Download Acquired Immunodeficiency Syndrome: AIDS

AIDS and Other
Immunodeficiencies
By: Luz Arboleda, Sameer Jain, and
Ranoo Patel.
Overview
I.
II.
III.
IV.
Immunodeficiency
Primary Immunodeficiency
Secondary Immunodeficiency
AIDS
i. Discovery of AIDS
ii. Origin of AIDS Virus
iii. Epidemiology & Statistics
iv. HIV-1
v. Transmission of HIV-1
vi. Treatment of HIV/AIDS
Introduction
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The immune system is subject to failure of
some or all of its parts.
If the system is not able to protect the host
from disease-causing agents or from malignant
cells, an immunodeficiency results.
There are two types of immunodeficiency:
Primary and secondary or acquired.
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Primary immunodeficiency results from a genetic
or developmental defect of the immune system.
The condition is present at birth, though it may not
manifest itself until later in life.
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Secondary (acquired) immunodeficiency is the
loss of immune function that results from exposure
to various agents. The most common example is
AIDS or acquired immunodeficiency syndrome,
which results from infection with the HIV-1. or
human immunodeficiency virus 1.
Primary Immunodeficiencies
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Primary Immunodeficiencies may affect either
adaptive (T or B cells) or innate (macrophages or complement)
immune functions, which enables us to categorize
them according to the type of developmental stage
of the cells involved.
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So, lymphoid cell disorders may affect T cells, B
cells, or, in combined immunodeficiencies, both B
and T cells. Myeloid cell disorders affect phagocytic
function.
Cellular Development in the Immune System
Figure 19-1
• Defects in the lymphoid lineage—
May involve B cells, T cells, or both of these
Lineages. B-cell immunodeficiency disorders
cause recurrent bacterial infections. T-cell
deficiency though, can affect both humoral and
cell-mediated responses.
SCID: Severe Combined Immunodeficiency
WAS: Wiskott - Aldrich syndrome
Interferon-Gamma-Receptor Defect
X-Linked Agammaglobulinemia
X-Linked Hyper-IgM Syndrome
CVI: Common Variable Immunodeficiency
Ataxia Telangiectasia
Immune Disorders Involving the Thymus
Interaction Between T and B Cells
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Defects in cell
interaction and signaling
can lead to severe
immunodeficiency.
A number of primary
immunodeficiencies are
rooted in defects in
these interactions.
SCID is an example.
Figure 19-3
• Defects in the myeloid lineage—
Defects affect the innate immune functions. Most
of them result in impaired phagocytic processes
that are manifested by recurrent microbial infection
of greater or lesser severity.
Reduction in Neutrophil Count
CGD: Chronic Granulomatous Disease
Chediak-Higashi Syndrome
LAD: Leukocyte Adhesion Deficiency
•
Defects in the Complement Lineage—
Many complement deficiencies are associated with
increased susceptibility to bacterial infections
and/or immune-complex diseases.
Treatment of Immunodeficiency
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Although there are no cures for immunodeficiency
disorders, there are various treatment possibilities.
In addition to complete isolation from exposure to
any microbial agent, treatment options for the
immunodeficiencies include:
1) Replacement of a missing protein
2) Replacement of a missing cell type or lineage
3) Replacement of a missing or defective gene
Secondary Immunodeficiencies
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Loss of immune function that results from exposure to
various agents.
Acquired Hypogammaglobulinemia
Recurrent infection that manifests itself in young
adults. There are usually very low levels of total
immunoglobulin, though T-cell numbers and function
may be normal. It is treated with gammaglobulin
therapy.
Agent-Induced Immunodeficiency
Results from exposure to any of a number of chemical
and biological agents that induce an immunodeficient
state.
AIDS: Acquired Immunodeficiency Syndrome
Discovery of AIDS
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AIDS was first reported in the United States in 1981 in
Los Angeles, New York, and San Francisco.
The first patients displayed unusual infections by
opportunistic agents, such as Pneumocystis carinii,
which causes PCP or P. carinii pneumonia, as well as
other rare opportunistic infections.
Opportunistic agents are microorganisms that healthy
individuals can harbor with no ill consequences but that
cause disease in those with impaired immune function.
They also displayed Kaposi’s sarcoma—an extremely
rare skin tumor.
Origin of AIDS Virus
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Within a few years after recognition of AIDS, the causative agent was
discovered to be a retrovirus.
Only one other human retrovirus has been described before HIV, the
human T-lymphotropic virus I or HTLV-I.
There is also another human virus known as HIV-2, which is less
pathogenic than HIV-1. It infects nonhuman primates that are not
infected by HIV-1.
Viruses related to HIV-1 have been found in nonhuman privates—such as
SIV: Simian immunodeficiency virus. Other animal retroviruses are the
feline and bovine immunodeficiency viruses and the mouse leukemia
virus. These don’t yield information pertinent to HIV-1. Only the
studies made on chimpanzees when infected with HIV-1 can be useful;
but they rarely develop AIDS.
Why isn’t there a suitable host to study HIV-1?
a) Lack of cell-surface receptors required for entry of virus into host.
b) Dependence of HIV on host-cell factors for early events in the
replication process, such as transcription and splicing of viral
messages.
Epidemiology & Statistics
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Since its discovery in 1981, AIDS has increased to
epidemic proportions.
According to the National Centers for Disease Control
and Prevention (CDC), 42 million people are estimated
to be living with HIV/AIDS. Of these, 38.6 million
are adults, 19.2 million are women, and 3.2 million are
children under 15.
An estimated 5 million people acquired the human
immunodeficiency virus (HIV) in 2002, including 2
million women and 800,000 children under 15.
Epidemiology & Statistics
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During 2002, AIDS caused the deaths of an estimated
3.1 million people, including 1.2 million women and
610,000 children under 15.
Women are becoming increasingly affected by HIV.
Approximately 50%, or 19.2 million, of the 38.6
million adults living with HIV or AIDS worldwide are
women. Compared to accounting for only 6% of the
total cases in 1985.
The UN predicts that by 2010, more than 25 million
children will have lost at least one parent to AIDS.
Global Estimates of HIV/AIDS
HIV-1 Virus
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The virus that causes AIDS
It is a retrovirus with two copies
of single stranded RNA
genome
It uses reverse transcriptase to
transform its ss-RNA genome
into a ds-DNA for integration
into its host genome
It has marker proteins (gp120)
in the protein coat that allow it
to recognize specific cells in the
human body
The protein coat also contains
MHC-I and MHC-II molecules
HIV genome
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gag gene codes for nucleocapsid proteins
env gene codes for envelope glycoproteins, i.e. gp41
(transmembrane protein) and gp120 (surface protein)
pol gene codes for enzymes such as reverse transcriptase,
protease and integrase
Other genes code for various activators and accessory proteins
Complete Activation of HIV
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While CD4 is recognized by the virus, it is not sufficient for viral attack; it
needs a costimulatory signal.
T cells: coreceptor is CXCR4, which also acts as a receptor for the chemokine
SDF-1; there is competitive inhibition between chemokine and HIV for
binding; the HIV strain is called T-tropic
Monocytes: coreceptor is CCR5, which is a receptor for chemokines, which
also act as competitive inhibitors to HIV; the HIV strain is called M-tropic
T-tropic HIV strains cause syncytia: formation of giant cells as a result of
fusion of cells via the gp120 protein on viral coats.
Infection of Human Cell with HIV
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HIV gp120 surface protein binds
CD4 on target cell
Transmembrane component, gp41,
binds coreceptor CXCR4 to
enhance fusion
Viral genome and other proteins are
able to enter the cell via
nucleocapsid
RT transcribes the ssRNA genome
The next DNA strand is made,
making a double stranded DNA
molecule called a provirus
The dsDNA is transferred to the
nucleus to be added to the host
genome via the viral integrase
protein at HIV LTR sites
Activation of Provirus
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In a latent cell, the integrated
provirus must be activates by
transcriptional factors to make
genomic ssRNA and mRNAs
Genomic RNA is exported
Host ribosomes transcribe viral
mRNAs, and the proteins are
either with the genomic RNA
or part of the membrane
The membrane buds to form a
viral envelope
The mature virus is released
outside the cell
These latent cells are dangerous
because they can remain latent
for long periods of time
HIV Infected T-Cell
Overview of
Infection
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The viral load is kept at a steady state; half
life for infected cells is roughly 1.5 days
In addition to these lytic cells, there are
small numbers of latent cells that can
persist for long periods of time
Diagnosis for AIDS includes finding the
HIV virus in the patient, <200 TH
cells/mm3, impaired DTH, and the
occurrence of opportunistic infections
Infections that result from the diminished
immune system include infections with
Candida albicans, flu, tuberculosis,
encephalopathy, and other abnormalities
of CNS and PNS.
Progression of HIV to AIDS
Testing for HIV
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Enzyme-linked immunosorbent assay (ELISA). This
screening test is usually the first test used to detect infection with
HIV. If antibodies to HIV are present (positive result), the test is
usually repeated.
Western blot. This test requires high technical skills. It is more
difficult than the ELISA to perform and interpret accurately, but
it is less likely to give a false-positive result because it can
distinguish HIV antibodies from other antibodies that may react
to the ELISA. A Western blot is usually done to confirm the
results of two positive ELISA tests.
Indirect fluorescent antibody (IFA). This test also detects
antibodies made to fight an HIV infection. Like a Western blot
test, it is used to confirm the results of an ELISA.
Polymerase Chain Reaction (PCR). This test detects the RNA
of HIV, rather than detecting antibodies to HIV. Therefore, PCR
can reveal an HIV infection before antibodies can be detected.
PCR can also accurately determine whether a baby born to an
infected mother has HIV.
Immunological problems associated
with HIV infection
Other Immune Evasions
Mechanisms of HIV
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TC cells are able to generate a response for years until finally they
are no longer effective against HIV
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The HIV peptides that act as epitopes to the MHC I molecules mutate at
a high rate and the TC cells are not able to keep up
Some HLA haplotypes are more susceptible to HIV attack than
others
HIV gene products have functions in addition to viral
replication functions; some are able to down regulate host cell
MHC-I expression so fewer peptides are presented to the
defense mechanisms
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Tat represses transcription of MHC-I
Vpu keeps MHC-I molecules from leaving the endoplasmic reticulum
Nef selectively internalizes some MHC-I molecules from the plasma
membrane, so that the cells have fewer MHC molecules in total. It leaves
the MHC-I molecules that will help prevent lysis by NK cells.
3 Points In HIV Cell Cycle Where Replication Can be Stopped
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Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Protease Inhibitors
All 3 of these treatments are usually prescribed at once. Known as HAART, the
combination of all 3 fights the ability of the virus to rapidly mutate.
Reverse Transcriptase Inhibitors
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Reverse Transcriptase Inhibitors interfere with the
reverse transcriptase (RT) enzyme that HIV needs to
make copies of itself. There are 2 types of inhibitors
each working differently.
Type 1: NRTI’s – nucleoside drugs provide faulty DNA
building blocks, stopping the DNA chain the virus uses to make
copies of itself.
Type 2: NNRTI’s- non-nucleoside RT inhibitors bind RT
so the virus cannot carry out its copying function
Examples Include: AZT, 3TC, Combivir, Nevirapine
Protease Inhibitors
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Protease Inhibitors (PI), discovered in 1995, block the
protease enzyme. When protease is blocked, HIV
makes copies of itself that can’t infect new cells.
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PI Side Effects: PI’s can cause high blood sugar and
consequently diabetes. Another main concern is
lipodystrophy, where your body absorbs fats and
nutrients in an irregular manner. Latent HIV can hide
out in these fat cells.
Death rate
Death rates per 100,000 population from leading causes of death
among persons 25–44 years old, United States, 1987–2000
What does the future hold?
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Scientists are working on more potent protease inhibitors,
less toxic RT inhibitors, as well as 2 new classes of drugs:
*Fusion Inhibitors- Drugs which act to block HIV
before it enters the human immune cell. This class of drugs
works to stop HIV replication at an earlier stage.
*Integrase Inhibitors- Aim to block the integration
of the virus’s DNA into the cell’s chromosome. 2 different
integrase inhibitors are currently in human trials.
Can HIV be Vaccinated Against?
Challenges
-HIV thrives in the presence of
circulating antibodies directed
against it.
- HIV integrates itself into the host genome
and may stay dormant for years. All retroviruses prove difficult to
remove
-HIV mutates and can show up to 109 viruses
per day, while the common cold with 100 subtypes has proven to
difficult to make a vaccine for
Summary of HIV transmission
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HIV is a retrovirus with a single stranded RNA
genome; it is the virus that causes AIDS
There are two major strains of HIV that infect T cells
or monocytes
The gp120 interacts with CD4 on the host cell, but
there are coreceptors that are necessary for attack
The viral load of the plasma is a good indicator of the
disease course
Many secondary diseases can afflict the patient from
the lowered immunity that results from AIDS
HIV/AIDS Therapy Summary
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3 primary methods to battle HIV/AIDS
- NRTI’s, NNRTI’s, PI’s
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All 3 combine to form HAART which has proven to be
much more effective against HIV’s mutations.
New drugs which eliminate side effects or target
different steps in the replication process are under
testing.
For now a vaccine still seems to be a pipe dream