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Immunodeficiency

& AIDS
1. Briefly explain the types, mechanisms and
consequences of immunodeficiency with
relevant examples
2. Outline the evaluation steps for detecting
immunodeficiency
3. Briefly describe the transmission of HIV infection in
human & the pathogenesis of HIV/AIDS (effects on
the immunesystem)
4. List out types of opportunistic pathogens associated
withAIDS
5. Briefly discuss the social consequences & ethical issues
of HIV/AIDS
Part-1

Immunodeficiency
• 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.
• Definition:
“A deficiency of immune response or a disorder
characterized by deficient or impaired immune
response”
• A person with an immunodeficiency disorder will
have frequent infections that are generally more
severe and last longer than usual.
Types of Immunodeficiency
10 20
Results from a genetic Loss of immune
or developmental function that results
defect of the from exposure to
Primary immune system Secondary various agents
(acquired)
The condition is Example: Acquired
present at birth, immunodeficiency
though it may not syndrome (AIDS),
manifest itself until which results from
later in life infection with the HIV-1
Example: Severe
Combined
Immunodeficiency
(SCID)
The deficiency is the
cause of this disease.
Primary Immunodeficiencies
• Affect either innate or adaptive immune
functions, which enables us to categorize
them according to the type of developmental
lineages or cellsinvolved.
• Defects may be in the:
1. Myeloid lineage
2. Lymphoid lineage
May involve B cells,
T cells, or both
3. Complement Lineage
Defects in the myeloidlineage—
• Affect the innate immune functions
resulting in:
1. impaired phagocytic processes

2. Reduction in Neutrophil Count

3. CGD: Chronic Granulomatous Disease

4. Chediak-Higashi Syndrome

5. LAD: Leukocyte Adhesion Deficiency


Defects in the lymphoid lineage—
• B-cell immunodeficiency disorders
cause recurrent bacterial infections.
• T-cell deficiency can affect both
humoral and cell- mediated
responses.

When there is a
defect in any
one of the
many steps
during
lymphocyte
development
Defects in the ComplementLineage—
• Affect the innate as well as adaptive immune functions.
– susceptibility to bacterial infections and/or immune-complex
diseases.

1. Deficiency of early complement components (C1, C4,C2):


– collagen vascular disorders (e.g., systemic lupus erythematosus
(SLE)]
– increased susceptibility to pyogenicinfections
2. C3 deficiency: severe pyogenic infections , SLE, and
glomerulonephritis
3. Deficiency of late complement components (C5, C6, C7,
C8):
– meningococcal sepsis and meningitis, and disseminated gonococcal
infections
4. Abnormalities of the control proteins of the alternative
pathway (factor H, factor I, properdin) may result in
recurrent infections.
Secondary Immunodeficiencies
• Deficiency is acquired as a result of other diseasesor
conditions:
» Infection-
» Example- HIV-1 leading to AIDS. Virus infection decreases
function of cellular immunity, decreased function of the Tcells.
» Malnutrition & other non infectious conditions
includingtrauma-
» Aging
» Starvation or Malnutrition
» Injury & Burns
» Splenectomy
» Immunosuppression
• Secondary immunodeficiency diseases(SIDD)
– occurs when the immune system is compromised due to an
environmental factor.
Secondary Immunodeficiencies
• Immunosuppression
– Immunosuppression by using drugs for a
long time
• antibiotics, antineoplastic drugs
– Immunosuppression by radiation
– Malignant tumors in immune organ
leadingto-
• decreased function of cellular immunity
• decreased function of the T and Bcells
• Example: Hodgkin`s and others malignancy
When to suspect Immunodeficiency?
• When recurrent infections are: • Other signs include:
– Severe – skin lesions (eg,
– Complicated eczema, warts,
– In multiple locations abscesses, pyoderma,
alopecia)
– Resistant to treatment
– oral or esophageal
– Caused by unusual organisms
thrush
• In infants or young childrenwith – oral ulcers
chronic diarrhea and failure to – periodontitis
thrive
– diarrhea caused by unusual
viruses (eg, adenovirus) or
fungi, parasites (eg,
Cryptosporidium sp).
When to suspect Immunodeficiency?
• Less common manifestations:
– Severe viral infection with herpes simplex or
varicella zoster virus
– CNS problems (eg, chronic encephalitis,
delayed development, seizure disorder).
• Frequent use of antibiotics - mask many symptoms&
signs.
• Patients with infections + an autoimmunedisorder
(eg, hemolytic anemia, thrombocytopenia).
Evaluation
History Physical Examination
• Important historical points • Look for-
– Frequency, duration, – General appearance,
severity, complications, weight, overall health
response to treatment – Skin & hair
– Risk factors – Dysmorphic features
• for infection or – Gingivitis, dental
symptoms
erosions
• for secondary
immunodeficiency – Signs of sinusitis
disorders – Tonsillar tissue,
– Family history adenopathy,
– Infection with low- splenomegaly
virulence – Arthritis
or unusual organisms – Ataxia
– Age of onset – Neuro deficits
Evaluation: Physical Examination
Oculocutaneous Telangiectasia
albinism

• Skin:
Disease Specific Skin Findings:
– Eczema and petechiae Wiskott-Aldrich Syndrome
– Telangiectasia Ataxia-Telangiectasia
(Louis–Bar syndrome)

– Oculocutaneous albinism Chediak-Higashi syndrome


– Dermatomyositis-like rash XLA
– Chronic dermatitis Hyper-IgE
– Extensive warts, candidiasis T-Cell defects
• Cervical lymph nodes • Tympanic membranes:
and adenoid and – may be scarred or perforated.
tonsillar tissue • Nostrils:
typically very small or – may be crusted, indicating purulent nasal
absent in- discharge.
– X-linked – Chronic cough is common, as are lung
agammaglobulinemia, crackles, especially in adults with CVID.
– X-linked hyper-IgM • The liver and spleen:
syndrome,
– often enlarged in patients with CVID or
– SCID, and
chronic granulomatous disease.
– other T-cell
immunodeficiencies. • Muscle mass and fat deposits of
• Lymph nodes of the the buttocks:
head & neck may be – decreased.
enlarged and • Skin around the anus:
suppurative in- – may break down because of chronic
– other diarrhea (In infants)
immunodeficiencies (eg, • Neurologic examination:
chronic granulomatous
– may detect delayed developmental
disease)
milestones or ataxia.
Evaluation: Laboratory Testing
Initial testing: Additional testing:
• Supporting a • Confirming a diagnosis
preliminary diagnosis and identifying the
of the deficiency type of deficiency
• Tests should include: • Tests:
– CBCwith manual – depends on the
differential results of initial
– Quantitative ‘Ig’ testing
measurements- Type Initial Tests Additional Tests

• Quantitative ‘Ig’ measurements- IgG, IgM, IgA, and IgElevels •

Antibody titers
B-cell deficiency B-cell phenotyping and count using flow cytometry and monoclonal
• Isohemagglutinin titers antibodies toBcells
• Antibody responsetovaccineantigens

T-cell deficiency • Absolute lymphocyte count • T-cell phenotyping and count using flow cytometry and monoclonal antibodies to

– Skin testing for delayed


• Delayed hypersensitivity skintests Tcells and subsets
• T-cell proliferative response to mitogens
• Chestx-ray for sizeof thymusininfants

• CBCwith manual differential

hypersensitivity Phagocytic cell defects

Complement deficiency



Phagocytic cell countandmorphology

C3 level
C4 level


Flow cytometricrespiratoryburstassay

Specific componentassays

– Chest X-ray
C=complement
Overall Management of
immunodeficiency disorders
Replacement of missing immune
Management of acuteinfection components
• Antibiotics • IV immune globulin is effective
replacement therapy in most
forms of antibody deficiency.
• Hematopoietic stem cell
• Surgery (to drain abscesses) transplantation is effective for
lethal T-cell deficiencies.
• Antivirals for viral infection – bone marrow
induced immunosuppression – cord blood
– adult peripheral blood stemcells
as in case of influenza, herpes
simplex, varicella-zoster , • Retroviral vector gene therapy
respiratory syncytial virus – successful in a few patients with X-
linked and ADA-deficient SCID
infections – not widely used because some patients
with X-linked SCID developed leukemia

Vaccines and avoidance of exposure to infection


Prognosis
• Depends on the type of immunodeficiencydisorder.

1. An ‘Ig’ or a complement deficiency - good prognosis


with a near-normal life expectancy if:
– diagnosed early
– treated appropriately
– no coexisting chronic disorders
2. A phagocytic cell defect or combined deficiencies - a
guarded prognosis-
– most require intensive and frequent treatment.
3. Patients with SCID- die during infancy unless
immunity is provided through transplantation
Part-2

Discovery of AIDS
• First reported in Los Angeles, New York, and San
Francisco in 1981
• The first patients displayed unusual infections by
opportunistic agents, such as Pneumocystis carinii
Opportunistic agents - microorganisms that healthy individuals can
harbor with no ill consequences but that cause disease in those with
impaired immune function

•Scientists identified a type of chimpanzee


in West Africa as the source of HIV infection

•Nobel Prize to:


– Françoise Barré-Sinoussi & Luc Montagnier
HIV-1 Virus Structure
• The virus that causesAIDS

• A retrovirus with two copiesof


ss-RNAgenome

• Uses reverse transcriptase to


transform its ss-RNA genome
into a ds-DNAfor integration

• Marker protein “gp120”-allow


it to recognize specific cells in
the human body
HIV is spherical & has a diameter of 1/10,000 of a mm
Core or capsid- made up of 2,000 copies of the viral protein, p24 21
HIV matrix protein (p17)- lies between the viral core and the viral envelope
HIV-2 Virus
• Another human virus
– In 1986 isolated from AIDS patients in WestAfrica
• Less pathogenic than HIV-1
• Commonly infects nonhuman primates that are not
infected by HIV-1
• same modes of transmission as HIV-1 and is associated
with similar opportunistic infections and AIDS
• Immunodeficiency seems to develop more slowly
– comparatively less infectious early in the course of infection
– As the disease advances, HIV-2 infectiousness seems to
increase;
– Compared with HIV-1, the duration of this increased
infectiousnessis shorter
How is HIV spread?
PRIMARILY modes of transmission

Unprotected sex with someone who has


HIV

Sharing needles, syringes, rinse water, or


other equipment used to prepare illicit
drugs for injection

Being born to an infectedmother


• HIV can be passed from mother to childduring
pregnancy, birth, or breast-feeding
How is HIV spread?
Less common modes of transmission
Being “stuck” with an HIV- Receiving blood transfusions,
contaminated needle or blood products, or organ/tissue
transplants that are
other sharp object. contaminated with HIV.

Through unsafe or unsanitary Eating food that has


injections or other medical or been pre-chewed by an
dental practices. HIV- infected person.

Being bitten by a personwith Contact between broken skin,


HIV. No risk of transmission wounds, or mucous membranes
and HIV-infected blood or blood-
if the skin is not broken.
contaminated body fluids.

During “French” or deep, open-mouth kissing


with an HIV-infected person if the HIV-infected
person’s mouth or gums are bleeding.
How HIV is NOT spread?

Air Water

Insects, including Saliva, tears, or


mosquitoes sweat

Casual contact like


Closed-mouth or
shaking hands or “social” kissing
sharing dishes

HIV cannot reproduce


outside the human body
AIDS Epidemiology
Risk factors
• Engage in anal, vaginal, or oral sex Are exposed to the virus as a fetus
with • men who have sex with or infant before or during birth or
men, multiple partners, or through breastfeeding from a
anonymous partners without using mother infected with HIV
a condom
Received a blood transfusion or
• Drug abusers - Inject drugs or clotting factor any time without
steroids where needles/syringes are proper screening of the donor
shared
• Doctor, nurses, lab personnel
• Have a sexually transmitted exposed to HIV patient blood
infection, such as syphilis, and/or otherbody fluids
genital herpes, chlamydia,
gonorrhea, bacterial vaginosis, • Researchers handling HIV
or trichomoniasis
virus
• Exchange sex for drugs or
• Veterinarians and zoo workers
money getting exposure to anonymous
• Engaged in unprotected sex animals might be unknown
with someone who has any reservoirs
of the risk factors listed
above
Mechanism of HIV Infecting Human Cell &
Pathogenesis
1. HIV gp120 surface protein
binds CD4 on target cell
2. Transmembrane component,
gp41, binds coreceptor CXCR4to
enhance fusion
3, 4. Viral genome and other
proteins are able to enter the
cell vianucleocapsid
5. RTtranscribes the ssRNAgenome
6. The next DNA strand is made,
making a dsDNAmolecule
called a provirus
7. Provirus is transferred to the
nucleus to be added to the host
genome via the viral integrase
protein at HIV LTRsites
Activation of Provirus
1. Activation of the integrated provirus
by transcriptional factors to make
genomic ssRNAandmRNAs
2. Genomic RNAis exported
3. Host ribosomes transcribe viral
mRNAs,
– viral genomic RNA or mRNA to
synthesize membrane proteins
4. The membrane buds to form a viral
envelope
5. Mature virus is released outside the
cell
* * Latent cells are dangerousbecause
t2h9ey can remain latent for long periods
HIV genes & their role in pathogenesis

• ‘gag’ - codes for nucleocapsidproteins


• ‘env’ - codes for envelope glycoproteins, i.e. gp41(transmembrane
protein) and gp120 (surfaceprotein)
• ‘pol’ - codes for enzymes suchas:
– reverse transcriptase, protease and integrase

• Other genes - code for various activators & accessory proteins


Associated Immunological problems in HIV
infection
Progression of HIV to AIDS
• Cycle of virus infection
and production, and
death of CD4+ve T
cells continues at a
steady state level

• Half life for infected


cellsis roughly 1.5 days

• There are small


numbers of latent
cells that can persist
for long periods of
time
Clinical manifestations
• Early Symptoms (within a month or • Later Symptoms
two) • severely weakens the immune
• Most people will have very few, if system,
any, symptoms; they may • victim may have the following
experience a flu-like illness,
including: symptoms:
– Fever – Rapid weight loss
– Headache – Recurring fever or profuse night
– Tiredness sweats
– Enlarged lymph nodes in neck & – Extreme and unexplained tiredness
– Prolonged swelling of the lymph
groinarea glands in
the armpits, groin, or neck
– Diarrhea that lasts for more thana
week
– Sores of the mouth, anus, or genitals
– Pneumonia
– Red, brown, pink, or purplish
blotches on or under the skin or
inside the mouth, nose, or eyelids
– Memory loss, depression, and other
neurologic disorders.
Clinical manifestations
Opportunistic Opportunistic infections–
infections–
• Pulmonary infection /
• Eyes- Causes retinitis
followed by retinal Pneumonia
necrosis – Mycobacterium avium
– Toxoplasma gondii complex
– Cytomegalovirus – Pneumocystis jiroveci
– Herpes simplex virus – Cryptococcus neoformans
– Varicella-Zoster virus – Histoplasma capsulatum
• Heart – Causes – Cytomegalovirus
myocarditis
– Toxoplasma gondii • Gastroenteritis
• Oral cavity- oral lesions
– Cryptosporidium parvum
– Candida albicans
Diagnosis of AIDS:
Techniques for testing HIVinfection
• Diagnosis for AIDS includes: • Enzyme-linked immunosorbent
– Finding the virus in patient body assay.
fluids – first test used to detect HIV infection
– Detecting antibody against HIV – If antibodies to HIV found positive, test
in serum/plasma is usually repeated.
– Less than 200 THcells/mm3
– Impaired DTH • Western blot.
– Occurrence of opportunistic – to confirm results of positive ELISA
infections tests

• Indirect fluorescent antibody (IFA).


HIV HIV
– Can detect anti-HIV antibodies.
– used to confirm the results of an ELISA.

• Polymerase Chain Reaction (PCR).


– This test detects the RNAof HIV.
IMU diagnostics IMU diagnostics – Reveal an HIV infection before
antibodies can be detected.
Treatment of HIV
5 major lines of antiretroviraltherapy
1. Reverse Transcriptase Inhibitors –
– interfere with the critical step reversetranscription.
– make faulty DNA building blocks, thereby blocking HIV from replicating in a
cell.
– bind to RT,interfering with its ability to convert the HIV RNA into DNA.
2. Protease Inhibitors –
– interfere with the protease enzyme that HIV uses to produce infectious viral
particles.
3. Fusion/Entry Inhibitors –
– interfere with the virus' ability to fuse with cellular membrane, thereby
blocking host cell entry.
4. Integrase Inhibitors
–block integrase, the enzyme HIV uses to integrate its genetic material into
its target host cell.
5. Multidrug Combination Products – highly active antiretroviral
therapy (HAART)
HAART

3 Points In HIV Cell Cycle Where Replication Can be Stopped 37


Prevention
• Currently, there is NO VACCINE to prevent HIV
infection nor is there a cure for HIV/AIDS.

• To reduce your risk of becoming infected with


HIV or transmitting the virus to others
– Get tested for HIV when suspected
– Remain faithful to your spouse or partner
– Consistently use male latex or female polyurethane
condoms
– Do not share needles

• Maturation inhibitor drugs- Yet to develop


– (could prevent proper assembling & maturing)
Social &psychological concerns in with HIV/AIDS
The main social concern The major psychological Social stigmatization
'Feeling very lonely’ concern
'Lack of interest in things‘
Ethical Issues to address
• Disclosure- • Suicide- High suicidal rate
– To tell or not?
• Duty to warn
• Disability rights – Is there a legal duty to
protect or warn third parties
• Economical issues-
– resources to support • Counseling implications
– Counselors require to be
• Employment rights- knowledgeable about federal,
– Can they decide whether to stay in their state, and local laws
current position or not? – Risk reduction counseling
• Safer sex practice
• Medication & Treatments-
– Dissatisfactory with the treatment providers • No needle sharing
– Treatment effects • Avoid pregnancy