD4+ T cells are
disabled and killed during the typical course of infection. These
cells, sometimes called "T-helper cells," play a central role in the
immune response, signaling other cells in the immune system to
perform their special functions.
A healthy, uninfected person usually has 800 to 1,200 CD4+ T
cells per cubic millimeter (mm3) of blood. During HIV infection, the
number of these cells in a person's blood progressively declines.
When a person's CD4+ T cell count falls below 200/mm3, he or she
becomes particularly vulnerable to the opportunistic infections and
cancers that typify AIDS, the end stage of HIV disease. People with
AIDS often suffer infections of the lungs, intestinal tract, brain,
eyes and other organs, as well as debilitating weight loss,
diarrhea, neurologic conditions and cancers such as Kaposi's sarcoma
and certain types of lymphomas.
Most scientists think that HIV causes AIDS by directly inducing
the death of CD4+ T cells or interfering with their normal function,
and by triggering other events that weaken a person's immune
function. For example, the network of signaling molecules that
normally regulates a person's immune response is disrupted during
HIV disease, impairing a person's ability to fight other infections.
The HIV-mediated destruction of the lymph nodes and related
immunologic organs also plays a major role in causing the
immunosuppression seen in people with AIDS.
Scope of the HIV Epidemic
Although HIV was first identified in 1983, studies of previously
stored blood samples indicate that the virus entered the U.S.
population sometime in the late 1970s. In the United States, 774,467
cases of AIDS, and 448,060 deaths among people with AIDS had been
reported to the Centers for Disease Control and Prevention (CDC) as
of the end of 2000. Approximately 40,000 new HIV infections occur
each year in the United States, 70 percent of them among men and 30
percent among women. Minority groups in the United States have been
disproportionately affected by the epidemic.
Worldwide, an estimated 36.1 million people (47 percent of whom
are female) were living with HIV/AIDS as of December 2000, according
to the Joint United Nations Programme on HIV/AIDS (UNAIDS). Through
2000, cumulative HIV/AIDS-associated deaths worldwide numbered
approximately 21.8 million: 17.5 million adults and 4.3 million
children younger than 15 years. Globally, approximately 5.3 million
new HIV infections and 3.0 million HIV/AIDS-related deaths occurred
in the year 2000 alone.
HIV is a Retrovirus
HIV belongs to a class of viruses called retroviruses.
Retroviruses are ribonucleic acid (RNA) viruses, and in order to
replicate they must make a deoxyribonucleic acid (DNA) copy of their
RNA. It is the DNA genes that allow the virus to replicate.
Like all viruses, HIV can replicate only inside cells,
commandeering the cell's machinery to reproduce. However, only HIV
and other retroviruses, once inside a cell, use an enzyme called
reverse transcriptase to convert their RNA into DNA, which can be
incorporated into the host cell's genes.
Slow viruses. HIV belongs to a subgroup
of retroviruses known as lentiviruses, or "slow" viruses. The course
of infection with these viruses is characterized by a long interval
between initial infection and the onset of serious symptoms.
Other lentiviruses infect nonhuman species. For example, the
feline immunodeficiency virus (FIV) infects cats and the simian
immunodeficiency virus (SIV) infects monkeys and other nonhuman
primates. Like HIV in humans, these animal viruses primarily infect
immune system cells, often causing immunodeficiency and AIDS-like
symptoms. These viruses and their hosts have provided researchers
with useful, albeit imperfect, models of the HIV disease process in
people.
The viral envelope. HIV has a diameter of
1/10,000 of a millimeter and is spherical in shape. The outer coat
of the virus, known as the viral envelope, is composed of two layers
of fatty molecules called lipids, taken from the membrane of a human
cell when a newly formed virus particle buds from the cell. Recent
evidence from NIAID-supported researchers indicates that HIV may
enter and exit cells through special areas of the cell membrane
known as "lipid rafts." These rafts are high in cholesterol and
glycolipids and may provide a new target for blocking HIV.
Embedded in the viral envelope are proteins from the host cell,
as well as 72 copies (on average) of a complex HIV protein
(frequently called "spikes") that protrudes through the surface of
the virus particle (virion). This protein, known as Env, consists of
a cap made of three molecules called glycoprotein (gp) 120, and a
stem consisting of three gp41 molecules that anchor the structure in
the viral envelope. Much of the research to develop a vaccine
against HIV has focused on these envelope proteins.
The viral core. Within the envelope of
a mature HIV particle is a bullet-shaped core or capsid, made of
2000 copies of another viral protein, p24. The capsid surrounds two
single strands of HIV RNA, each of which has a copy of the virus's
nine genes. Three of these, gag, pol and env, contain information
needed to make structural proteins for new virus particles. The env
gene, for example, codes for a protein called gp160 that is broken
down by a viral enzyme to form gp120 and gp41, the components of
Env.
Six regulatory genes, tat, rev, nef, vif, vpr and
vpu, contain information necessary for the production of
proteins that control the ability of HIV to infect a cell, produce
new copies of virus or cause disease. The protein encoded by nef,
for instance, appears necessary for the virus to replicate
efficiently, and the vpu-encoded protein influences the release of
new virus particles from infected cells.
The ends of each strand of HIV RNA contain an RNA sequence called
the long terminal repeat (LTR). Regions in the LTR act as switches
to control production of new viruses and can be triggered by
proteins from either HIV or the host cell.
The core of HIV also includes a protein called p7, the HIV
nucleocapsid protein; and three enzymes that carry out later steps
in the virus's life cycle: reverse transcriptase, integrase and
protease. Another HIV protein called p17, or the HIV matrix protein,
lies between the viral core and the viral envelope.
Entry of HIV into cells. Infection
typically begins when an HIV particle, which contains two copies of
the HIV RNA, encounters a cell with a surface molecule called
cluster designation 4 (CD4). Cells carrying this molecule are known
as CD4 positive (CD4+) cells.
One or more of the virus's gp120 molecules binds tightly to CD4
molecule(s) on the cell's surface. The binding of gp120 to CD4
results in a conformational change in the gp120 molecule allowing it
to bind to a second molecule on the cell surface known as a
coreceptor. The envelope of the virus and the cell membrane then
fuse, leading to entry of the virus into the cell. The gp41 of the
envelope is critical to the fusion process. Drugs that block either
the binding or the fusion process are being developed and tested in
clinical trials.
Studies have identified multiple coreceptors for different types
of HIV strains; these coreceptors are promising targets for new
anti-HIV drugs, some of which are now being tested in pre-clinical
and clinical studies. In the early stage of HIV disease, most people
harbor viruses that use, in addition to CD4, a receptor called CCR5
to enter their target cells. With disease progression, the spectrum
of coreceptor usage expands in approximately 50 percent of patients
to include other receptors, notably a molecule called CXCR4. Virus
that utilizes CCR5 is called R5 HIV and virus that utilizes CXCR4 is
called X4 HIV.
Although CD4+ T cells appear to be the main targets of HIV, other
immune system cells with and without CD4 molecules on their surfaces
are infected as well. Among these are long-lived cells called
monocytes and macrophages, which apparently can harbor large
quantities of the virus without being killed, thus acting as
reservoirs of HIV. CD4+ T cells also serve as important reservoirs
of HIV: a small proportion of these cells harbor HIV in a stable,
inactive form. Normal immune processes may activate these cells,
resulting in the production of new HIV virions
Cell-to-cell spread of HIV also can occur through the
CD4-mediated fusion of an infected cell with an uninfected cell.
Reverse transcription. In the cytoplasm
of the cell, HIV reverse transcriptase converts viral RNA into DNA,
the nucleic acid form in which the cell carries its genes. Nine of
the 15 antiviral drugs approved in the United States for the
treatment of people with HIV infection -- AZT, ddC, ddI, d4T, 3TC,
nevirapine, delavirdine, abacavir and efavirenz -- work by
interfering with this stage of the viral life cycle.
Integration. The newly made HIV DNA
moves to the cell's nucleus, where it is spliced into the host's DNA
with the help of HIV integrase. HIV DNA that enters the DNA of the
cell is called a "provirus." Integrase is an important target for
the development of new drugs.
Transcription. For a provirus to
produce new viruses, RNA copies must be made that can be read by the
host cell's protein-making machinery. These copies are called
messenger RNA (mRNA), and production of mRNA is called
transcription, a process that involves the host cell's own enzymes.
Viral genes in concert with the cellular machinery control this
process: the tat gene, for example, encodes a protein that
accelerates transcription. Genomic RNA is also transcribed for later
incorporation in the budding virion (see below).
Cytokines, proteins involved in the normal regulation of the
immune response, also may regulate transcription. Molecules such as
tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, secreted
in elevated levels by the cells of HIV-infected people, may help to
activate HIV proviruses. Other infections, by organisms such as
Mycobacterium tuberculosis, may also enhance transcription by
inducing the secretion of cytokines.
Translation. After HIV mRNA is
processed in the cell's nucleus, it is transported to the cytoplasm.
HIV proteins are critical to this process: for example, a protein
encoded by the rev gene allows mRNA encoding HIV structural proteins
to be transferred from the nucleus to the cytoplasm. Without the rev
protein, structural proteins are not made.
In the cytoplasm, the virus co-opts the cell's protein-making
machinery - including structures called ribosomes - to make long
chains of viral proteins and enzymes, using HIV mRNA as a template.
This process is called translation.
Assembly and budding. Newly made HIV
core proteins, enzymes and genomic RNA gather just inside the cell's
membrane, while the viral envelope proteins aggregate within the
membrane. An immature viral particle forms and buds off from the
cell, acquiring an envelope that includes both cellular and HIV
proteins from the cell membrane. During this part of the viral life
cycle, the core of the virus is immature and the virus is not yet
infectious. The long chains of proteins and enzymes that make up the
immature viral core are now cleaved into smaller pieces by a viral
enzyme called protease. This step results in infectious viral
particles.
Drugs called protease inhibitors interfere with
this step of the viral life cycle. Six such drugs -- saquinavir,
ritonavir, indinavir, amprenavir, nelfinavir, and lopinavir -- have
been approved for marketing in the United States.
Transmission of HIV
Among adults, HIV is spread most commonly during sexual
intercourse with an infected partner. During sex, the virus can
enter the body through the mucosal linings of the vagina, vulva,
penis, or rectum after intercourse or, rarely, via the mouth and
possibly the upper gastrointestinal tract after oral sex. The
likelihood of transmission is increased by factors that may damage
these linings, especially other sexually transmitted diseases that
cause ulcers or inflammation.
Research suggests that immune system cells of the dendritic cell
type, which reside in the mucosa, may begin the infection process
after sexual exposure by binding to and carrying the virus from the
site of infection to the lymph nodes where other immune system cells
become infected.
HIV also can be transmitted by contact with infected blood, most
often by the sharing of needles or syringes contaminated with minute
quantities of blood containing the virus. The risk of acquiring HIV
from blood transfusions is now extremely small in the United States,
as all blood products in this country are screened routinely for
evidence of the virus.
Almost all HIV-infected children acquire the virus from their
mothers before or during birth. In the United States, approximately
25 percent of pregnant HIV-infected women not receiving
antiretroviral therapy have passed on the virus to their babies. In
1994, researchers demonstrated that a specific regimen of the drug
zidovudine (AZT) can reduce the risk of transmission of HIV from
mother to baby by two-thirds. The use of combinations of
antiretroviral drugs has further reduced the rate of mother-to-child
HIV transmission in the United States. In developing countries,
cheap and simple antiviral drug regimens have been proven to
significantly reduce mother-to-child transmission in resource-poor
settings.
The virus also may be transmitted from an HIV-infected mother to
her infant via breastfeeding.
Early Events in HIV Infection
Once it enters the body, HIV infects a large number of CD4+ cells
and replicates rapidly. During this acute or primary phase of
infection, the blood contains many viral particles that spread
throughout the body, seeding various organs, particularly the
lymphoid organs. Lymphoid organs include the lymph nodes, spleen,
tonsils and adenoids.
Two to four weeks after exposure to the virus, up to 70 percent
of HIV-infected persons suffer flu-like symptoms related to the
acute infection. The patient's immune system fights back with killer
T cells (CD8+ T cells) and B-cell-produced antibodies, which
dramatically reduce HIV levels. A patient's CD4+ T cell count may
rebound somewhat and even approach its original level. A person may
then remain free of HIV-related symptoms for years despite
continuous replication of HIV in the lymphoid organs that had been
seeded during the acute phase of infection.
One reason that HIV is unique is the fact that despite the body's
aggressive immune responses, which are sufficient to clear most
viral infections, some HIV invariably escapes. This is due in large
part to the high rate of mutations that occur during the process of
HIV replication. Even when the virus does not avoid the immune
system by mutating, the body's best soldiers in the fight against
HIV - certain subsets of killer T cells that recognize HIV may be
depleted or become dysfunctional.
In addition, early in the course of HIV infection, patients may
lose HIV-specific CD4+ T cell responses that normally slow the
replication of viruses. Such responses include the secretion of
interferons and other antiviral factors, and the orchestration of
CD8+ T cells.
Finally, the virus may hide within the chromosomes of an infected
cell and be shielded from surveillance by the immune system. Such
cells can be considered as a latent reservoir of the virus.
Course of HIV Infection
Among patients enrolled in large epidemiologic studies in western
countries, the median time from infection with HIV to the
development of AIDS-related symptoms has been approximately 10 to 12
years in the absence of antiretroviral therapy. However, researchers
have observed a wide variation in disease progression. Approximately
10 percent of HIV-infected people in these studies have progressed
to AIDS within the first two to three years following infection,
while up to 5 percent of individuals in the studies have stable CD4+
T cell counts and no symptoms even after 12 or more years.
Factors such as age or genetic differences among individuals, the
level of virulence of an individual strain of virus, and
co-infection with other microbes may influence the rate and severity
of disease progression. Drugs that fight the infections associated
with AIDS have improved and prolonged the lives of HIV-infected
people by preventing or treating conditions such as Pneumocystis
carinii pneumonia, cytomegalovirus disease, and diseases caused by a
number of fungi.
HIV co-receptors and disease
progression. Recent research has shown that most
infecting strains of HIV use a co-receptor molecule called CCR5, in
addition to the CD4 molecule, to enter certain of its target cells.
HIV-infected people with a specific mutation in one of their two
copies of the gene for this receptor may have a slower disease
course than people with two normal copies of the gene. Rare
individuals with two mutant copies of the CCR5 gene appear - in most
cases - to be completely protected from HIV infection. Mutations in
the gene for other HIV co-receptors also may influence the rate of
disease progression.
Viral burden predicts disease
progression. Numerous studies show that people with
high levels of HIV in their bloodstream are more likely to develop
new AIDS-related symptoms or die than individuals with lower levels
of virus. For instance, in the Multicenter AIDS Cohort Study (MACS),
investigators demonstrated that the level of HIV in an untreated
individual's plasma 6 months to a year after infection - the
so-called viral "set point" - is highly predictive of the rate of
disease progression; that is, patients with high levels of virus are
much more likely to get sicker, faster, than those with low levels
of virus. The MACS and other studies have provided the rationale for
providing aggressive antiretroviral therapy to HIV-infected people,
as well as for routinely using newly available blood tests to
measure viral load when initiating, monitoring and modifying
anti-HIV therapy.
Potent combinations of three or more anti-HIV drugs known as
highly active antiretroviral therapy or HAART can reduce a person's
"viral burden" to very low levels and in many cases delay the
progression of HIV disease for prolonged periods. However,
antiretroviral regimens have yet to completely and permanently
suppress the virus in HIV-infected people. Recent studies have shown
that HIV persists in a replication-competent form in resting CD4+ T
cells even in patients receiving aggressive antiretroviral therapy
who have no readily detectable HIV in their blood. Investigators
around the world are working to develop the next generation of
anti-HIV drugs.
HIV is Active in the Lymph Nodes
Although HIV-infected individuals often exhibit an extended
period of clinical latency with little evidence of disease, the
virus is never truly completely latent although individual cells may
be latently infected. Researchers have shown that even early in
disease, HIV actively replicates within the lymph nodes and related
organs, where large amounts of virus become trapped in networks of
specialized cells with long, tentacle-like extensions. These cells
are called follicular dendritic cells (FDCs).
FDCs are located in hot spots of immune activity in lymphoid
tissue called germinal centers. They act like flypaper, trapping
invading pathogens (including HIV) and holding them until B cells
come along to initiate an immune response.
Close on the heels of B cells are CD4+ T cells, which rush into
the germinal centers to help B cells fight the invaders. CD4+ T
cells, the primary targets of HIV, may become infected as they
encounter HIV trapped on FDCs. Research suggests that HIV trapped on
FDCs remains infectious, even when coated with antibodies. Thus,
FDCs are an important reservoir of HIV, and the large quantity of
infectious HIV trapped on FDCs may explain in part how the momentum
of HIV infection is maintained
Once infected, CD4+ T cells may infect other CD4+ cells that
congregate in the region of the lymph node surrounding the germinal
center.
Over a period of years, even when little virus is readily
detectable in the blood, significant amounts of virus accumulate in
the lymophoid tissue, both within infected cells and bound to FDCs.
In and around the germinal centers, numerous CD4+ T cells are
probably activated by the increased production of cytokines such as
TNF-alpha and IL-6 by immune system cells within the lymphoid
tissue. Activation allows uninfected cells to be more easily
infected and increases replication of HIV in already infected
cells.
While greater quantities of certain cytokines such as TNF-alpha
and IL-6 are secreted during HIV infection, other cytokines with key
roles in the regulation of normal immune function may be secreted in
decreased amounts. For example, CD4+ T cells may lose their capacity
to produce interleukin 2 (IL-2), a cytokine that enhances the growth
of other T cells and helps to stimulate other cells' response to
invaders. Infected cells also have low levels of receptors for IL-2,
which may reduce their ability to respond to signals from other
cells.
Breakdown of FDC networks. Ultimately,
accumulated HIV overwhelms the FDC networks. As these networks break
down, their trapping capacity is impaired, and large quantities of
virus enter the bloodstream.
Although it remains unclear why FDCs die and the FDC networks
dissolve, some scientists think that this process may be as
important in HIV pathogenesis as the loss of CD4+ T cells. The
destruction of the lymphoid tissue structure seen late in HIV
disease may preclude a successful immune response against not only
HIV but other pathogens as well. This devastation heralds the onset
of the opportunistic infections and cancers that characterize
AIDS.
Role of CD8+ T Cells
CD8+ T cells are critically important in the immune response to
HIV. These cells attack and kill infected cells that are producing
virus. Thus, vaccine efforts are directed toward eliciting or
enhancing these killer T cells, as well as eliciting antibodies that
will neutralize the infectivity of HIV.
CD8+ T cells also appear to secrete soluble factors that suppress
HIV replication. Several molecules, including RANTES, MIP-1alpha,
MIP-1beta, and MDC appear to block HIV replication by occupying the
co-receptors necessary for the entry of many strains of HIV into
their target cells. There may be other immune system molecules - yet
undiscovered - that can suppress HIV replication to some degree.
Rapid Replication and Mutation of HIV
HIV replicates rapidly; several billion new virus particles may
be produced every day. In addition, the HIV reverse transcriptase
enzyme makes many mistakes while making DNA copies from HIV RNA. As
a consequence, many variants of HIV develop in an individual, some
of which may escape destruction by antibodies or killer T cells.
Additionally, different strains of HIV can recombine to produce a
wide range of variants or strains.
During the course of HIV disease, viral strains emerge in an
infected individual that differ widely in their ability to infect
and kill different cell types, as well as in their rate of
replication. Scientists are investigating why strains of HIV from
patients with advanced disease appear to be more virulent and infect
more cell types than strains obtained earlier from the same
individual.
Theories of Immune System Cell Loss in HIV
Infection
Researchers around the world are studying how HIV destroys or
disables CD4+ T cells, and many think that a number of mechanisms
may occur simultaneously in an HIV-infected individual. Recent data
suggest that billions of CD4+ T cells may be destroyed every day,
eventually overwhelming the immune system's regenerative
capacity.
Direct cell killing. Infected CD4+ T
cells may be killed directly when large amounts of virus are
produced and bud off from the cell surface, disrupting the cell
membrane, or when viral proteins and nucleic acids collect inside
the cell, interfering with cellular machinery.
Apoptosis. Infected CD4+ T cells may be
killed when the regulation of cell function is distorted by HIV
proteins, probably leading to cell suicide by a process known as
programmed cell death or apoptosis. Recent reports indicate that
apoptosis occurs to a greater extent in HIV-infected individuals,
both in the bloodstream and lymph nodes. Apoptosis is closely
correlated with the aberrant cellular activation seen in HIV
disease.
Uninfected cells also may undergo
apoptosis. Investigators have shown in cell cultures
that the HIV envelope alone or bound to antibodies sends an
inappropriate signal to CD4+ T cells causing them to undergo
apoptosis, even if not infected by HIV.
Innocent bystanders. Uninfected cells
may die in an innocent bystander scenario: HIV particles may bind to
the cell surface, giving them the appearance of an infected cell and
marking them for destruction by killer T cells after antibody
attaches to the viral particle on the cell. This process is called
antibody dependent cellular cytotoxicity.
Killer T cells also may mistakenly destroy uninfected cells that
have consumed HIV particles and that display HIV fragments on their
surfaces. Alternatively, because HIV envelope proteins bear some
resemblance to certain molecules that may appear on CD4+ T cells,
the body's immune responses may mistakenly damage such cells as
well.
Anergy. Researchers have shown in cell
cultures that CD4+ T cells can be turned off by activation signals
from HIV that leaves them unable to respond to further immune
stimulation. This inactivated state is known as anergy.
Damage to Precursor Cells. Studies
suggest that HIV also destroys precursor cells that mature to have
special immune functions, as well as the microenvironment of the
bone marrow and the thymus needed for the development of such cells.
These organs probably lose the ability to regenerate, further
compounding the suppression of the immune system.
Central Nervous System Damage
Although monocytes and macrophages can be infected by HIV, they
appear to be relatively resistant to killing by the virus. However,
these cells travel throughout the body and carry HIV to various
organs, including the brain, which may serve as a hiding place or
"reservoir" for the virus that may be relatively impervious to most
anti-HIV drugs.
Neurologic manifestations of HIV disease are seen in up to 50
percent of HIV-infected people, to varying degress of severity.
People infected with HIV often experience cognitive symptoms,
including impaired short-term memory, reduced concentration, and
mental slowing; motor symptoms such as fine motor clumsiness or
slowness, tremor, and leg weakness; and behavioral symptoms
including apathy, social withdrawal, irritability, depression, and
personality change. More serious neurologic manifestations in HIV
disease typically occur in patients with high viral loads, generally
when an individual has advanced HIV disease or AIDS.
Neurologic manifestations of HIV disease are the subject of many
research projects. Current evidence suggests that although nerve
cells do not become infected with HIV, supportive cells within the
brain, such as astrocytes and microglia (as well as
monocyte/macrophages that have migrated to the brain) can be
infected with the virus. Researchers postulate that infection of
these cells can cause a disruption of normal neurologic functions by
altering cytokine levels, by delivering aberrant signals, and by
causing the release of toxic products in the brain. The use of
anti-HIV drugs frequently reduces the severity of neurologic
symptoms, but in many cases does not, for reasons that are
unclear.
Role of Immune Activation in HIV Disease
During a normal immune response, many components of the immune
system are mobilized to fight an invader. CD4+ T cells, for
instance, may quickly proliferate and increase their cytokine
secretion, thereby signaling other cells to perform their special
functions. Scavenger cells called macrophages may double in size and
develop numerous organelles, including lysosomes that contain
digestive enzymes used to process ingested pathogens. Once the
immune system clears the foreign antigen, it returns to a relative
state of quiescence.
Paradoxically, although it ultimately causes immune deficiency,
HIV disease for most of its course is characterized by immune system
hyperactivation, which has negative consequences. As noted above,
HIV replication and spread are much more efficient in activated CD4+
cells. Chronic immune system activation during HIV disease may also
result in a massive stimulation of B cells, impairing the ability of
these cells to make antibodies against other pathogens.
Chronic immune activation also can result in apoptosis, and an
increased production of cytokines that may not only increase HIV
replication but also have other deleterious effects. Increased
levels of TNF-alpha, for example, may be at least partly responsible
for the severe weight loss or wasting syndrome seen in many
HIV-infected individuals.
The persistence of HIV and HIV replication plays an important
role in the chronic state of immune activation seen in HIV-infected
people. In addition, researchers have shown that infections with
other organisms activate immune system cells and increase production
of the virus in HIV-infected people. Chronic immune activation due
to persistent infections, or the cumulative effects of multiple
episodes of immune activation and bursts of virus production, likely
contribute to the progression of HIV disease.
NIAID Research on the Pathogenesis of AIDS
NIAID-supported scientists conduct research on HIV pathogenesis
in laboratories on the campus of the National Institutes of Health
(NIH) in Bethesda, Md., at the Institute's Rocky Mountain
Laboratories in Hamilton, Montana, and at universities and medical
centers in the United States and abroad.
An NIAID-supported resource, the NIH AIDS Research and Reference
Reagent Program, in collaboration with the World Health
Organization, provides critically needed AIDS-related research
materials free to qualified researchers around the world.
In addition, the Institute convenes groups of investigators and
advisory committees to exchange scientific information, clarify
research priorities and bring research needs and opportunities to
the attention of the scientific community.
Fact sheets on various HIV-related topics, including HIV/AIDS
vaccine research, clinical trials for AIDS therapies and vaccines,
and AIDS-related opportunistic infections are available from the
NIAID Office of Communications. To receive free copies, call (301)
496-5717, Monday through Friday, 8:30 a.m. to 5:00 p.m. Eastern
Time. These materials also are available via the NIAID home page on
the Internet at http://www.niaid.nih.gov/.
NIAID, a component of the National Institutes of Health, supports
research on AIDS, tuberculosis, malaria and other infectious
diseases, as well as allergies and immunology. NIH is an agency of
the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are
available on the NIAID home page at http://www.niaid.nih.gov/.
Glossary
apoptosis:cellular suicide, also known as
programmed cell death. HIV may induce apoptosis in both infected and
uninfected immune system cells.
B cells:white blood cells of the immune system
that produce infection-fighting proteins called antibodies.
CD4+ T cells:white blood cells that orchestrate
the immune response, signalling other cells in the immune system to
perform their special functions. Also known as T helper cells, these
cells are killed or disabled during HIV infection.
CD8+ T cells:white blood cells that kill cells
infected with HIV or other viruses, or transformed by cancer. These
cells also secrete soluble molecules that may suppress HIV without
killing infected cells directly.
cytokines:proteins used for communication by
cells of the immune system. Central to the normal regulation of the
immune response.
cytoplasm:the living matter within a cell.
dendritic cells:immune system cells with long,
tentacle-like branches. Some of these are specialized cells at the
mucosa that may bind to HIV following sexual exposure and carry the
virus from the site of infection to the lymph nodes. See also
follicular dendritic cells.
enzyme:a protein that accelerates a specific
chemical reaction without altering itself.
follicular dendritic cells (FDCs):cells found
in the germinal centers (B cell areas) of lymphoid organs. FDCs have
thread-like tentacles that form a web-like network to trap invaders
and present them to B cells, which then make antibodies to attack
the invaders.
germinal centers:structures within lymphoid
tissues that contain FDCs and B cells, and in which immune responses
are initiated.
gp41:glycoprotein 41, a protein embedded in the
outer envelope of HIV. Plays a key role in HIV's infection of CD4+ T
cells by facilitating the fusion of the viral and cell membranes.
gp120:glycoprotein 120, a protein that
protrudes from the surface of HIV and binds to CD4+ T cells.
gp160:glycoprotein 160, an HIV precursor
protein that is cleaved by the HIV protease enzyme into gp41 and
gp120.
integrase:an HIV enzyme used by the virus to
integrate its genetic material into the host cell's DNA.
Kaposi's sarcoma:a type of cancer characterized
by abnormal growths of blood vessels that develop into purplish or
brown lesions.
killer T cells:see CD8+ T cells.
lentivirus:"slow" virus characterized by a long
interval between infection and the onset of symptoms. HIV is a
lentivirus as is the simian immunodeficiency virus (SIV), which
infects nonhuman primates.
LTR:long terminal repeat, the RNA sequences
repeated at both ends of HIV's genetic material. These regulatory
switches may help control viral transcription.
lymphoid organs:include tonsils, adenoids,
lymph nodes, spleen and other tissues. Act as the body's filtering
system, trapping invaders and presenting them to squadrons of immune
cells that congregate there.
macrophage:a large immune system cell that
devours invading pathogens and other intruders. Stimulates other
immune system cells by presenting them with small pieces of the
invaders.
monocyte:a circulating white blood cell that
develops into a macrophage when it enters tissues.
opportunistic infection:an illness caused by an
organism that usually does not cause disease in a person with a
normal immune system. People with advanced HIV infection suffer
opportunistic infections of the lungs, brain, eyes and other
organs.
pathogenesis:the production or development of a
disease. May be influenced by many factors, including the infecting
microbe and the host's immune response.
protease:an HIV enzyme used to cut large HIV
proteins into smaller ones needed for the assembly of an infectious
virus particle.
provirus:DNA of a virus, such as HIV, that has
been integrated into the genes of a host cell.
retrovirus:HIV and other viruses that carry
their genetic material in the form of RNA and that have the enzyme
reverse transcriptase.
reverse transcriptase:the enzyme produced by
HIV and other retroviruses that allows them to synthesize DNA from
their RNA.
(Source: excerpt from How HIV Causes AIDS , NIAID Fact Sheet: NIAID)
Medical news summaries relating to HIV/AIDS:
The following medical news items are relevant to causes of HIV/AIDS:
Cause statistics for HIV/AIDS:
The following are statistics from various sources about the causes of HIV/AIDS:
- 57.5% of adult males with AIDS contracted it through sex with other men in the US 2001 (US Centers for Disease Control and Prevention, US Census Bureau)
- 24% of adult males with AIDS contracted it through injecting drugs in the US 2001 (US Centers for Disease Control and Prevention, US Census Bureau)
- 9.5% of adult males with AIDS contracted it through heterosexual contact in the US 2001 (US Centers for Disease Control and Prevention, US Census Bureau)
- 38% of adult females with AIDS contracted it through injecting drugs in the US 2001 (US Centers for Disease Control and Prevention, US Census Bureau)
- 59% of adult females with AIDS contracted it through heterosexual contact in the US 2001 (US Centers for Disease Control and Prevention, US Census Bureau)
- more statistics...»
Related information on causes of HIV/AIDS:
As with all medical conditions,
there may be many causal factors.
Further relevant information on causes of HIV/AIDS may be found in:
Causes of HIV/AIDS: Online Medical Books
16 MEDICAL BOOKS ONLINE!
Review excerpts from medical books online, free, without registration,
for more information about the causes of HIV/AIDS.
Hearing Loss – Acquired:
Differential Diagnosis
(In A Page: Pediatric Signs and Symptoms)
Conductive (CHL)
-
Cerumen impaction
-
External auditory canal foreign body
-
Middle ear effusion (MEE)
–Frequently follows acute otitis media
-
Tympanic membrane (TM) perforation
–Usually due to trauma, chronic otitis media
-
Cholesteatoma
–Acquired cholesteatoma is accompanied by TM retraction or perforation
–Congenital cholesteatoma is usually over an intact TM
-
Ossicular erosion or fixation due to middle ear disease
-
Ossicular chain discontinuity (generally posttraumatic)
-
External auditory canal stenosis from chronic otitis externa
-
Middle ear tumor
–Paraganglioma (glomus tympanicum), facial neuroma, histiocytosis X, etc.
Sensorineural (SNHL)
-
Meningitis, especially bacterial
-
Viral, especially mumps
-
Autoimmune disease
–Vasculitis, scleroderma, Kawasaki disease
–Idiopathic
-
Acoustic trauma (noise-induced)
-
Ototoxic medications
–Aminoglycosides
–Diuretics (especially loop diuretics)
–Salicylates
–Cytotoxic (chemotherapeutic) agents, e.g., cisplatinum
-
Temporal bone fracture
–SNHL more likely with transverse than longitudinal fracture
-
Perilymphatic fistula (PLF)
–Hearing loss may be progressive or
fluctuating
- Cerebellopontine angle (CPA) tumor
–Vestibular schwannoma (a.k.a. acoustic neuroma, associated with type II neurofibromatosis), meningioma, etc.
–SNHL will be unilateral - Ménière disease
–Characterized by hearing loss, vertigo, tinnitus, sensation of aural fullness
» READ BOOK EXCERPT ONLINE »
Source: In A Page: Pediatric Signs and Symptoms, 2007
Kaposi's sarcoma:
Causes and incidence
(Professional Guide to Diseases (Eighth Edition))
The exact cause of Kaposi's sarcoma is unknown, but the disease may be related to immunosuppression. Genetic or hereditary predisposition is also suspected. In people with AIDS, Kaposi's sarcoma is caused by an interaction between the human immunodeficiency virus (HIV), immune system suppression, and human herpesvirus-8 (HHV-8).
Occurrence has been linked with sexual transmission of HIV and HHV-8. Approximately 3 out of every 100,000 people develop Kaposi's sarcoma each year.
» READ BOOK EXCERPT ONLINE »
Source: Professional Guide to Diseases (Eighth Edition), 2005
Acquired immunodeficiency syndrome:
Causes and incidence
(Professional Guide to Diseases (Eighth Edition))
AIDS results from infection with HIV, which has two forms: HIV-1 and HIV-2. Both forms of HIV have the same modes of transmission and similar opportunistic infections associated with AIDS, but studies indicate that HIV-2 develops more slowly and presents with milder symptoms than HIV-1.
Transmission occurs through contact with infected blood or body fluids and is associated with identifiable high-risk behaviors. It’s disproportionately represented in:
❑ homosexual and bisexual men
❑ persons who use illicit I.V. drugs
❑ neonates of infected females
❑ recipients of contaminated blood or blood products (incidence dramatically decreased since mid-1985)
❑ heterosexual partners of persons in the former groups.
» READ BOOK EXCERPT ONLINE »
Source: Professional Guide to Diseases (Eighth Edition), 2005
Kaposi's sarcoma:
Causes
(Handbook of Diseases)
The exact cause of Kaposi’s sarcoma is unknown, but the disease may be related to immunosuppression. Genetic or hereditary predisposition is also suspected.
» READ BOOK EXCERPT ONLINE »
Source: Handbook of Diseases, 2003
Human immunodeficiency virus infection:
Causes
(Handbook of Diseases)
The virus has two major strains: HIV-1, which is closely related to the primate retrovirus called simian immunodeficiency virus, and HIV-2, which is associated with immunodeficiency but less pathogenic that HIV-1, results from infection with HIV, which strikes cells bearing the CD4+ antigen; the latter (normally a receptor for major histocompatibility complex molecules) serves as a receptor for the retrovirus and lets it enter the cell. HIV prefers to infect the CD4+ lymphocyte or macrophage but may also infect other CD4+ antigen-bearing cells of the GI tract, uterine cervical cells, and neuroglial cells. The virus gains access by binding to the CD4+ molecule on the cell surface along with a co-receptor (thought to be the receptor CCR5). After invading a cell, HIV either replicates, which leads to cell death, or becomes latent. HIV infection leads to profound pathology, either directly, through destruction of CD4+ T cells, other immune cells, and neuroglial cells, or indirectly, through the secondary effects of CD4+ T-cell dysfunction and resultant immunosuppression.
The infection process takes three forms:
❑ immunodeficiency (opportunistic infections and unusual cancers)
❑ autoimmunity (lymphoid interstitial pneumonia, arthritis, hypergammaglobulinemia, and production of autoimmune antibodies)
❑ neurologic dysfunction (AIDS dementia complex, HIV encephalopathy, and peripheral neuropathies).
Transmission
HIV is transmitted by direct inoculation during intimate sexual contact, especially associated with the mucosal trauma of receptive rectal intercourse; transfusion of contaminated blood or blood products (a risk diminished by routine testing of all blood products); sharing of contaminated needles; or transplacental or postpartum transmission from an infected mother to the fetus (by cervical or blood contact at delivery and in breast milk).
HIV isn’t transmitted by casual household or social contact. The average time between exposure to the virus and diagnosis is 8 to 10 years, but shorter and longer incubation times have also been recorded. Most people develop antibodies within 6 to 8 weeks of contracting the virus.
» READ BOOK EXCERPT ONLINE »
Source: Handbook of Diseases, 2003
Chronic fatigue and immune dysfunction syndrome:
Causes
(Handbook of Diseases)
Although the cause of CFIDS is unknown, researchers suspect that it may be found in human herpesvirus 6 or in other herpesviruses, enteroviruses, or retroviruses. Rising levels of antibodies to EBV, once thought to implicate EBV infection as the cause of CFIDS, are now considered a result of this disease.
CFIDS may be associated with a reaction to viral illness that’s complicated by dysfunctional immune response and by other factors that may include sex, age, genetic disposition, prior illness, stress, and environment.
» READ BOOK EXCERPT ONLINE »
Source: Handbook of Diseases, 2003
Human Papilloma Virus:
Human Papilloma Virus - risk factors
(The 5-Minute Pediatric Consult)
- Infants:
- Primarily vertical transmission at birth
- Adolescents:
- Behavioral risks, including young age at 1st coitus, multiple partners, cigarette use, and having older male partners
- Biologic risk in adolescent girls secondary to cervical anatomy
Human Papilloma Virus - pathophysiology
- Transmission is primarily through sexual contact.
- It can also be acquired during the birth process.
- Transmission from nongenital sites occurs rarely.
- The incubation period is variable and ranges from 3 months to several years.
- The virus is trophic for epithelial cells and infects the basal layer of actively dividing cells.
- Infection results in koilocytosis and nuclear atypia. Genital infections may progress to severe dysplasia and carcinoma in situ (CIS).
- Spontaneous regression of clinical disease occurs in 90% of low-risk types and 75% of high-risk types
- Recurrence is common.
» READ BOOK EXCERPT ONLINE »
Source: The 5-Minute Pediatric Consult, 2008
Community-acquired Pneumonia:
Etiology
(Pediatric Infectious Disease)
The primary bacterial pathogen in neonatal pneumonia is group B streptococci,
although
Escherichia coli and Listeria monocytogenes have also been reported. The mechanism is similar to that in neonatal sepsis,
where colonization from the mother results in neonatal colonization and
breakthrough infection.
Chlamydia trachomatis is the most common sexually transmitted infection in the United States. The
organism may reside in the genital tract of pregnant women and be transmitted
in about 60% of cases to infants at the time of delivery. About one half of
infants who acquire the organism develop conjunctivitis, and 20% eventually
develop lower respiratory disease.
» READ BOOK EXCERPT ONLINE »
Source: Pediatric Infectious Disease, 2004
The treatment of HIV can be very complex with medicines that have to be taken several times a day. Now there are medicines that can be taken once a...
In an effort to keep pace with new treatments and clinical practice, the government convenes a panel of experts to develop recommendations for the...
When people with HIV have good access to health care, they can expect to live long and well. That's because doctors have learned to combine drugs...
Lipodystrophy is a condition that many people with HIV develop. Their appearance can change dramatically and they may experience dangerous...
See full list of 35 related videos
» Next page: Risk Factors for HIV/AIDS
Rate This Website
What do you think about the features of this website?
Take our user survey and have your say:
Website User Survey
Medical Tools & Articles:
Next articles:
Tools & Services:
Medical Articles:
Forums & Message Boards
- Ask or answer a question at the Boards:
