KITSO AIDS Training Program

Lecture 2:

HIV Pathophysiology and

Epidemiology

delivered by
Dr. Daniel J. Baxter, ACHAP
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 Learning Objectives
• Lifecycle of HIV-1.
• CD4 cell and host defense system.
• Natural history of HIV-1 disease.
• Immune responses to HIV-1 and
mechanisms of immune evasion by
HIV.
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 Worldwide Distribution of
HIV-1 Viral Subtypes

B B
Northern America: Western Europe: Eastern Europe &
Central Asia:
C
920,000 540,000
700,000

Caribbean:
Northern Africa & C,E Eastern Asia & the
Pacific: 640,000
Middle East:
390,000 Southern &
400,000
Southeastern

Latin America: C Asia:

7 million
1.4 million Sub - Saharan Africa:
Australia &
B 25.3 million New Zealand:
:
15,000

Source: WHO/UNAIDS (data as of December, 2000)

B
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 Viruses
• A virus is the simplest, most primitive life form
on earth.

• A virus is unable to replicate (reproduce) on

its own and must first infect a living cell in
order to replicate.

• HIV is a retrovirus. A retrovirus is an RNA

virus which uses DNA as an intermediary for
its replication.
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Human Immunodeficiency Virus

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HIV-1 Particle

6
HIV Life Cycle

7
 HIV Life Cycle
RNA
Reverse Protease
HIV Transcriptase
RNA RNA
RNA

RNA RNA

DNA RNA
RNA
RNA

Proviral
CD4 T -Lymphocyte DNA 8
HIV Variability

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 HIV Variability
• HIV has enormous potential for change
(mutations)

• The HIV copies in an infected person are not

all identical but are rather like a swarm of
closely related viruses.

• Reverse Transcriptase is a very error-prone

enzyme.
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 Effects of HIV Mutations
• Mostly of no consequence.

• Viral fitness increased or decreased.

• Viral infectivity/pathogenicity increased or

decreased.

• Escape from immune control.

• ARV drug resistance. 11

Immunology

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 Host Defense System
Self versus Non-Self (antigen)

Innate Adaptive
Immunity Immunity

-Skin, mucosa
B-Lymphocytes T-Lymphocytes
-Cells
White blood cells
Macrophages
-Complement
Plasma cells CD4 cells CD8 cells

High Specificity/ Memory Cells

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 Helper Function of CD4 Cells

Macrophage
T helper cell (CD4)

B Lymphocyte Cytotoxic T Lymphocyte

(CD8)
Infected cell

Antibody secreting
Killed
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(plasma) cell
 White Blood Cell Distribution
Absolute/Total Percent
cells/uL

Neutrophils 4000 55% WBC

Lymphocytes CD4 1000 30%

Lymphocytes
CD8 500
Basophils
Eosinophils
Monocytes
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 CD4 Counts in Botswana
• Uninfected: 750 cells/uL
(IQR: 560-900)

• Asymptomatic HIV-1 positive: 350 cells/uL

(IQR: 268-574)

• Patients with AIDS: 121 cells/uL

(IQR: 50-250)
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Surrogate Markers of HIV Disease

• CD4 is an indicator of the strength of the

immune system.

• Viral Load is an indicator of the amount of

viral replication.

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Natural History of
HIV Infection

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Natural History of HIV-1 Infection
Acute
Retroviral Clinical AIDS
Syndrome Latency

1-12 weeks 6-10 years 1-2 years 19

 Acute Retroviral Syndrome

1-12 weeks 8-10 years 1-2 years 20

 Acute Retroviral Syndrome
• Non-specific ‘flu-like’ symptoms;
– Fever
– Fatigue
– Pharyngitis
– Lymphadenopathy
– Rash

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 Pathogenesis of Acute HIV-1
Infection
• Initial infection of CD4 cells and macrophages
at site of exposure.
• Dissemination of infection to lymph nodes.
• Burst of viral replication results in intense
viremia.
• Development of humoral immunity (HIV-
specific antibodies).
• Development of cellular immunity (HIV-specific
CD4 and CD8 cells). 22
 Acute HIV-1 Infection

HIV-antibodies

CD4 cell count

Viral load

0 3 6 12 weeks after HIV infection23

 Clinical Latency

1-12 weeks 6-10 years 1-2 years 24

 Clinical Latency
• At CD4 cell counts over 500 cells/uL
many complications overlap with conditions
found in uninfected populations (bacterial
pneumonia, tuberculosis, minor skin
conditions), but they may be more frequent.

• At CD4 counts between 200 and 500

cells/uL other conditions and opportunistic
infections may begin to appear (Kaposi’s
sarcoma, oral/genital candidiasis, herpes
zoster, etc.). 25
 Pathogenesis of Chronic HIV-1
Infection
• High turnover of CD4 cells.
– Continuous destruction and compensatory
increased production of CD4 Lymphocytes.

• Viral load plateaus at viral set point.

• Non-specific, generalized, immune activation

resulting in immune dysfunction.

• Viral reservoirs in resting infected cells.

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Relative Control of HIV-1:
Viral Set Points
Predictor for:
- Disease progression
- Risk of transmission

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Year 1
 AIDS

1-12 weeks 6-10 years 1-2 years 28

29
Immune Evasion by HIV

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Inability to Eradicate HIV-1 Infection
• CD4 T cell decline
• CTL response inadequate
• Viral reservoir
• Viral infection in sanctuaries (brain and genito-urinary
tract)
• Viral persistence in lymphoid tissue
• Latency – archiving in resting cells

• Mutational Potential of HIV-1

• Escape of HIV from CD8 immune response and
neutralizing antibodies 31
Viral load
Variability of Response to HIV Infection

CD4 count
Typical Progressor

Time

CD4 count
Viral load

Rapid Progressor

Time 32
 Immune Response in Children
• Viral set point is higher in children.

• Disease progression similar to adults.

• 15-20% of children develop AIDS or die

within 1 year.

• 10% survive for a prolonged period (5-6

years). 33
Immune Response in Children (2)
• Because the infant’s immune system is
immature, disease progression is expressed
as CD4%.

• CD4% is the percent of total lymphocytes that

are CD4 cells.

– e.g., if total lymphocytes are 4000 cells per uL

and 1000 of these cells are CD4 cells, the CD4%
is 25%. 34
 HIV Transmission and Prevention
• Modes of Transmission
• Mucosa (genital/rectal)
• Blood (transfusion, MTCT, needle stick injury)
• Breast Feeding

• Prevention
• Avoidance of infected mucosal secretions
• Safe blood transfusion service
• Post-exposure prophylaxis
• Prevention of Mother-to-Child Transmission
• Avoidance of breast feeding

• Universal precautions
• Hand washing
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• Safe disposal of infected material
 Summary
• HIV life cycle involves transcription of viral RNA into
DNA and integration into human genome.

• Mutational potential of HIV-1 results in worldwide

diversity (subtypes), viral escape from immune
response and development of drug resistance.

• Viral replication persists throughout infection.

• Fundamental pathology is the inability of the host

immune system to eradicate HIV infection, which results
in progressive destruction of the immune system.
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