KITSO AIDS Training Program

Lecture 2:

HIV Pathophysiology and Epidemiology

delivered by

Dr. Daniel J. Baxter, ACHAP 1

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. 2

Worldwide Distribution of HIV-1 Viral Subtypes B Northern America: 920,000 Western Europe: 540,000 B Eastern Europe & Central Asia: 700,000 C Caribbean: 390,000

:

Latin America: 1.4 million B Northern Africa & Middle East: 400,000 C Sub - Saharan Africa: 25.3 million

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

C,E Eastern Asia & the Pacific: 640,000 Southern & Southeastern Asia: 7 million Australia & New Zealand: 15,000 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 5

HIV-1 Particle 6

HIV Life Cycle

7

HIV RNA RNA

HIV Life Cycle

Reverse Transcriptase Protease RNA RNA RNA RNA DNA RNA RNA RNA Proviral DNA

CD4 T -Lymphocyte 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.

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Immunology

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Host Defense System Self versus Non-Self (antigen)

Innate

Immunity -Skin, mucosa -Cells White blood cells Macrophages Complement B-Lymphocytes

Adaptive

Immunity T-Lymphocytes Plasma cells CD4 cells CD8 cells

Helper Function of CD4 Cells Macrophage T helper cell (CD4) B Lymphocyte Cytotoxic T Lymphocyte (CD8) Infected cell Antibody secreting (plasma) cell Killed 14

White Blood Cell Distribution

Absolute/Total cells/uL Neutrophils

4000

Lymphocytes

CD4 CD8 1000 500

Basophils Eosinophils Monocytes Percent

55% WBC 30% Lymphocytes 15

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) 16

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 Syndrome Clinical Latency AIDS 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 21

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).

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Acute HIV-1 Infection

HIV-antibodies CD4 cell count Viral load

0 3 6 12 weeks after HIV infection 23

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.).

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Pathogenesis of Chronic HIV-1 Infection • High turnover of CD4 cells.

– Continuous

destruction

increased

production

and compensatory 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. 26

Relative Control of HIV-1: Viral Set Points

Predictor for

: - Disease progression - Risk of transmission 27

Year 1

AIDS

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

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Immune Evasion by HIV 30

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

Variability of Response to HIV Infection Typical Progressor

Time

Rapid Progressor

Time

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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).

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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 • Safe disposal of infected material 35

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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