Topic 20 The Immune System
in AIDS
Introduction
An immune deficiency disease that
has become the focus of much global concern is acquired immunodeficiency
syndrome (AIDS).
Beginning in 1979, physicians began
to notice a remarkable increase in case of two unusual conditions among active
male homosexuals. These conditions were
a rare tumour known as Kaposi’s sarcoma and a severe pneumonia caused by
a parasite called Pneumocystis carinii. Affected individuals were found to be profoundly immunosuppressed
as a result of an almost total loss of their T cells. Since then the spread of AIDS has been
dramatic, and reached epidemic proportions in some parts of the
world. It is interesting to note that
from the discovery of AIDS in the early 1980s until today, the scientific
progress made in understanding the cause and the epidemiology of the disease
was so rapid that it has no parallel with other infectious diseases. This explosion of information about AIDS has
expanded our understanding of the immune system to such an extent that this
entire lesson is devoted to AIDS, the immunodeficiencies associated with it,
and efforts to develop an AIDS vaccine.
Objectives
On completion of this section and
the required reading, you should be able to:
n draw and label a cross sectional diagram
of an HIV virion;
n draw and label a diagram of the genome of
HIV-1;
n discuss the factors that contribute to the
genetic variation of HIV;
n construct a table of the cell types that
can be infected by HIV;
n draw and label a diagram that shows the
steps in the infection of a target cell by HIV;
n draw and label a diagram that shows
activation of an HIV provirus;
n discuss the origins of HIV-1, HIV-2 and
HIV-0;
n draw a diagram to show the early and late
stages in the expression of HIV-1 proviral DNA;
n label a diagram of HIV-1 envelope
glycoproteins;
n describe the screening tests for HIV
infection;
n describe the clinical symptoms of AIDS;
n describe the various mechanisms for the
depletion of CD4+ cells in AIDS patients;
n construct a table summarizing the
immunologic abnormalities associated with HIV infection.
Required Reading
Please refer to the Textbook Key for
the required reading for this section.
P Key Words
|
• opportunistic
infections • Acquired
immunodeficiency syndrome(AIDS) • Human
immunodeficiency virus (HIV) • 1HIV • HIV-2,
|
• HIV-0,
• retroviruses, • transforming
retroviruses • cytopathic
retroviruses • simian
immunodeficiency virus (SIV) |
P Key Concepts
n AIDS is a disease syndrome caused by
infection with human immune deficiency virus (HIV).
n HIV is an enveloped retrovirus containing
ssRNA that is the causative agent for AIDS.
n HIV infects cells bearing CD4 on their
surface. It thus infects and destroys
helper T cells, although other cells of immunological importance are also
affected in AIDS patients.
n The clinical signs of AIDS are almost
entirely due to secondary infections developing as a result of a loss of CD4+
cells.
n Currently, several approaches are being
tried in the extensive effort to develop an effective AIDS vaccine, however the
development of an effective AIDS vaccine has been hampered by the extensive
antigenic variation exhibited by HIV, its ability to exist as a provirus in
host cells, and the lack of a good animal model for AIDS.
DID YOU KNOW?
What is antiretroviral therapy?
Antiretroviral therapy is a name for a treatment with drugs that
help prevent HIV, the retrovirus that causes AIDS, from reproducing and
infecting cells in the body. This type of treatment is effective in slowing the
progression of the HIV disease in many people.
What drugs are available?
There are three general types of antiretroviral drugs that are currently
available by prescription or through pharmaceutical companies or clinical
trials.
Antiretroviral drug categories include:
• Nucleoside reverse transcriptase inhibitors (NRTIs) This group, which has been studied the most,
includes zidovudine (AZT, ZDV, Retrovir); didanosine (ddI, Videx); zalcitabine
(ddC, HIVID); stavudine (d4T, Zerit); and lamivudine (3TC, Epivir). These drugs
act by blocking a step in the reproduction of HIV called reverse transcription.
This step is necessary for HIV to be prepared for incorporation into the
genetic material of cells. All of these agents are available by prescription.
In addition, the experimental drugs, 1592U89 and adefovir, are available
through expanded access programs and clinical trials.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs). This group
includes nevirapine (Viramune) and delavirdine (Rescriptor), both of which are
available by prescription. An experimental drug, DMP-266, is available through
an expanded access program and clinical trials. Non-nucleoside agents also
block HIV reverse transcription, but they do so in a different way than
nucleoside drugs.
• Protease inhibitors (PIs)
This group includes saquinavir (Invirase, Fortovase), ritonavir
(Norvir), indinavir (Crixivan), and nelfinavir (Viracept). These drugs target a different enzyme of the
virus — protease — which is essential for HIV to assemble working copies of
itself. Protease inhibitors are the
most active group of anti-HIV drugs discovered to date.
• The fourth group of drug is now under study; the Ribonucleotide
Reductase Inhibitor. This class targets
an enzyme which the virus needs and which is made by blood cells. So far, the only available drug which works
this way is hydroxyurea, which was approved years ago to treat certain cancers.
But at least one more drug like this is under development.
Antiretroviral Therapy Update 1998
The introduction of highly active antiretroviral therapy has been
associated with a change in the epidemiology of HIV-associated diseases.
Certain opportunistic diseases, such as cytomegalovirus and Mycobacterium avium
complex, have virtually disappeared. Others such as Kaposi’s sarcoma often
respond to HIV therapy. At the same time, the incidence of community-acquired
pneumonia and NHL have remained almost unchanged while there are early reports
of an increased incidence of HPV conditions. Clinicians who treat HIV disease
must be prepared for this changing clinical picture. In addition, a number of
key issues are yet to be resolved:
• The degree and quality of immune repair following antiretroviral
therapy. The vast majority patients who are treated aggressively achieve a
significant rise in CD4 (or CD4+) cells.
This is also seen even in patients in whom complete viral suppression is
not achieved. Moreover, CD4 counts often remain stable for eighteen months or
more after plasma HIV-RNA becomes detectable in patients who were initially
fully suppressed. This paradoxical finding becomes relevant as clinicians
consider treatment changes, not wanting to abandon a regimen prematurely.
• The mechanisms of HIV pathogenesis – how does HIV kill cells?
• HIV reservoirs and eradication.
David Ho and others have presented disturbing news that certain cells
are longer-lived than we once thought,
dashing hopes for viral eradication – certainly for the near term and
potentially for the long term as well.
• Early events in HIV infection.
There has been an increasing interest in HIV receptors over the past
year. We know that HIV infection
requires an interaction between HIV gp120 and CD4 which complexes with the cell
surface sugars and is presented to the chemokine receptor (CCR5). Once this
occurs, an uncoiling of gp41 inserts a portion of the molecule into the cell
membrane, triggering fusion.
Given the imperfect state of current knowledge, a number of
controversies in HIV treatment have evolved:
When should antiretroviral treatment be initiated? What should be included in the initial
regimen? What constitutes success?
Should we utilize the ultra sensitive RNA assays? When should resistance assays
be used? How do we access adherence?
What interventions are useful? What
combinations of drugs will allow the best hope for sustained control of HIV
replication?
The ideal time to treat HIV is before irreparable damage to the
immune system has occurred at a clinically significant level and before there
is any significant risk for serious complications. Hampering our efforts is our
inability to determine this exact point in time. In addition, the intervention
should occur before HIV has evolved to a more virulent form and before disease
progression compromises the therapeutic response. Most significantly, therapy
cannot be initiated until the patient is ready and is fully committed to the
regimen. The established regimen to
accomplish viral suppression for the longest proven duration includes one
protease inhibitor (PI) and two nucleoside reverse transcriptase inhibitors
(RTIs). A more aggressive approach could include the use of two protease
inhibitors and may be appropriate in some settings. Another approach utilizes
two RTIs and one non-nucleoside reverse transcriptase inhibitor (NNRTI),
targeting the same point in the viral life cycle. Other options, which have
fewer data to support them, include the use of hydroxyurea with any of the
previously mentioned regimens, one NNRTI with one PI, or three NRTIs.
Although the benefits of antiretroviral therapy are well known,
clinicians must remain cognizant of potential hazards. Inappropriate use may
lead to the selection of drug-resistant variants and treatment failure. In
addition, reports from the World AIDS Conference held in June 1998 in Geneva,
Switzerland confirm cases of transmission of a multi-drug resistant virus.
Toxicities, such as lipodystrophies, have been reported in association with
protease inhibitor use, but may simply be a result of factors not yet
identified.
Recently, there has been an increased interest in the role of NNRTIs
in initial therapy. Three drugs of this class are now approved for marketing in
the United States: nevirapine, delavirdine, and efavirenz. Although all have
demonstrated high potency in vitro, in vivo comparative data are lacking.
Because resistance may occur with a single point mutation, high level
resistance can develop quite rapidly, with resulting cross-resistance among the
three. The term “treatment failure” is
used frequently in discussing a patient’s response to treatment but has a
number of potential meanings: Plasma viral load above the limit of assay
detection; viral load becomes detectable after initial response; CD4 cell count
falls or fails to rise; resistance tests show sentinel mutations in a patient
with a stable viral load or patient experiences toxicity or clinical
progression.
Each definition is valid, and clinicians must be very careful to use
them in the appropriate context, since any change may or may not improve the
outcome. In order to develop strategies to deal with failure, what is meant by
failure must be clearly understood.
More sensitive viral load assays are becoming available with limits
of detection of 20-200 copies/mL. These may be particularly useful in
monitoring the effects of aggressive antiretroviral therapy. In addition, there
is mounting evidence that a high level of viral suppression is necessary to
limit the evolution of drug-resistant variants and thus prolong the duration of
response. At the same time, new management issues accompany the use of these
assays. A greater length of time is required to reach undetectable levels when
these assays are employed and questions arise when there is the occasional
detection of the virus. Finally, since approximately 80 percent of patients who
achieve viral suppression to <<500 copies/mL also achieve suppression to
<<50 copies/mL, one must determine what clinical situations warrant the
use of the ultrasensitive assay.
Given the association between adherence and treatment success, there
has been increasing interest in simplifying treatment regimens. A number of
antiretroviral agents may be dosed on a twice daily basis: ZDV, 3TC, d4T,
nevirapine, efavirenz, and ritonavir. Preliminary data on the use of nelfinavir
and saquinavir soft gel capsules in bid regimens are quite promising.
Regrettably, Merck & Co recently announced that it had discontinued the
evaluation of twice-daily dosing regimens of indinavir, in combination with
nucleoside analogues, because of poor long-term results.
Paul Volberding, M.D.
Professor of Medicine, University of California San Francisco
Director, AIDS Program, San Francisco General Hospital
San Francisco, California
Review Questions
1. Textbook Study Questions
Review questions at the end of the
Chapter 22. The answers with
explanations are available at the end of the textbook.
2. Multiple Choice Questions
1. A healthy woman gave
birth to a baby. The newborn infant was
found to be seropositive, with serum IgG to the HIV-1 virus. This finding is most likely the result of
A) the virus being transferred
across the placenta to the baby
B) the baby making anti-virus
antibodies
C) the baby’s erythrocyte
antigens cross-reacting with the virus
D) the mother’s erythrocyte
antigens cross-reacting with the virus
E) none of the above
2. A CD8:CD4 ratio of less
than 1 means that an individual
A) is normal
B) is immunosuppressed
C) has activated macrophages
D) has enhanced immunity
E) has AIDS
3. Which of the following
species can contract a lentivirus infection that causes an immunodeficiency
similar to that seen in AIDS.
A) dog
B) cat
C) horse
D) rabbit
E) mouse
4. Which component of the
HIV envelope is responsible for binding to T cells?
A) CD4
B) CD8
C) gp120
D) p24
E) p17
5. Which tumour is commonly
observed in AIDS patients?
A) melanoma
B) Kaposi’s sarcoma
C) lymphosarcoma
D) carcinoma
E) Burkitt’s lymphoma.
3. Definitions/short Answer Questions
1. List the reasons why an
effective vaccine has not been developed against AIDS. Which are the most significant?
2. What immunological test
would you use to determine whether a patient has AIDS? Does this test detect antibody or
antigen? Which test is preferable? One
for antibody or one for antigen?
3. List the major clinical
features of AIDS. How can they be
distinguished from other immunodeficiency diseases?
4. HIV can cause destruction
of both infected and uninfected CD4+ cells. Explain.
5. Describe immunologic
abnormalities characteristic to AIDS.
6. What are the current drugs
given to AIDS patients, and what is the mechanism of their action? Why does the “cocktail” approach seem to so
effective?