Transcript HIV

Immunodeficiency Disease
• Def: Immunodeficiency- an abnormality of the immune
system that renders a person susceptible to diseases
normally prevented by a normal functioning immune
system
• Four Categories Immune Mechanisms
– Humoral (Antibody-mediated):
• Specific type of mechanism
– Cell-mediated (T-cell mediated)
• Specific type of mechanism
– Compliment system
• Non-specific type of mechanism
– Phagocytosis
• Non-specific type of mechanism
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Immunoglobulins
• An antibody or immunoglobulin:
– Large Y-shaped protein
– Used by the immune system to identify and neutralize foreign
objects
• For example bacteria and viruses.
– Each antibody recognizes a specific antigen unique to its target.
– Two tips of the "Y" of the antibody contain a paratope (a
structure analogous to a lock) that is specific for one particular
epitope (analogous to a key) on an antigen, allowing these two
structures to precisely bind together.
– This precise binding mechanism allows an antibody to tag a
microbe or an infected cell for attack by other parts of the
immune system, or to directly neutralize its target (i.e. by
blocking a part of a microbe that is essential for its invasion
and survival).
– The production of antibodies is the main function of the
humoral immune system.
Antigen/Antibody Binding
• Immunodeficiency : Two types
– Primary immunodeficiency: congenital or
inherited
– Secondary immunodeficiency: acquired
• Regardless whether the cause is primary or
secondary the spectrum of the disease will be the
same
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Humoral (B-cell) Immunodeficiencies
• Caused by the improper production of one or all of the
immunoglobins (antibodies)
– Results in an increased of infections from
Staphylococcus, Streptococcus, Haemophilus,and
Pseudomonas.
• Primary Humoral Immunodeficiencies include:
– X-Linked (Bruton’s) Agammaglobinulinemia
– Common Variable Immunodeficiency
– Selective Immunoglobin A Deficiency
• Secondary Humoral Immunodeficiencies:
– General comments
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Primary Humoral Immunodeficiency
Disorders
• X-Linked (Bruton’s) Agammaglobinulinemia:
– Genetic disease that only affects males which results in
undetectable levels of all serum immunoglobins
– The genetic defect inhibits the differentiation of B-cells into
plasma cells which ultimately are responsible for producing
immunoglobins
– Because of abnormally low immunoglobin levels, the child is
susceptible to certain infections such as:
• Meningitis
• Recurrent ear infections
• Chronic sinus/upper respiratory infections
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Primary Humoral Immunodeficiency
Disorders
•
Common Variable Immunodeficiency:
– Similar to X-linked agammaglobulinemia
– The terminal differentiation from mature B cells to plasma
cells is blocked resulting in reduced serum immunoglobin
levels
– Symptoms are similar to agammaglobulinemia, but the onset
occurs between 15 and 35 years.
– Patients have a tendency for chronic lung disease,
autoimmune disorders, hepatitis, gastric carcinoma, and
chronic diarrhea associated with malabsorption.
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Primary Humoral Immunodeficiency
Disorders
• Selective Immunoglobin A Deficiency:
– Most common immunoglobin deficiency affecting 1 in 400
to 1 in 1000 persons
– Main physical characteristic is a severe reduction in the
levels of serum and secretory IgA that results from the
inability of mature B cells to transform into IgA secreting
plasma cells
– Usually there are no overt S/S because IgG and IgM can
compensate
– Persons with this disease tend to be affected with:
• Chronic upper respiratory infections
• Chronic GI infections
• Increased incidence of allergic diseases such as asthma
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Secondary Humeral
Immunodeficiency Disorders
• Can occur as a consequence of selective loss of
immunoglobulin through the gastrointestinal or genitourinary tracts.
– Example would be a person with Nephrotic syndrome
who losses IgA and IgG in the urine because of
abnormal glomerular filtration.
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Cellular (T-cell) Immunodeficiencies
• Caused by problem with T lymphocytes (both CD4+ helper cells
and CD8+ cytotoxic killer cells)
• Patient’s have more severe symptoms than with humeral
immunodeficiencies
• Children rarely survive beyond infancy or childhood
• Primary Cell Mediated Immunodeficiency disorders include:
– DiGeorge Syndrome
– X-Linked Immunodeficiency with Hyper-IgM
• Secondary Cell-Mediated immunodeficiency:
– General comments
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Primary Cell-Mediated
Immunodeficiency Disorders
• DiGeorge Syndrome:
– Disease affecting both sexes
– Caused by embryonic developmental defect resulting in the
malformation of the:
• Thymus gland
• Parathyroid gland
• Head/neck area
• Heart
– Associated facial abnormalities include increased distance
between the eyes, upward bowing of upper lip (fish mouth),
low-set/posteriorly angulated ears, split uvula
– children are required to undergo blood transfusions/bone
marrow transplants in order to survive
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Primary Cell-Mediated
Immunodeficiency Disorders
• X-Linked Immunodeficiency with Hyper-IgM
– Occurs only in males
– Characterized by low levels of IgA and IgG and high
levels of IgM
• Once thought of a B cell disorder, however, now
traced to T cells
• There is a failure of T cells to signal B cells to
produce IgA and IgG and instead only produce IgM
– Children become symptomatic the first 2 years of life
with recurrent pyogenic infections
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Secondary Cell-Mediated
Immunodeficiency
• More common than primary cell-mediated
immunodeficiency
• Associated with acute viral infections (HIV, Herpesvirus)
and with certain malignancies (Lymphoma, Hodgkin's
disease).
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Combined T-Cell and B-Cell
Immunodeficiencies
• Severe Combined Immunodeficiency (SCID)
– Caused by diverse genetic mutations resulting in the absence
of ALL immune function
– Infants with this disease lead a short life (avg 2 years) with
chronic opportunistic infections
– There is a milder form known as combined
immunodeficiency syndrome having a low, but not absent Tcell function. Antibody forming capacity is impaired, not
absent.
• Children are prone to recurrent pulmonary infections,
failure to thrive, oral and cutaneous candidiasis, chronic
diarrhea, recurrent skin infections, sepsis, and urinary tract
infections.
• Although they live longer than children with SCID they
often die early in life.
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Combined T-Cell and B-Cell
Immunodeficiencies
• Ataxia – Telangiectasia:
– Results from a mutation on chromosome 11
– Condition consists of worsening ataxia (lack of coordination)
and telangiectasia (dilated capillaries and arterioles) on the
skin and conjunctiva.
• Also results in endocrine and hepatic abnormalities also
– Children have reduced levels of IgA, IgE, and IgG, and
decreased ratio of CD4+ helper T cells to CD8+ cells.
– Children are prone to recurrent upper and lower respiratory
infections and an increased risk of malignancy.
• Death from lymphoma is common
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Combined T-Cell and B-Cell
Immunodeficiencies
• Wiskott-Aldrich Syndrome:
– Patient has decreased IgM and elevated levels of IgA and IgE.
• T-cell dysfunction is initially mild then progressively
worsens making child susceptible to Hodgkin’s disease and
lymphoma
– They are also susceptible to infections (including septicemia
and meningitis) caused by encapsulated microorganisms
– Signs and symptoms:
• eczema
• chronic infections
• low platelet counts
– Bone marrow transplants have been helpful in these children
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Disorders of Complement System
• Complement system is an important part of the non-specific
immune response.
• Complement promotes chemotaxis, opsonization, and
phagocytosis of invasive pathogens, bacteriolysis, and
anaphylactic reactions.
• Primary complement disorders are caused by genetic problems
– Deficiency of C1 and C4 are not at increased risk for infection
because alternate pathways can be activated.
• These patients are more prone to autoimmune diseases
such as Lupus Erythematosus.
– Deficiency of C2: causes susceptibility to multiple life
threatening bacteria
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Disorders of Complement System
• Secondary Disorders of Complement
– Occur in persons with normal complement systems who have
rapid activation or turnover of complement components
– Can also occur with conditions where there is a decreased
production complement components such as in liver cirrhosis
or malnutrition
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Disorders of Phagocytosis
• Phagocytic system:
– Composed primarily of:
• Neutrophils
• Eosinophils
• Monocytes.
• Phagocytic cells function to migrate to site of infection,
adhere to the tissue, engulf invading material, and then
digest it.
• A defect in the phagocytic system results in a decreased
number of phagocytic cells.
• Persons are prone to bacterial infections, often by Candida
and filamentous fungi.
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Hypersensitivity Disorders
• Hypersensitivity disorders are excessive or inappropriate
activation of the immune system caused by immune
responses to antigens that produce tissue-injury causing
inflammation
• hypersensitivity disorders are divided into 4 categories
– Type 1Hypersensitivity reaction
– Type 2 Hypersensitivity reaction
– Type 3 Hypersensitivity reaction
– Type 4 Hypersensitivity reaction
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Type I Hypersensitivity (IgEMediated) Disorders
• Type I reactions are immediate-type (within 30 min)
hypersensitivity reactions that are triggered by the binding of
an antigen to IgE located on the surface of a mast cell
• Release of chemical mediators such as histamine produces an
allergic reaction that stimulates the inflammatory process
• Physiologic effects of histamine include:
– Promotes vasodilation of blood vessels
– Increases the permeability of blood vessels
– Causes smooth muscle contraction
– Causes bronchial constriction
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• Examples of Type I hypersensitivity disorders include:
– Allergic Rhinitis:
• Typical S/S include:
– Sneezing
– Itching
– Watery discharge from eyes/nose
• Typical antigens include:
– Pollens from ragweeds, grass, weeds
– Fungal spores
– House dust mites
– Animal dander/feathers
– Food Allergies: the most common food allergies include:
milk, peanuts, shellfish, and eggs
• Food allergies may produce a severe allergic response
called anaphylaxis
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• Type II-Antibody Mediated Disorders:
– AKA cytotoxic responses
– Result from the interaction between IgG and IgM
antibodies and antigens which results in the activation of
cytotoxic immune cells
– Examples include:
• Mismatched blood transfusions
• Hemolytic disease
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• Type III- Immune Complex Disorders:
– Caused by the formation of insoluble antigen/antibody
complexes that adversely increases immune function
and result in the release of certain chemicals that cause
tissue damage
– Most common areas of the body affected by Type II
disorders include:
• Renal glomerulus
• Lung
• Synovial membrane of joints
– The two most common examples of Type II disorders
include:
• Rheumatoid arthritis (RA)
• Systemic Lupus Erythematosis (SLE)
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• Type IV- Cell Mediated Disorders:
– Delayed type of reaction that is mediated by T-cells not
antibodies
– Usually occur 24 to 72 hours after antigen exposure
– Mediated by T lymphocytes
– Examples include:
• Allergic Contact Dermatitis- is an inflammatory
response confined to the skin that results when the skin
comes in contact with an irritating substance
» usually produces inflamed blisters on skin
» common causes include exposure to:
1. poison ivy
2. cosmetics
3. topical medications
4. latex
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Autoimmune Disease
• Def: Self-tolerance: to function properly the immune
system must be able to distinguish foreign antigens and
self-antigens
• Autoimmune disease- occurs when the immune system
cannot differentiate antigens from self-antigens and begins
to attack host tissue of the body that results in localized or
systemic injury
– Examples of autoimmune diseases include:
• Myasthenia gravis (MG)
• Rheumatoid arthritis (RA)
• Systemic Lupus Erythematosis (SLE )
• Graves’ Disease
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• Loss of B-Cell Tolerance: results in autoimmune diseases
that produce autoantibodies:
– Example is Graves disease: produces hyperthyroidism
due to autoantibodies that stimulate the TSH receptors
on the thyroid gland.
• Loss of T-Cell Tolerance: results from the release of selfreactive T cells from the thymus.
– Normally T-cells that have a high affinity for host cells
undergo apoptosis. If these cells do not die they leave
the thymus gland and cause tissue damage.
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HIV AIDS
• The pathogen of AIDS is HIV (Human Immunodeficiency Virus)
• At the end of 2006:
– Nearly 40 million worldwide were living with HIV/AIDS
– 25 million people had died of the infection
– 4.3 million new infections (2006)
• 50% of these women and children
• Projected: over the 10 next years there will be 100 million people
infected with HIV.
– Most new infections: people under 25 in developing countries.
• Sub-Sarahan Africa will be most affected.
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The AIDS Epidemic
• S/S associated with decreased immune function were first
recognized in homosexual men in 1981
• Although initially thought to affect the gay male population
specifically, AIDS cases began to be diagnosed in the following
high risk groups:
– IV drug users
– Hemophiliacs
– Blood transfusion recipients
– High risk heterosexuals
• As a result of HIV infection, the body’s immune system begins
to progressively fail making the infected person more susceptible
to infections that are normally harmless to the body
(Opportunistic infections)
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Transmission of HIV
• Sexual contact:
– Most frequent mechanism
– 75-80% via unprotected sex
– The virus can pass from semen and vaginal secretions into the
bloodstream through mucous membranes and wounds in the
skin.
• Blood-to-blood contact:
– Needles, syringes, or Transfusions
• Perinatally:
– Transmission can occur in utero, during labor and delivery, or
by breast feeding
• Studies still show that HIV is not spread through casual contact
nor by vectors such as mosquitoes
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• Def: Seroconversion: The point where an infected person
converts from being negative for HIV antibodies to having HIV
antibodies
– Occurs 1 to 3 months after exposure to HIV.
– But can take up to 6 months
• Def: Window period: The period of time after infection but
before seroconversion.
– During this time the patient does not have symptoms, nor
antibodies for HIV that can be picked up on a blood test.
– This patient can unknowingly transmit the disease
– As a result the FDA requires collection center to screen
potential donors through interviews designed to identify
behavior known to present risk for HIV infection.
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Pathophysiology and Clinical Course
• 2 forms of HIV
– HIV 1
• Most associated with AIDS in the US, Europe, and Central
Africa
– HIV 2
• Prevalent in West Africa
• Spreads more slowly in comparison to HIV 1
• Causes disease more slowly in comparison to HIV 1
• Cells attacked by HIV
– CD4+ T lymphocytes
– Macrophages
– Dendritic cells: specialized protective cells found in tissues
where antigens enter the body
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The HIV Virus
• HIV is a retrovirus: carries its genetic information on RNA
• The virus is spherical in shape with a core in the center
surrounded by a lipid envelope (membrane)
– Core: contains
• A protein (p24)
• Two copies of RNA
• 3 viral enzymes:
– Protease
– Reverse transcriptase
– Integrase
– Envelope: contains a protein matrix called p17 which lies
directly beneath the viral envelope. Viral envelope is
studded by 2 viral glycoproteins, gp120 and gp41 which are
important for the infection process
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Life cycle of the HIV-1
Eight steps
1. Attachment of the HIV virus to CD4+ receptor:
a. Virus attaches to the surface of a CD4+ cell
b. The virus then binds its gp 120 and gp 41 glycoproteins
with chemokine receptors on the CD4+ cell
2. Internalization:
a. Once the virus has attached, viral peptides fuse
with the CD4+ cell membrane causing an uncoating
of the virus.
b. Viral contents (viral RNA, reverse transcriptase,
integrase, and protease) then enter the cell.
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3. Reverse transcription:
a. Viral RNA must be converted to DNA (in order to
reproduce)
b. Done by the enzyme reverse transcriptase which produces
a mirror image of the viral RNA
c. The result is a double-stranded DNA molecule
4. Integration:
a. Newly created viral DNA enters nucleus of CD4+
b. Viral DNA becomes part of the cell DNA using integrase
enzyme
5. Transcription of inserted viral DNA:
a. Inserted viral DNA to produce viral mRNA
1. mRNA has the instructions for building new HIV
viruses
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6.
7.
Translation of viral messenger:
a. rRNA uses the instructions of mRNA to create viral
proteins and enzymes known as polyprotein
1. Polyprotein enzymes are needed to construct viral
components into new viruses
Cleavage:
a. During this stage protease enzymes cut viral proteins into
single proteins
b. These proteins will make up the new viruses
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8.
Assembly and release:
a. Proteins and viral RNA are assembled into new viruses
b. New viruses are built inside the cell resulting in the death of
the CD4+ cell
c. When the CD4+ cell dies, the viral particles (virions) are
released into the bloodstream to infect other CD4+ cells.
d. Every day millions of CD4+ cells are destroyed, releasing
billions of viral particles into the blood
e. The immune system is able to keep up with the infection by
producing new T-cells, however, over years, the T-cell count
decreases and the amount of virus in the blood increases.
f. Until a person’s T-cell count falls to a very low level, a
person can remain asymptomatic, even though viral
replication is taking place.
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Infected helper T-cell; the small blue globules are HIV particles.
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Classification of HIV
• 3 Categories relating to the amount of CD4+ cells per
microliter of blood (normal is 800 to 1000 cells/microliter)
– Category 1: >500 cells/microliter
– Category 2: 200 to 499 cells/mircroliter
– Category 3: <200 cells/microliter.
• 3 Clinical categories based on symptoms:
– Clinical Category A: persons who are asymptomatic or
have persistent generalized lymphadenopathy, or
symptoms of primary infection
– Clinical Category B: person has symptoms of immune
deficiency, however, not severe enough to be AIDS
– Clinical Category C: person has AIDS defining
illnesses such as pneumocystis carinii pneumonia.
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Phases of HIV
• 3 phases which occur over 8 to 12 years
• Primary Infection phase:
– Signs and symptoms appear 2 to 4 weeks after exposure
lasting a few days to 2 weeks
– Patient has fever, fatigue, myalgia, sore throat, night seats,
GI problems, lymphadenopathy, maculopapular rash, and
headache.
– During this phase there is a high amount of viral replication
(up to 1 million/ml) and a decreasing amount of CD4+
– After a few weeks the immune system catches up controlling
viral replication where it remains for several years.
– If diagnosed in this stage and therapy is started treatment
may reduce the number of long-living CD4+ infected cells
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• Chronic Asymptomatic (Latency Phase)
– Patient has no signs or symptoms of illness
– On average this phase lasts 10 years
– There is a decreasing amount of CD4+ cells down to
200 per microliter or lower.
• AIDS Phase
– Occurs when the CD4+ cell count falls less than
200/microliter
– Patient is susceptible to opportunistic infections
– Without antiretroviral therapy this phase can lead to
death within 2 to 3 years
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Clinical Course of HIV
• Typical progressors: 60% to 70% acquire AIDS 10 to 11 years
after infection
• Rapid progressors: 10% to 20% progress rapidly and acquire
AIDS in less than 5 years
• Slow progressors: 5% to 15% are slow progressors, who do not
progress to AIDS for more than 15 years
– Long-term non-progressors: 1% have been infected for at least
8 years, are antiretroviral naive, have high CD4+ cell counts
and usually very low viral loads
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Opportunistic Infections Affecting AIDS
• Bacterial opportunistic infections
– Bacterial pneumonia, TB , salmonella, mycobacterium aviumintracellulare complex (MAC)
• Fungal opportunistic infections
– Candidiasis, coccidiomycosis, cryptococcosis, and
histoplasmosis
• Protozoal opportunistic infections
– Cryptosporidiosis, isosporiasis, pneumocystiasis, and
toxoplasmosis
• Viral infections
– Cytomegalovirus (CMV), herpes, and progressive multifocal
leukoencephalopathy (PML)
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Most Common Opportunistic Infections
Affecting AIDS in the U.S.
•
•
•
•
Pneumocystis carinii pneumonia (PCP)
CMV
Oropharyngeal or esophageal candidiasis (thrush)
Infections caused by MAC (mycobcacterium avium-intrcellulare
complex)
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Clinical Manifestations
1. Respiratory Manifestations: the most common respiratory diseases
in person with AIDS include:
a) Pneumocystis carinii pneumonia (PCP)- is caused by
a protozoa that is common in soil, and houses
• patients tend to complain of:
– Cough, fever, shortness of breath, and weight loss
b) Mycobacterium tuberculosis: is the leading cause of death for
people with AIDS worldwide
• infections site is primarily in the lungs but may also be
found in the kidneys and bone marrow
• common S/S include: fever, night sweats, cough and
weight loss
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2) Gastrointestinal Manifestations- diseases of the GI tract are
the most frequent complications of AIDS and usually
include:
a) Esophageal Candidiasis (Thrush)- presents as cheesy
matter along the entire GI tract including the mouth
b) Diarrhea (Gastroenteritis)- is the most common
complaint in persons with AIDS and is usually caused
by the protozoa Cryptosporidium parvum
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3) Nervous System Manifestations: due to severe immune
compromise, both the CNS and PNS are susceptible to several
neurological disorders that can include:
a) AIDS Dementia Complex- is a syndrome involving both
cognitive and motor system dysfunction that is caused by the
pathological effects of HIV itself
• typical S/S include:
– loss of attention span/concentration
– decrease in mental speed and agility
– decrease in overall motor function
– apathetic behavior
b) Toxoplasmosis- is an opportunistic parasitic infection that
affects the CNS
• typical S/S include:
– fever
– headache
– confusion/lethargy
– visual disturbances
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– seizure activity
4) Cancers and Malignancies- the increased incidence of
malignancies is directly related to the HIV-induced impaired
immune function and include:
a) Kaposi’s Sarcoma- is a malignancy of the endothelial cells
that line small blood vessels
• is the most frequent malignancy related to AIDS
• physical S/S include:
– dark plaque-like lesions located on the skin, oral cavity,
GI tract, lungs
– organ failure-related S/S occur due to tumor blocking
blood flow
b) Non-Hodgkin’s Lymphoma- is a malignancy of the lymph
nodes
• typical S/S include:
– fever
– night sweats
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– weight loss
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5) Wasting Syndrome- is characterized by involuntary weight
loss of at least 10% of baseline body weight in the
presence of no AIDS induced opportunistic infection
• typical S/S include:
– constant diarrhea
– chronic weakness
– fever
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6) Metabolic Disorders- the two main AIDS induced metabolic
disorders include:
a) Lipodystrophy- alterations in body appearance due to
abnormal fat metabolism that present as:
• increase in abdominal girth
• abnormal fat deposition in the supraclavicular area
• wasting of fat from face/extremities
• breast enlargement in both sexes
• associated metabolic changes including elevated serum
cholesterol, elevated triglyceride levels, and insulin
resistance
» may be due to effects of protease inhibitor therapy
or nucleoside reverse transcriptase inhibitor
therapy
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Diagnostic Methods
• Laboratory methods to determine infection
– HIV antibody test
• Most accurate and inexpensive
– Western blot test
• Used as a confirmatory test when the antibody test is
positive
• Test is more specific than the antibody test
– OraSure test
• Tests for antibodies from oral fluids
• Person collects their own sample and sends it to the lab
where the antibody and Western blot test are performed
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– Polymerase chain reaction (PCR)
• Detects the presence of the virus rather than the
antibody
• Useful in infants who have maternal HIV antibodies,
yet they themselves may not be infected.
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HIV Antiretroviral Medications
• Reverse transcriptase inhibitors
– Inhibit viral replication by acting on the enzyme reverse
transcriptase
• Protease inhibitors
– Inhibits the action of protease, thereby preventing the cleaving
of the polyprotein chain
• Fusion inhibitors
– Prevents HIV virus from fusing with the CD4+ cell, thereby
blocking the insertion of the viral genetic material.
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HIV Infection in Pregnancy, Infants,
Children
• HIV can be passed from mother to infant
– During labor and delivery
– Through breast-feeding
• Diagnosis of HIV infection in children born to HIV infected
mothers is complicated by the presence of maternal HIV antibody
crossing the placenta to the fetus
• The course of HIV infection is different for children than adults
– Failure to thrive
– CNS abnormalities
– Developmental delays
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