1. KITSO AIDS Training Program
KITSO AIDS Training Program Lecture 2: HIV Pathophysiology and Epidemiology delivered by Dr. Daniel J. Baxter, ACHAP
HIV Pathophysiology and Epidemiology

2. KITSO AIDS Training Program
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.
HIV Pathophysiology and Epidemiology

3. KITSO AIDS Training Program
Worldwide Distribution of
HIV-1 Viral Subtypes B B C
Northern America:
Western Europe:
Eastern Europe &
Central Asia:
920,000
540,000
700,000
C,E
Eastern Asia & the
Northern Africa &
Pacific:
640,000
Caribbean:
Middle East:
390,000
400,000
Southern &
Southeastern C
Asia:
Latin America:
7 million
1.4 million
Sub -
Saharan
Africa: B
25.3 million
Australia &
New Zealand: :
15,000 B
Source: WHO/UNAIDS (data as of December, 2000)
HIV Pathophysiology and Epidemiology

4. KITSO AIDS Training Program
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.
HIV Pathophysiology and Epidemiology

5. Human Immunodeficiency Virus
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Human Immunodeficiency Virus
HIV Pathophysiology and Epidemiology

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HIV-1 Particle
HIV Pathophysiology and Epidemiology

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HIV Life Cycle
HIV Pathophysiology and Epidemiology

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HIV Life Cycle
RNA
Reverse Transcriptase
Protease
HIV
RNA
RNA
RNA
CD4
RNA
RNA
RNA
DNA
RNA
RNA
Proviral
DNA
CD4 T -Lymphocyte
HIV Pathophysiology and Epidemiology

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HIV Variability
HIV Pathophysiology and Epidemiology

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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.
HIV Pathophysiology and Epidemiology

11. Effects of HIV Mutations
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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.
HIV Pathophysiology and Epidemiology

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Immunology
HIV Pathophysiology and Epidemiology

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Host Defense System
Self versus Non-Self (antigen)
Innate Immunity
Adaptive Immunity
B-Lymphocytes
T-Lymphocytes
-Skin, mucosa
-Cells
White blood cells
Macrophages
-Complement
CD4 cells
CD8 cells
Plasma cells
High Specificity/ Memory Cells
HIV Pathophysiology and Epidemiology

14. Helper Function of CD4 Cells
KITSO AIDS Training Program
Helper Function of CD4 Cells
Macrophage
T helper cell (CD4)
B Lymphocyte
Cytotoxic T Lymphocyte (CD8)
Infected cell
Antibody secreting (plasma) cell
Killed
HIV Pathophysiology and Epidemiology

15. White Blood Cell Distribution
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White Blood Cell Distribution
Absolute/Total
cells/uL
Percent
Neutrophils
4000
55% WBC
Lymphocytes
CD4
CD8
1000
500
30% Lymphocytes
Basophils Eosinophils
Monocytes
HIV Pathophysiology and Epidemiology

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CD4 Counts in Botswana
Uninfected: 750 cells/uL
(IQR: )
Asymptomatic HIV-1 positive: 350 cells/uL (IQR: )
Patients with AIDS: 121 cells/uL
(IQR: )
HIV Pathophysiology and Epidemiology

17. Surrogate Markers of HIV Disease
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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.
HIV Pathophysiology and Epidemiology

18. Natural History of HIV Infection
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Natural History of HIV Infection
HIV Pathophysiology and Epidemiology

19. Natural History of HIV-1 Infection
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Natural History of HIV-1 Infection
Acute Retroviral Syndrome
Clinical
Latency
AIDS
Viral Load CD4 count
1-2 years
1-12 weeks
6-10 years
HIV Pathophysiology and Epidemiology

20. Acute Retroviral Syndrome
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Acute Retroviral Syndrome
Viral Load CD4 count
1-12 weeks
8-10 years
1-2 years
HIV Pathophysiology and Epidemiology

21. Acute Retroviral Syndrome
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Acute Retroviral Syndrome
Non-specific ‘flu-like’ symptoms;
Fever
Fatigue
Pharyngitis
Lymphadenopathy
Rash
HIV Pathophysiology and Epidemiology

22. Pathogenesis of Acute HIV-1 Infection
KITSO AIDS Training Program
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).
HIV Pathophysiology and Epidemiology

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Acute HIV-1 Infection
HIV-antibodies
Viral Load CD4 count
CD4 cell count
Viral load
weeks after HIV infection
HIV Pathophysiology and Epidemiology

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Clinical Latency
Viral Load CD4 count
1-2 years
1-12 weeks
6-10 years
HIV Pathophysiology and Epidemiology

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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.).
HIV Pathophysiology and Epidemiology

26. Pathogenesis of Chronic HIV-1 Infection
KITSO AIDS Training Program
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.
HIV Pathophysiology and Epidemiology

27. Relative Control of HIV-1: Viral Set Points
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Relative Control of HIV-1: Viral Set Points
Predictor for:
Disease progression
Risk of transmission
Viral load
Year 1
HIV Pathophysiology and Epidemiology

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Viral Load CD4 count
1-2 years
1-12 weeks
6-10 years
HIV Pathophysiology and Epidemiology

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HIV Pathophysiology and Epidemiology

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Immune Evasion by HIV
HIV Pathophysiology and Epidemiology

31. Inability to Eradicate HIV-1 Infection
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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
HIV Pathophysiology and Epidemiology

32. Variability of Response to HIV Infection
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Variability of Response to HIV Infection
Typical Progressor
Viral load
CD4 count
Time
Rapid Progressor
CD4 count
Viral load
Time
HIV Pathophysiology and Epidemiology

33. Immune Response in Children
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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).
HIV Pathophysiology and Epidemiology

34. Immune Response in Children (2)
KITSO AIDS Training Program
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%.
HIV Pathophysiology and Epidemiology

35. HIV Transmission and Prevention
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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
Safe disposal of infected material
HIV Pathophysiology and Epidemiology

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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.
HIV Pathophysiology and Epidemiology