Immunology of HIV /AIDS With

reference to CD4 cells

 Learning Objectives
• To know the structure and functions of the
white cells
• HIV interaction with the human immune
system
• Mechanisms of the depletion of the CD 4
cell count
• Monitoring immunity by CD 4 count

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Hematopoietic System

CD4+ T helper CD8+ T

lymphocytes cytotoxic/suppressor
lymphocytes

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§Eosinophil §Eosinophil §Basophil

§Neutrophil §Eosinophil

§Neutrophil

§Lymphocyt
e
§Basophil
§Monocyte
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Types
Types of
of lymphocytes
lymphocytes
There are two types of lymphocytes. Both form from
bone marrow stem cells:

§T cells mature in §B cells mature in

the thymus the bone marrow

§Both cell types enter the lymph nodes and spleen after
they are mature. From there they can look for foreign
invaders in the§Lab
bloodstream.
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Steps in T cell development
Positive selection thymic cortex

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Steps in T cell development

Negative selection occurs in the thymic medulla.

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Types of T cells
Based on function, there are different types
including:

• helper T cells – start the immune response

• cytotoxic T cells – kill the body’s abnormal
cells, like virus-infected cells and cancer cells
• suppressor T cells – suppress the activities of
other T cells, helping to end the immune
response

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 §1
3

B cells
• produced and mature in bone marrow

• each B cell produces and wears a unique antibody on

its surface

• clonal selection - when a B cell encounters a matching

antigen, it begins to divide rapidly. Some then
become plasma cells that all produce the same
antibody, and then die. Others become memory cells.

• the specific antibody produced by a plasma cell is also

secreted in soluble form and circulates in the blood

§Lab workers §Health workers §Counselors

 HIV Virus Structure

§Immunology §Lab workers §Health workers §Counselors §Slide 14

§Immunology §Lab workers §Health workers §Counselors §Slide 15
 Virion Interaction with CD4 Receptor and CXCR4
Co-receptor

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 HIV Interaction with CD4 Cell

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 Binding and Entry

Nucleus

Cytoplasm

Neutralizing
Antibodies
CD4+ Cell
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 Multiple Steps of HIV Replication

1. Cell entry

2. Reverse transcrip-
tion & integration

4. Viral
3. Virus production Maturation

§Immunology §Lab workers §Health workers §Counselors §Slide 19

 Virus Production
Regulatory
Proteins

Transcription

Structural
Proteins

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 Replication Is Completed in 1.5 to 2
Days

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 Progression of HIV infection to AIDS
Typical progressors (80% to 90%): 10 Yrs
Rapid progressors (5% to 10%): 3-4 yrs
Long term nonprogressors (5%): 15 yrs

Host Factors Viral Factors

Immune status Load

Age Strain

Genetic Other infections

§Virology & §Lab workers §Health workers §Counselors §Slide 22

 Summary of HIV Kinetics In-vivo
• Life span of productively infected cells is
2.2 days
• Rate of CD4+ lymphocyte production is 2
X 109 cells / day
• 1010 HIV virions produced each day
• HIV-1 generation time is 2.6 days

Source: Ho et al Nature 1995; Wei et al Nature 1995 Perelson et al Science 1996

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 Immune Status

• No of CD4 cells –decreased in HIV

• Percentage of CD4 cells-decreased in HIV
• CD4/CD8 ratio decreased

§Virology & §Lab workers §Health workers §Counselors §Slide 24

Direct mechanism of CD4+ T cell depletion
• Loss of plasma membrane
integrity due to viral budding.

•Accumulation of un integrated
viral DNA

•Syncytia formation

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 Indirect mechanism of CD4
depletion
•gp-120- CD4 mediated fusion of infected and
uninfected cells
•Super antigen mediated activation of T cells
•Innocent bystander killing of viral antigen
coated cells.
•Apoptosis due to functional exhaustion.
•Elimination of HIV uninfected cells by CD4-
gp120 complex formation by ADCC
(Antibody Dependent Cell Mediated
Cytotoxicity)

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Correlation of CD 4 T-cell count with Opportunistic
infections

§Lab workers §Health workers §Counselors

 Natural History of HIV Infection
Without the Use of Antiretroviral
Therapy
1200

1100

1000

900
CD4 + T Lymphocyte Count (cells/mmm3)

CD4 + T Lymphocyte Count (cells/mmm3)

800

700

600

500

400

300

200

100

0
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11
Weeks Ye ars

§Source:
Virology &
Fauci, A., Pantaleo, D., Stanley S., Weismann, D. Annals of Internal Medicine 124: 6754-3,
§Lab workers §Health workers §Counselors
1996
§Slide 28
 Natural History of HIV Infection
Without the Use of Antiretroviral
Therapy 107

HIV/RNA Copies per ml Plasma

HIV/RNA Copies per ml Plasma

106

105

104

103

102
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10  11
Weeks Years

§Source:
Virology &
Fauci, A., Pantaleo, D., Stanley S., Weismann, D. Annals of Internal Medicine 124: 6754-3,
§Lab workers §Health workers §Counselors
199629
§Slide
 Natural History of HIV Infection
Without the Use of Antiretroviral
Therapy Primary Death
1200 Infection + Acute HIV syndrome 107
Wide dissemination of virus Opportunistic
1100
Seeding of lymphoid organs Diseases

HIV/RNA Copies per ml Plasma

1000
106
900 Clinical latency
CD4 + T Lymphocyte Count (cells/mmm3)

800

700 Constitutional 105

Symptoms
600

500 104

400

300
103
200

100

0 102
0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11
Weeks Years

§Source:
Virology &
Fauci, A., Pantaleo, D., Stanley S., Weismann, D. Annals of Internal Medicine 124: 6754-3, 1996
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Schedule for CD4 count enumeration in
pre-ART care
Pre ART CD4 monitoring and Follow up
Schedule
CD4 Count Repeat at
< 350 and not on ART 3 months
>350 and not on ART 3 months
On ART (any value) 6 months
>500 Annual Screening
Note: If the CD4 count is between 250 to 300
cells/mm3 and the patient is not on ART; repeat
CD4 assessment after 4 weeks

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Initiation of ART in Adults and Adolescents
(National Guideline April 2009)
 

Who clinical CD4

staging (cells/cu.mm)
I and II Treat if CD4+ T
cell count <250
III Treat if CD4+ T
cell count <250
IV Treat irrespective
of CD4+ T cell
count
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 The criteria for treatment failure
(National Guidelines 2007)
Clinical failure New or recurrent WHO stage 4
condition, after at least 6 months of ART
Immunological  Fall of CD4 counts to baseline or
failure below
 50% fall from the on-treatment peak
value (if known)
 Persistent CD4 levels below 100
cells/cu.mm
Virological Plasma viral load >10,000 copies/mL
failure
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 Revised classification of CD4 immune
suppression in children

Classificatio Age related CD4 values

n of HIV- CD4% CD4 count
associated Age Age Age > 5 years
immunodefi <11 months 12-35 months 36-59 months
ciency

Normal >35 >30 >25 >500

Mild 30-35 25-30 20-25 350-499
Advanced 25-30 20-25 15-20 200-349
Severe < 25% or < 20% or < 15% or < 15% or
CD4 count CD4 count CD4 count CD4 count <200
§Lab workers §Health workers §Counselors §Slide 34
When to perform CD4 counts in children
If the child is found to be HIV infected,

1) CD4+ T lymphocyte enumeration should

be performed at 1st and 3rd month of age
and repeated for every three months.

2) The frequency of CD4 testing should be

increased to every 4 - 6 weeks if the
CD4+ T lymphocyte count or percentage
declines rapidly
§Lab workers §Health workers §Counselors §Slide 35
Thank You