How
HIV Causes AIDS
from the National Institute of Allergy and Infectious Diseases (NIAID)
An important focus of the National Institute of Allergy and Infectious Diseases (NIAID) is research devoted to the pathogenesis of human immunodeficiency virus (HIV) disease -- the complex mechanisms that result in the destruction of the immune system of an HIV-infected person. A detailed understanding of HIV and how it establishes infection and causes the acquired immunodeficiency syndrome (AIDS) is crucial to identifying and developing effective drugs and vaccines to fight HIV and AIDS. This fact sheet summarizes what scientists are learning about this process and provides a brief glossary of terms.
Overview
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,
signalling 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 intestinal tract, lungs, brain, eyes and other organs, as well
as debilitating weight loss, diarrhea, neurologic conditions and cancers
such as Kaposi's sarcoma and lymphomas. Most scientists think that HIV
causes AIDS by directly killing CD4+ T cells and by triggering other events
that weaken a person's immune function. For example, the network of signalling
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, 513,486 cases of people with
AIDS had been reported to the Centers for Disease Control and Prevention
(CDC) as of Dec. 31, 1995. Among these individuals, 319,849 had died by
the end of 1995. AIDS is now the leading killer of people aged 25 to 44
in this country. Worldwide, an estimated 27.9 million people had become
HIV-infected through mid-1996, and 7.7 million had developed AIDS, according
to the World Health Organization (WHO). Various projections indicate that,
by the year 2000, between 40 and 110 million people worldwide will be
HIV-infected.
HIV is
a Retrovirus
HIV belongs to a class of viruses called retroviruses, which have genes
composed of ribonucleic acid (RNA) molecules. The genes of humans and
most other organisms are made of a related molecule, deoxyribonucleic
acid (DNA). 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. Scientists use these and other viruses and their
animal hosts as models of HIV disease.
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.
Embedded in the viral envelope are proteins from the host cell, as well
as 72 copies (on average) of a complex HIV protein that protrudes from
the envelope surface. This protein, known as Env, consists of a cap made
of three or four molecules called glycoprotein (gp)120, and a stem consisting
of three or four 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. Three regulatory
genes, tat, rev and nef, and three auxiliary genes, 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.
Life
Cycle of HIV
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 with 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 membranes of the virus and
the cell fuse, a process that probably involves both gp41 and a second
"fusion cofactor" molecule on the cell surface. Recent research
by NIAID intramural and extramural researchers has identified two fusion
cofactors for different types of HIV strains. Following fusion, the virus's
RNA, proteins and enzymes are released into the cell. Although CD4+ T
cells appear to be HIV's main target, other immune system cells with 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. Scientists suspect that HIV also may infect cells without CD4
on their surfaces, using other docking molecules. For example, cells of
the central nervous system may be infected via a receptor known as galactosyl
ceramide. The role of HIV fusion cofactors in this process is currently
under intense investigation. 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.
Six of the nine antiviral drugs approved in the United States for the
treatment of people with HIV infection -- AZT, ddC, ddI, d4T, 3TC and
nevirapine -- 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. Once incorporated
into the cell's genes, HIV DNA is called a "provirus." Billions
of cells in an HIV-infected person may contain HIV DNA.
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. Cytokines, proteins
involved in the normal regulation of the immune response, also may initiate
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 initiate transcription.
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 RNA gather just inside the cell's
membrane, while the viral envelope proteins aggregate within the membrane.
An immature viral particle forms and pinches 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. Three such drugs -- saquinavir,
ritonavir and indinavir -- have been approved for marketing in the United
States.
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 years. 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 5 to 10 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.
Viral burden predicts disease progression
Recent studies show that people with high levels of HIV in their bloodstream
are more likely to develop new AIDS-related symptoms or to die than individuals
with lower levels of virus. New anti-HIV drug combinations that reduce
a person's "viral burden" to very low levels may delay the progression
of HIV disease, but it remains to be seen if these drugs will have a prolonged
benefit. Other 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.
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, rectum or, very rarely,
via the mouth. 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 called dendritic cells, 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 drug 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. NIAID-sponsored
researchers have shown 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 virus also may be transmitted from a nursing HIV-infected
mother to her infant.
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. During the acute phase
of infection, the number of CD4+ T cells in the bloodstream decreases
by 20 to 40 percent. Scientists do not yet know whether these cells are
killed by HIV or if they leave the blood and go to the lymphoid organs
in preparation to mount an immune response. 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 to 80 to 90 percent of its original level. A person then may remain
free of HIV-related symptoms for years despite continuous replication
of HIV in the lymphoid organs seeded during the acute phase of infection.
One reason HIV is unique is that despite the body's aggressive immune
responses, which are sufficient to clear most viral infections, some HIV
invariably escapes. One explanation is that the immune system's best soldiers
in the fight against HIV -- certain subsets of killer T cells -- multiply
rapidly following initial HIV infection and kill many HIV-infected cells,
but then appear to exhaust themselves and disappear, allowing HIV to escape
and continue replication. Additionally, in the few weeks that they are
detectable, these specific cells appear to accumulate in the bloodstream
rather than in the lymph nodes, where most HIV is sequestered.
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
latent. NIAID 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 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, probably become infected in large numbers as they encounter
HIV trapped on FDCs. Research suggests that HIV trapped on FDCs remains
infectious, even when coated with antibodies. Once infected, CD4+ T cells
may leave the germinal center and 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 germinal centers,
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, possibly secreted
by B cells. 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, others 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 lymph node 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 important in the immune response to HIV during the acute
infection and the clinically latent stage of disease. These cells attack
and kill infected cells that are producing virus. CD8+ T cells also appear
to secrete soluble factors that suppress HIV replication. Three of these
molecules -- RANTES, MIP-1alpha and MIP-1beta -- apparently block HIV
replication by occupying receptors necessary for the entry of certain
strains of HIV into their target cells. Researchers have hypothesized
that an abundance of RANTES, MIP-1alpha or MIP-1beta, or a relative lack
of receptors for these molecules, may help explain why some individuals
have not become infected with HIV, despite repeated exposure to the virus.
CD8+ T cells probably also secrete other soluble factors -- as yet unidentified
-- that suppress HIV replication.
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, HIV can recombine with
itself 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.
Syncytia formation
Infected cells also may fuse with nearby uninfected cells, forming balloon-like
giant cells called syncytia. In test-tube experiments at NIAID and elsewhere,
these giant cells have been associated with the death of uninfected cells.
The presence of so-called syncytia-inducing variants of HIV has been correlated
with rapid disease progression in HIV-infected individuals.
Apoptosis
Infected CD4+ T cells may be killed when cellular regulation is distorted
by HIV proteins, probably leading to their 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. Uninfected cells also may undergo apoptosis. Normally,
when CD4+ T cells mature in the thymus gland, a small proportion of these
cells are unable to distinguish self from non-self. Because these cells
would otherwise attack the body's own tissues, they receive a biochemical
signal from other cells that results in apoptosis. Investigators have
shown in cell cultures that gp120 alone or bound to gp120 antibodies sends
a similar but inappropriate signal to CD4+ T cells causing them to die
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. Killer T cells
also may mistakenly destroy uninfected CD4+ T 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 a signal from HIV that leaves them unable to respond to further
immune stimulation. This inactivated state is known as anergy.
Superantigens
Other investigators have proposed that a molecule known as a superantigen,
either made by HIV or an unrelated agent, may stimulate massive quantities
of CD4+ T cells at once, rendering them highly susceptible to HIV infection
and subsequent cell death.
Damage to Precursor Cells
Studies suggest that HIV also destroys precursor cells that mature to
have special immune functions, as well as the parts 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. However, these cells travel throughout
the body and carry HIV to various organs, especially the lungs and brain.
People infected with HIV often experience abnormalities in the central
nervous system. Neurologic manifestations of HIV disease, seen in 40 to
50 percent of HIV-infected people, are the subject of many research projects.
Investigators have hypothesized that an accumulation of HIV in brain and
nerve cells, or the inappropriate release of cytokines or toxic byproducts
by these cells, may be to blame.
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 signalling
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. During HIV infection, however, the immune system
may be chronically activated, with 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 a person's 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 probably 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 HIV pathogenesis research in laboratories
on the campus of the National Institutes of Health (NIH) in Bethesda,
Md., at the Institute's Rocky Mountain Laboratories in Hamilton, Mont.,
and at universities and medical centers in the United States and abroad.
An NIAID-supported collaborative center of the World Health Organization,
known as the NIH AIDS Research and Reference Reagent Program, provides
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. The NIAID HIV/AIDS Research Agenda and fact
sheets on NIAID 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 and other infectious diseases, as well as allergies
and immunology. NIH is an agency of the U.S. Public Health Service, U.S.
Department of Health and Human Services.
This information
is designed to support, not replace, the relationship that exists between
you and your doctor.
©1998. AEGIS.
