Defense Mechanisms of the Body
Another factor associated with decreased immune func-
tion is sleep deprivation. For example, loss of a single night’s
sleep has been observed to reduce the activity of blood NK
cells. The mechanism of this response is uncertain but the
results have been replicated by numerous investigators.
Resistance to infection will be impaired if one of the
basic resistance mechanisms itself is defi cient, as, for example,
in people who have a genetic defi ciency that impairs their abil-
ity to produce antibodies. These people experience frequent
and sometimes life-threatening infections that can be pre-
vented by regular replacement injections of gamma globulin.
Another genetic defect is
combined immunodefi
is an absence of both B and T cells. If untreated, infants with
this disorder usually die within their fi rst year of life from over-
whelming infections. Combined immunodefi ciency can be
cured by a bone marrow transplant, which supplies both B cells
and cells that will migrate to the thymus and become T cells.
An environmentally induced decrease in the production
of leukocytes is also an important cause of lowered resistance.
This can occur, for example, in patients given drugs specifi -
cally to inhibit the rejection of tissue or organ transplants (see
the section on graft rejection that follows).
In terms of the numbers of people involved, the most
important example of the lack of a basic resistance mechanism
is the disease called
acquired immune defi
ciency syndrome
Acquired Immune Defi
ciency Syndrome (AIDS)
AIDS is caused by
human immunodefi
ciency virus
which incapacitates the immune system. HIV belongs to the
retrovirus family, whose nucleic acid core is RNA rather than
DNA. Retroviruses possess an enzyme called reverse tran-
scriptase, which, once the virus is inside a host cell, transcribes
the virus’s RNA into DNA, which is then integrated into the
host cell’s chromosomes. Replication of the virus inside the
cell causes the death of the cell.
Unfortunately, the cells that HIV preferentially (but not
exclusively) enters are helper T cells. HIV infects these cells
because the CD4 protein on the plasma membrane of helper
T cells acts as a receptor for one of the HIV’s surface proteins
(gp120). Thus, the helper T cell binds the virus, making it
possible for the virus to enter the cell. Very importantly, this
binding of the HIV gp120 protein to CD4 is not suffi cient
to grant the HIV entry into the helper T cell. In addition,
another surface protein on the helper T cell, one that serves
normally as a receptor for certain chemokines, must serve as a
coreceptor for the gp120. It has been found that persons who
have a mutation in this chemokine receptor are highly resis-
tant to infection with HIV. Much research is now focused on
the possible therapeutic use of chemicals that can interact with
and block this coreceptor.
Once in the helper T cell, the replicating HIV directly
kills the helper T cell and also indirectly causes its death via
the body’s usual immune attack. The attack is mediated in this
case mainly by cytotoxic T cells attacking the virus-infected
cells. In addition, by still poorly understood mechanisms,
HIV causes the death of many
helper T cells by
apoptosis. Without adequate numbers of helper T cells, nei-
ther B cells nor cytotoxic T cells can function normally. Thus,
the AIDS patient dies from infections and cancers that the
immune system would ordinarily readily handle.
AIDS was fi rst described in 1981, and it has since reached
epidemic proportions worldwide. The great majority of per-
sons now infected with HIV have no symptoms of AIDS. It
is important to distinguish between the presence of the symp-
tomatic disease—AIDS—and asymptomatic infection with
HIV. (The latter is diagnosed by the presence of anti-HIV
antibodies or HIV RNA in the blood.) It is thought, how-
ever, that most infected persons will eventually develop AIDS,
although at highly varying rates.
The path from HIV infection to AIDS commonly takes
about 10 years in untreated persons. Typically, during the fi rst
fi ve years the rapidly replicating viruses continually kill large
numbers of helper T cells in lymphoid tissues, but these are
replaced by new cells. Therefore, the number of helper T cells
stays normal (about 1000 cells/mm
of blood), and the per-
son is asymptomatic. During the next fi ve years, this balance
is lost; the number of helper T cells, as measured in blood,
decreases to about half the normal level, but many people still
remain asymptomatic. As the helper T cell count continues to
decrease, however, the symptoms of AIDS begin—infections
with bacteria, viruses, fungi, and parasites. These are accom-
panied by systemic symptoms of weight loss, lethargy, and
fever—all caused by high levels of the cytokines that induce
the acute phase response. Certain unusual cancers (such as
Kaposi’s sarcoma
) also occur with relatively high frequency.
In untreated persons, death usually ensues within two years
after the onset of AIDS symptoms.
The major routes of transmission of HIV are through
(1) transfer of contaminated blood or blood products from
one person to another; (2) unprotected sexual intercourse
with an infected partner; (3) transmission from an infected
mother to her fetus across the placenta during pregnancy and
delivery; or (4) transfer via breast milk during nursing.
There are two components to the therapeutic manage-
ment of HIV-infected persons: one directed against the virus
itself to delay progression of the disease, and one to prevent or
treat the opportunistic infections and cancers that ultimately
cause death. The present recommended treatment for HIV
infection itself is a simultaneous battery of at least four drugs.
Two of these inhibit the action of the HIV enzyme (reverse
transcriptase) that converts the viral RNA into the host cell’s
DNA, a third drug inhibits the HIV enzyme (
that cleaves a large protein into smaller units required for the
assembly of new HIV, and a fourth drug blocks fusion of the
virus with the T cell. The use of this complex and expensive
regimen (called
for highly active anti-retroviral
therapy) greatly reduces the replication of HIV in the body
and ideally should be introduced very early in the course of
HIV infection, not just after the appearance of AIDS.
The ultimate hope for prevention of AIDS is the devel-
opment of a vaccine. For a variety of reasons related to the
nature of the virus (it generates large numbers of distinct sub-
species) and the fact that it infects helper T cells, which are
crucial for immune responses, vaccine development is not an
easy task.
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