1. A L I S A R C O N S U L T A N T S
E - m a i l : j u s t k i n s f o l k @ y a h o o . c o m
A.I.D.S.
A
AC
CQ
QU
UI
IR
RE
ED
D I
IM
MM
MU
UN
NE
E D
DE
EF
FI
IC
CI
IE
EN
NC
CY
Y S
SY
YN
ND
DR
RO
OM
ME
E
Which represents the late stage of infection by a retrovirus called HUMAN
IMMUNODEFICIENCY VIRUS (HIV).
A L I S A R C O N S U L T A N T S
Mohammad Ali Bahu
Soharwardians
justkinsfolk@yahoo.com
2. A L I S A R C O N S U L T A N T S
E - m a i l : j u s t k i n s f o l k @ y a h o o . c o m
The immune deficiency is caused by the loss of the CD4+
T cells that are essential for
both cell-mediated immunity and antibody-mediated immunity.
HIV — Human Immunodeficiency Viruses:
There are two of them:
HIV-1 — the cause of AIDS in the Western Hemisphere and in Europe
HIV-2 — the major cause of AIDS in Africa and Southeast Asia.
They are retroviruses.
Infection:
HIV can only enter cells that express
the transmembrane protein CD4 found on helper T cells and
a second "co receptor" on these cells:
o Strains of HIV (designated "R5") bind the co receptor CCR5. These are the strains
that are most infectious.
o Strains of HIV (designated "X4") bind the co receptor CXCR4.
o Both strains usually coexist in an ongoing infection with X4 tending to dominate in
the final stages of AIDS.
The virion binds to both CD4 and either co receptor with molecules on its surface called
glycoprotein 120 (gp120).
This binding triggers an allosteric change in a second molecule, called glycoprotein 41
(gp41), which penetrates the host plasma membrane allowing the virion to get inside.
When HIV infects a
cell
its molecules of
reverse transcriptase
and integrase are
carried into the cell
attached to the viral
RNA molecules.
The reverse
transcriptase
synthesizes DNA
copies of the RNA.
These enter the
nucleus where the
integrase catalyzes
their insertion into the
DNA of the host's chromosomes.
The HIV DNA is transcribed into fresh RNA molecules which reenter the cytosol
where
o some are translated by host ribosomes.
The env gene is translated into molecules of the envelope protein (gp160).
Proteases of the host cell then cut gp160 into
gp120 which sits on the surface of the virions (and is the target of most of the
vaccines currently being tested).
gp41, a transmembrane protein associated with gp120.
3. A L I S A R C O N S U L T A N T S
E - m a i l : j u s t k i n s f o l k @ y a h o o . c o m
the gag and pol genes are translated into a single protein molecule which is cleared
by the viral protease into
6 different capsid proteins
the protease
reverse transcriptase
the integrase
o other RNA molecules become incorporated into fresh virus particles
Disease Transmission
HIV is present in body fluids
especially blood and semen
especially in the early and late phases of the disease
Breaks or abrasions in mucous membranes and skin allow the virus in.
In North America, transmission occurs primarily
between men when one ejaculates into the rectum (or mouth — the adenoids and
tonsils are filled with dendritic cells) of the other
among intravenous drug users who share needles
in women who are the sexual partners of bisexual men or i.v. drug users
in the newborn babies of these women
in recipients of infected blood or blood products. This last category accounted for
a devastating epidemic among hemophiliacs in the 1980s who unknowingly used HIV-
contaminated preparations of factor VIII. In some areas, 90% or more of the
hemophiliacs developed AIDS.
That risk, and the risk from blood transfusions, is now virtually zero because
o all donated blood is now tested to see if the donor has been infected with HIV (as
well as some other viruses);
o plasma-derived preparations of factors 8 and 9 are now treated with heat and/or
solvents to destroy any viruses that might be present;
o recombinant factor 8 and recombinant factor 9 made by genetic engineering are
now available.
Disease Progression
Infection by HIV produces three phases of disease:
an early phase that
o lasts about 2 weeks
o is accompanied by fever, aches, and other flu-like symptoms
o is accompanied by high levels of virus in the blood.
a middle phase with these features:
o lasts for months or even years
o produces few, if any, symptoms
o The patient's blood contains few viruses, but contains antibodies to the virus. These
antibodies are the basis of the most common test for HIV infection.
o Continuous infection, death, and replacement of CD4+
T cells. The T cells are
probably killed by the patient's CD8+
cytotoxic T cells (CTL). Some may die from
apoptosis.
It is the late phase that is called AIDS. It has these features:
4. A L I S A R C O N S U L T A N T S
E - m a i l : j u s t k i n s f o l k @ y a h o o . c o m
o A rapid decline in the number of CD4+
T cells. When these drop below about 400
per µl (normal is >1000), the patients immunity is sufficiently weakened that
opportunistic infections begin. These are infections caused by organisms that ordinarily
do not cause disease symptoms in immunocompetent people. They include:
viruses, e.g., herpes simplex, herpes varicella-zoster, Epstein-Barr virus (EBV)
bacteria, e.g., Mycobacterium tuberculosis
fungi, e.g. Candida albicans (the cause of "thrush"), Pneumocystis jirovecii
(causes pneumonia)
protozoans, e.g., Microsporidia
o When the CD4+
count drops below 200 per µl, opportunistic infections become
more severe and cancer (e.g., lymphoma, Kaposi's sarcoma) may develop. These usually
kill the patient within a year or so.
Treatment
In affluent countries, the progression of HIV disease has been markedly slowed by the
use of HAART (= Highly Active AntiRetroviral Therapy).
This refers to combined therapy with three or more drugs, usually two that target the
reverse transcriptase and one that targets the viral protease.
Reverse Transcriptase Inhibitors:
Nucleoside analogs. Examples:
o zidovudine (AZT)(Retrovir®)
o lamivudine (Epivir®)
o didanosine (Videx®)
Each of these drugs "fools" the reverse transcriptase into incorporating it into the growing
DNA strand which then halts further DNA synthesis.
Other Reverse Transcriptase Inhibitors
These drugs, e.g., efavirenz (Sustiva®) inhibit the enzyme by other mechanisms.
Protease Inhibitors:
These block the viral protease so that the proteins needed for assembly of new viruses
cannot be cleaved from the large protein precursor. Examples:
indinavir (Crixivan®)
saquinavir (Invirase®)
ritonavir (Norvir®)
Fusion Inhibitors:
The allosteric change that enables gp41 to penetrate the host plasma membrane involves
noncovalent binding between two segments of its chain designated HR1 and HR2.
Enfuvirtide, a synthetic polypeptide containing 36 of the amino acids present in the HR2
segment, interferes with this process. It probably acts as a kind of competitive inhibitor,
binding to HR1 thus preventing HR2 from binding HR1.
Enfuvirtide (Fuzeon®) has shown promise in phase III clinical trials.
Integrase Inhibitors:
A drug that inhibits the HIV-1 integrase has safely slowed disease progression in
experimental animals (monkeys) and is undergoing clinical trials in humans.
Inhibiting Coreceptor Binding:
Several drugs — as well as some monoclonal antibodies — that inhibit the binding of
HIV to the coreceptors CCR5 and CXCR4 are being tested for safety and efficacy.
5. A L I S A R C O N S U L T A N T S
E - m a i l : j u s t k i n s f o l k @ y a h o o . c o m
Problems with drug treatment
Despite the great advances in
slowing the progression of the disease
reversing — at least for a time — the symptoms of the late stages of the disease
preventing the infection of babies born to infected mothers
drug therapy has many drawbacks.
The drugs are so expensive ($7,000 to $10,000 per year) that they not only drain
resources in affluent countries but are simply unavailable in the many poor countries
where the epidemic rages.
They have many unpleasant side-effects (e.g., nausea, diarrhea, liver damage).
They demand a very complicated dosing regimen: over a dozen pills a day (not
counting those needed to cope with the accompanying opportunistic infections).
They often lose effectiveness as they select for the emergence of drug-resistant
virions in the patient. This latter problem is particularly serious because of the speed at
which mutations occur in HIV (as we shall now see).
Genetic Variability of HIV
Reverse transcription (RNA → DNA) lacks the proofreading capabilities of DNA
replication or of normal transcription (DNA → RNA). Therefore errors, i.e., mutations,
are frequent. Because of these,
The population of viruses in a single patient becomes genetically more diverse as
time goes by. This can lead to:
o appearance of strains that invade other types of cells such as X4 strains that target T
cells and strains that target cells of the brain, etc.
o Development of resistance to the anti-viral drugs being used.
New strains and subtypes of HIV-1 and HIV-2 arise in the human population.
o These complicate the efforts to develop a vaccine against HIV
o But — as we shall now see — have helped to unravel the origins of the disease.
Origin of HIV
Genome sequencing of different isolates of HIV-1 and HIV-2 shows that each is related
to retroviruses that occur in primates in Africa. These are designated simian
immunodeficiency viruses (SIV) although they do not cause immune deficiency (or any
disease) in their natural host. However, on those occasions when a SIV accidentally
infects a primate of a different species, it does cause disease in the new host. The human
epidemic is one example.
HIV-1 is most closely related to a SIV found in chimpanzees (Pan troglodytes
troglodytes)
HIV-2 is most closely related to a SIV that occurs in the sooty mangabey
(Cercocebus atys).
Genome analysis also permits the construction of phylogenetic trees which reveal
different clades of HIV just as such analysis reveals evolutionary relationship between
species.
HIV-1 appears to have jumped from chimpanzees to human on at least 3 separate
occasions (there are three clades; M, N, and O). Except in parts of West Africa, most
human cases are caused by members of Group M.
6. A L I S A R C O N S U L T A N T S
E - m a i l : j u s t k i n s f o l k @ y a h o o . c o m
HIV-2 appears to have jumped from sooty magabeys to humans on at least 4 different
occasions (there are 4 clades).
How? These (and other) primates are often slaughtered for food and exposure to their
blood and tissues is probably the route of transmission. In fact the chimpanzee SIV that
gave rise to HIV-1 appears to be itself the product of recombination between two monkey
SIVs that infected chimpanzees. (Chimps often eat monkeys.)
Just as with other evolutionary trees, one can also estimate from genome sequences the
time of divergence of two branches. This evidence indicates that the Group M clade of
HIV-1 invaded humans sometime early in the 20th century perhaps around 1930.
But the worldwide epidemic of AIDS did not get its start until the 1980s.
What took so long? An answer to that requires an appreciation of the way in which
contagious diseases spread. Their rate of spread depends on:
The ease of transmission. The transmissibility of HIV is very low. HIV is not
influenza or measles which spread like wildfire.
The length of time the host remains contagious. Again, HIV is not like influenza or
measles where the period of contagiousness is just a few days. For HIV, it can be years.
The number of susceptible contacts; that is, the proximity of potential new hosts.
For sexually-transmitted diseases (STDs), that means the number of sexual contacts.
So diseases like HIV only smolder in isolated populations because they lack the density
of susceptible contacts. In crowed populations, the equation changes. (There has been a
dramatic population shift from rural to urban areas in sub-Saharan Africa since 1950.) In
the case of STDs, the availability of multiple sexual contacts — perhaps accompanied by
changing sexual mores — tips the scales. In any case, the major factor today in the spread
of HIV is promiscuity, whether homosexual or heterosexual.
Prevention of AIDS
Vaccines
Many once-feared infectious diseases have been reduced or eliminated by the
development of a vaccine to prevent the disease.
Over two dozen experimental anti-HIV vaccines have been developed and clinical trials
of some of these have been — and are presently being — undertaken.
So far, the results have been disappointing. There are probably several reasons.
Some of the vaccines attempt to induce antibodies, e.g., against the outer portion of the
envelope protein (called gp120). But antibody-mediated immunity may not give adequate
protection.
The gene (env) encoding the envelope protein mutates too rapidly.
The virus may be able to stay within cells out of the reach of circulating antibodies.
High levels of antibodies (the basis of the most common test of infection) persist even
while the disease pursues its inexorable course.
So other vaccines have been designed to favor the development of cell-mediated
immunity; e.g., cytotoxic T cells.
Many of these are DNA vaccines — molecules of DNA that incorporate
a plasmid or live virus such as canarypox (a harmless relative of smallpox) which
serves as
a vector for introducing HIV genes.
It is hoped that expression of these genes within the cells (e.g., muscle) of the subject will
induce a protective immune response.
7. A L I S A R C O N S U L T A N T S
E - m a i l : j u s t k i n s f o l k @ y a h o o . c o m
Behavior
Because HIV transmission is so difficult, changing behavior could go a long way toward
stopping the epidemic.
Reducing the number of sexual partners.
If injecting drugs cannot be stopped, then using sterile needles (thus not sharing them)
would prevent infection.
Using condoms and/or other (e.g., chemical) barriers to prevent contact with
infectious semen.
In the words of Anthony S. Fauci, Director of the National Institute of Allergy and
Infectious Diseases,
"Unlike microbial scourges, such as malaria and tuberculosis (among many others), for
which there is very little that people can do to prevent infection, HIV infection in adults
is entirely preventable by behavior modification”.