AIDS
Acquired Immune Deficiency Syndrome AIDS is a destruction of the immune
system resulting from infection with the human
immunodeficiency virus HIV. With the loss of immune function a clinical syndrome (a group
of various illnesses that together characterize a disease) occurs over time and
results in death from opportunistic infections or cancers. In HIV-infected
individuals there is a gradual loss of immune cells (called CD4 T-lymphocytes)
and immune function so that the patient becomes vulnerable to pneumonia, fungal
infections and other common ailments.
The mechanisms by which HIV causes
immune deficiency are still not completely understood. It generally takes six
to ten years from the point of infection to develop AIDS. In the early 1980’s
deaths by opportunistic infections, previously observed mainly in transplant
recipients receiving immunosuppressive therapy, were recognized in otherwise
healthy homosexual men. In 1983 Luc Montagnier and scientists at the Pasteur Institute in
Detection and Diagnosis
With the identification of HIV in
1983 came the opportunity to develop a method of specific detection.
Importantly in 1984 Robert Gallo's group at the NCI developed a method for
continuous production of HIV, providing an abundant source of virus to use in
the initial diagnostic test. These tests now have improved specificity. This
means the proportion of disease-free people who react negatively to a test: the
higher the specificity, the fewer the “false positives”. Improved specificity
has been achieved through the use of recombinant DNA technology, and the tests
detect if an individual has serum antibodies against HIV—an indication of
exposure to the virus. An estimated 50 million blood samples are tested each
year in the 
from around the world, they too will
need to be evaluated for detection by these tests. There is a brief period
(normally four to eight weeks) after exposure to HIV where an individual will
remain negative on these serological detection tests because the immune
response has not had enough time to make antibodies against HIV. During this
period, other methods that detect some component of the virus itself (and not
just antibodies against it) can determine if an individual is infected with
HIV.
Being HIV infected does not
necessarily imply that a person has AIDS, although “having AIDS” is often
mistakenly used to mean “HIV-positive”. A person can remain HIV-positive for a
long period—greater than 10 years—without developing the clinical illness that
defines and constitutes a diagnosis of AIDS. The Centers for Disease Control
and Prevention (CDC) in Atlanta established an authoritative definition for the
diagnosis of AIDS: in an HIV-positive individual, the CD4 count must be below
200 cells per cu mm of blood, or there must be the clinical appearance of an
initial AIDS-defining opportunistic infection, including Pneumocystis carinii pneumonia (PCP), oral candidiasis (thrush), pulmonary tuberculosis or invasive
cervical carcinoma. In
Nature of the Disease
Clinical Progression
of AIDS
The progression from the point of
HIV infection to the clinical diseases that define AIDS may take six to ten
years or more. The progression to disease in HIV-infected individuals can be
monitored using surrogate markers, laboratory data that correlate with disease
progression or clinical endpoints, illnesses that are associated with more
advanced disease. Surrogate markers for the various stages of HIV disease
include the progressive loss of CD4 T-lymphocytes (CD4 T-cells), the major
white blood cell lost due to HIV infection. In general, the lower the patient's
CD4 T-cell count, the more advanced the immunosuppressed
disease state. The amount of HIV circulating in the blood is a second surrogate
marker. Using new sensitive detection techniques, the quantities of HIV in the
blood correlate with the clinical stage of the disease and appear to predict
the rate of disease progression and the response to antiviral therapy. An
infected individual's immune response to the virus (the ability to produce
antibodies against HIV proteins) can also be used to determine the progression
of AIDS. However, this surrogate marker is less precise during more advanced
AIDS due to the overall loss of immune function.
A well-recognized progression of
disease occurs in HIV-infected individuals. Within one to three weeks after infection
with HIV many individuals experience non-specific
flu-like symptoms (fever, headache, skin rash, tender lymph nodes and
malaise) lasting approximately one to two weeks. This phase termed acute
retroviral syndrome is important because HIV reproduces itself to very high
levels, circulates through the blood and establishes infections throughout the
body, especially in the lymph nodes. Patients' CD4 cell counts fall briefly but
return to near-normal levels as the immune system responds to the infection and
limits HIV replication and spread.
Individuals then enter a prolonged
asymptomatic phase that can last ten years or more. During this period, the
infected individuals remain in good health, with levels of CD4 cells in the
low-normal range (750-500 cells per cu mm). HIV continues to replicate during
the asymptomatic phase, although maintained at low levels, to cause a
progressive destruction of the immune system. Eventually, the immune system
declines and patients enter the early symptomatic phase. This phase can last
from only a few months to several years and is characterized by rapidly falling
levels of CD4 cells (500-200 cells per cu mm) and non-life-threatening
opportunistic infections. From this phase, patients undergo more extensive
immune destruction and serious illness that characterize the late symptomatic
phase. The late phase again can last from only a few months to years and
patients may have CD4 cell levels below 200 along with other AIDS-defining
opportunistic infections. A wasting syndrome of progressive weight loss and
debilitating fatigue is observed in a large proportion of patients in this
stage. The immune system is now in severe failure and patients eventually enter
the advanced AIDS phase, where CD4 cell numbers are below 50 and death from
severe life-threatening opportunistic infections and cancers is imminent,
within one to two years.
Opportunistic Illnesses
Death from AIDS is generally not due
to HIV infection itself, but due to opportunistic infections. These infections occur
when the immune system can no longer provide protection against agents normally
found in the environment. The appearance of any one of more than 20 different
opportunistic infections, termed AIDS-defining illnesses, provides the clinical
diagnosis of AIDS in HIV-infected individuals.
The most common opportunistic
infection seen in AIDS is Pneumocystis carinii pneumonia (PCP) caused by a fungus (P. carinii) that exists in the airways of all individuals. Bacterial
pneumonia (due to several types of bacteria including Streptococcus and Haemophilus) and tuberculosis (TB: a bacterial respiratory
infection caused by Mycobacterium tuberculosis) are also commonly associated
with AIDS. In late-stage AIDS, disseminated infection by Mycobacterium avium intracellulare complex (MAI
or MAC) can cause fever, weight loss, anaemia, and diarrhoea. Additional bacterial infections of the
gastrointestinal tract (from Salmonella, Campylobacter, Shigella
or other bacteria) commonly cause diarrhoea, weight
loss, anorexia and fever.
Besides PCP other fungal infections
or mycoses are frequently observed in AIDS patients. Oral candidiasis
is seen early in the symptomatic phase in a high proportion of patients. Other
mycoses include infections with Cryptococcus species a major cause of
meningitis in up to 13% of AIDS patients. Also disseminated histoplasmosis,
due to Histoplasma capsulatum,
affects up to 10% of AIDS patients causing general weight loss, fever and
respiratory complications or severe central nervous system complications,
including forms of dementia, if the infection reaches the brain.
Viral opportunistic infections,
especially with members of the herpes virus family, are common in AIDS
patients. One herpes family member, cytomegalovirus (CMV), infects the retina
and can result in blindness. Another herpes virus, Epstein-Barr virus (EBV) may
result in a cancerous transformation of blood cells. Also common are infections
with herpes simplex virus (HSV) types 1 and 2 that result in progressive oral,
genital, and perianal lesions.
Many AIDS patients develop cancers
the most common being Kaposi's sarcoma (KS) and B-cell lymphoma. KS (a cancer of
blood vessels resulting in purple lesions on the skin that can spread to internal
organs and cause death) occurs with unusually high frequency among HIV-positive
homosexual men but is rare among other HIV-infected persons. This and other
aspects of KS epidemiology suggested that a sexually transmitted agent might be
involved and a link between a new herpes-like virus known as Kaposi's sarcoma
associated herpes virus (KSHV) or human herpes virus 8 (HHV-8), and KS was
recently described.
Cause of Aids
Human Immunodeficiency Virus (HIV)
The widely accepted etiological
agent of AIDS is HIV, a human retrovirus. HIV is an enveloped virus, meaning
that the viral genetic material is surrounded by a lipid membrane derived from
the host cell. Into this lipid membrane, HIV inserts its envelope glycoprotein,
called gp120, that specifically recognizes and 
binds to the CD4 molecule (a cell surface
protein important for normal immune interactions) on human cells. The gp120-CD4
interaction allows HIV to fuse with and infect those cells, eventually leading
to viral replication and death of the host cell.
Any human cell that expresses the
surface CD4 molecule is a potential target for HIV infection. However, it is
the specific class of human white blood cells, called helper T-lymphocytes,
that are most affected during AIDS because these cells express high levels of
the CD4 molecule; they are therefore referred to 
as “CD4 T-cells”. HIV replication in
CD4 T-cells can directly kill them or they may be killed or rendered
dysfunctional by indirect means without ever being infected with HIV. CD4
T-cells are critical in the normal immune system because they help other types
of immune cells respond to invading organisms. Therefore, as CD4 T-cells are
specifically targeted and lost during HIV infection (a hallmark feature of
AIDS), no help is available for immune responses. General immune system failure
occurs and permits the opportunistic infections and cancers that characterize
the clinical picture of AIDS.
While it is generally agreed that
HIV is the virus that causes AIDS and HIV replication can directly kill CD4
T-cells, the large variation among patients in the time of progression to AIDS
has led to speculation that other factors can influence the course of disease.
The exact nature of these factors remains uncertain; possible candidates
include herpes virus infections, genetic factors, and the nature of the
infected person's immune response to HIV. However, it is very clear that HIV
must be present for the development of AIDS.
Modes of Transmission
HIV is spread by either homosexual
or heterosexual contact with an infected person and this route represents the
majority of transmissions. Present in the sexual secretions of both men and
women, HIV gains access to the bloodstream of the uninfected partner by
infecting cells in mucous membranes or via 
small abrasions that occur as a
consequence of intercourse. HIV is also spread by sharing needles or syringes,
most commonly done by those using intravenous (IV) drugs,
that results in a direct exposure to the blood from an infected
individual. HIV transmission through medical transfusions or blood-clotting
factors is now very rare (less than 1 in 100,000) because of extensive
screening of the blood supply. HIV can also be transmitted from an infected
mother (either before giving birth, or through breastfeeding), but only about
30% of babies born to HIV-infected mothers actually become infected.
Although these routes of HIV
transmission are well established, public fear still exists concerning the
potential for transmission by other means. There is no evidence that HIV can be
transmitted through the air or by biting insects. If this were the case, the
pattern of HIV infections would be dramatically different from what has been
observed and cases of AIDS would be reported more frequently in individuals
with no identifiable risk for infection (now only a very small percentage of
reported cases).
Although HIV is a very fragile virus
and does not survive well when exposed to the environment, fear also exists for
HIV transmission by casual contact in a household, school, workplace, or
food-service setting. No documented cases of HIV transmission by casual contact
with, or even kissing an infected individual have been identified. However,
practices that increase the likelihood of blood contact, such as sharing toothbrushes
or razors, should be avoided.
Public fear has also persisted for
HIV transmission from infected health care workers, because of a single case of
transmission from a dentist to several patients. This now appears to be an
extremely rare and isolated case of transmission and, in general, infected
health care workers pose no risk to their patients. There is no risk of HIV
transmission while donating blood.
Occurrence
In 1995 HIV was estimated to infect almost 20 million people
worldwide with the cumulative estimate of AIDS cases being several million. The epidemiology (incidence and
distribution) of AIDS is an evolving picture. Initially in the United States
HIV infection was mainly concentrated in the homosexual community, where
widespread transmission occurred because of unprotected anal intercourse and in
hemophiliacs and people receiving other blood products. HIV infection became
established among IV drug users, among whom were
prostitutes who spread it by heterosexual contact into all groups of society
through high-risk sexual practices.
Currently, homosexual behavior and
IV drug use account for about 50 and 25% of transmissions, respectively.
Heterosexual spread in the
By December 1995, 11,872 cases of
AIDS had been registered in
On a global scale, the AIDS epidemic
continues a frightful expansion. Although 
Other distantly related strains of
HIV-1 have been identified in various geographical areas of the world. Although
some strains cannot be detected using the current blood-screening methods,
there is thought to be little risk of spread across continents because of the
geographical isolation of the viruses. Even with HIV-2, spread outside of
Treatment
Although never considered to be a
cure for HIV infection, the hope was that drugs would have a significant impact
on the progression of AIDS. They were initially used one at a time in sequence,
but their effects were disappointingly short-lived. Greater success has been
achieved by using them in combination regimens, which can significantly delay
the onset of opportunistic infections and prolong life. Nevertheless, they can
cause a relatively high rate of side-effects.
Reverse Transcriptase Inhibitors
The development of antiviral drugs
to attack HIV has targeted specific stages in the viral replication cycle. One
such target is the requirement for HIV to undergo reverse transcription (the
conversion of viral genomic RNA into DNA—See Nucleic Acids) at an early stage
of infecting a host cell; this is a process unique to retroviruses and
performed by the viral enzyme, reverse transcriptase (RT).
The first anti-HIV drugs to be
developed were all RT inhibitors. At present, five RT inhibitors have been
licensed by the US Food and Drug Administration (FDA): zidovudine
(also known as AZT and made by Glaxo Wellcome with the brand name Retrovir),
didanosine (ddI or Videx, from Bristol-Myers Squibb), zalcitabine
(ddC or HIVID from Roche), stavudine (d4T or Zerit
from Bristol-Myers Squibb), and 3TC (Epivir from Glaxo Wellcome). In
Protease Inhibitors
More recently, a new class of
anti-HIV agents has been developed which specifically interferes with the
action of the HIV protease enzyme. Protease is employed at a later stage of the
viral replication cycle, when new virus particles are being produced within an
HIV-infected cell. The protein from which the core and envelope of the new
particles will be formed is initially synthesized in a long strip, which has to
be cut up by protease into smaller functional proteins. When the protease
enzyme is inhibited, an HIV-infected cell can only produce immature,
non-infectious viral progeny. In the 
Sharp & Dohme),
and ritonavir (Norvir, from
Abbott). Ritonavir will be licensed by the EMEA. Others
are yet to be approved in the
One problem with all anti-HIV drugs
produced to date is the development of viral resistance. HIV's replication
process is relatively imprecise, resulting in the steady production of mutant
variants of the virus, some of which are resistant to the effects of specific
anti-HIV agents. The selective pressure exerted by treatment drugs means that
within treated people these drug-resistant strains have a survival advantage
over “wild-type” drug-sensitive strains. The constant high rate of HIV
replication allows resistant strains to become dominant within a matter of
weeks.
Clinicians are still developing
experience in the optimum use of anti-HIV drugs. Extremely pronounced anti-HIV
effects have been seen from the use of two nucleoside analogues and a protease
inhibitor in combination therapy regimens. Researchers believe that a regimen
that can rapidly suppress viral replication to very low levels should also
minimize the chances of drug-resistant HIV mutants emerging.
Other anti-HIV drugs currently in
development include agents that inhibit HIV's integrase
enzyme, used to insert the viral DNA into the host
cell's DNA after reverse transcription has been completed. Some 
therapeutic consideration has also
been given to targeting cellular processes that are strictly required for viral
replication. Inhibiting these processes should not incur a risk of viral
resistance because the selective pressure will not be directed at the virus
itself, although toxicity is a concern. Several drugs have shown preliminary
promise, most notably hydroxyurea.
Gene Therapy
Gene therapy is also being studied
as a potential treatment for HIV-infected persons. One approach uses small
molecules called anti-sense oligonucleotides which
bind to the viral RNA strand, preventing it from acting as a template for viral
proteins. Another anti-viral strategy uses molecules called ribozymes that can detect specific parts of
HIV's RNA within infected cells and splice it, rendering it inactive. Other
researchers are using gene therapy to insert a gene into immune cells taken
from infected people, either to boost the cellular immune response against HIV
or to protect the CD4 cells from infection. This is called adoptive cell
therapy. The main problems with all these gene therapy approaches are
delivering the new genes into cells, and ensuring that the altered cells are
not identified as “foreign” and attacked by the host immune system.
Immune System Responses
Considerable research is continuing
into the basic biology of HIV and its interactions with the immune system. Many
scientists believe that better medicines could be developed if there was a
fuller understanding of pathogenesis (the mechanisms by which HIV causes
disease). Researchers are also intensively studying individuals who have been
infected with HIV for many years without suffering immune damage, and those who
have been exposed to HIV on multiple occasions yet have so far remained
uninfected. The hope is that there may be some unique characteristics of their
immune responses or genetic make-up that could be utilized in the development
of treatments or vaccines.
Prophylactic Treatments
Many of the improvements in quality
and quantity of life among people with HIV have resulted from better drugs to
prevent or treat the AIDS-associated opportunistic infections. The use of
prophylactic (preventative) antibiotics has dramatically reduced the incidence
of PCP and toxoplasmosis, and clinicians have grown increasingly skilled at
preventing and treating fungal infections. Consequently, many HIV-infected
people do not now develop an AIDS-defining illness until they reach an advanced
stage of immune suppression, when they become vulnerable to infections that are
still challenging to treat or to prevent, such as CMV and MAI. Intravenous
drugs such as foscarnet, ganciclovir
and cidofovir are available to treat CMV disease and
an oral formulation of ganciclovir has been
introduced for maintenance therapy and potentially for prophylaxis.
Vaccines
Efforts are underway to develop an
effective vaccine for HIV that could be either protective (preventing infection
if an immunized person is exposed) or therapeutic (slowing immune destruction
or prolonging survival in people who are already infected).
Most of the current experimental
vaccines consist of one or more of HIV's structural proteins, such as the core
protein p24 or the outer “envelope” proteins gp120 and gp160, used in
combination with an adjuvant 
to boost the immune response.
Trials to date have been largely
discouraging. Studies of therapeutic vaccines have found that some are
immunogenic, but have not yet shown any evidence of effects on disease
progression or survival rates.
Researchers working on preventive
vaccines face a range of technical problems, including the difficulty of
producing a vaccine that might offer protection against the range of HIV
sub-types found around the world and the varying strains caused by HIV's high
mutation rate. An effective vaccine would need to protect the individual
against infection when exposed to either free HIV particles or HIV-infected
cells and to stimulate effective immune responses when the virus enters the
body through the blood (such as during injecting drug use or occupational
exposure) or across mucous membranes (such as during sexual intercourse).
Prevention
HIV infection and AIDS are
considered by many to be completely preventable, because the routes of HIV
transmission are so well documented. It is clear that a reliable protective
vaccine will not be available for many years. In the absence of a vaccine, the
only means of preventing the spread of infection is to avoid personal behaviors
that carry a risk of transmission. This has been the focus of AIDS education
campaigns throughout the world.
Globally, the most common route of
HIV transmission is through unprotected anal or vaginal intercourse. The risk
can be eliminated by avoiding intercourse, or minimized by using a condom,
since HIV cannot pass through an intact latex barrier. HIV transmission through
oral sex is possible but rare and AIDS organizations in most countries do not
routinely recommend condom use for this activity. HIV transmission through
drug-injecting equipment can be prevented by avoiding injecting drug use or by
only using sterile equipment.
Many safer sex campaigns have been
conducted to encourage the general public and the groups most at 
risk from HIV to avoid unprotected
sex. However, research on health promotion repeatedly shows that the simple
provision of information is usually not in itself sufficient to lead to
behavior changes. That may require additional factors; for example, campaigns
are more likely to succeed if they present acceptable and achievable options,
and are reinforced by peer pressure in favor of certain forms of behavior and
against others. The most successful safer sex campaigns were those conducted by
and for urban gay communities in the 1980’s, where the reduction in unprotected
anal intercourse has been identified as the greatest health-related behavior
change ever achieved.
Prevention efforts to promote sexual
awareness through open discussion and condom use through distribution in
schools have raised opposition from certain groups in society from fear that
these efforts promote sexual promiscuity among young adults. Prevention efforts
involving identification of HIV-infected individuals and notification (in the
United States) of the sexual partners and HIV testing at the time of marriage
or pregnancy have been criticized as an invasion of personal privacy. In these
cases, the issue of personal privacy has to be weighed against the
responsibilities of society to ensure public health and control the spread of
HIV.
Needle exchange programs have been
introduced in many countries to minimize HIV transmission among drug users. In
the
In recent years there has been
intense debate about the proper allocation of AIDS education funds. In many
countries, HIV transmission still occurs primarily among definable population
groups and their sexual partners, yet the majority of resources has been spent on campaigns targeted at the general
population rather than at the groups most at risk. In the
In the early years of the epidemic
many cases of HIV transmission occurred through contaminated blood products and
transfusions; the introduction of screening and heat treatment procedures means
that infection through these routes is now extremely unlikely.
Social Issues
Prevention efforts through public
awareness have been propelled by community-based organizations, such as the
Terrence Higgins Trust in
In the
