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KITSO AIDS Training Program

Lecture 2:

HIV Pathophysiology and Epidemiology

delivered byDr. 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

Australia &New Zealand:

15,000

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

Caribbean:390,000

Eastern Europe &Central Asia:

700,000

Eastern Asia & thePacific: 640,000

Latin America:1.4 million

Northern Africa &Middle East:

400,000

Northern America:920,000

Southern & Southeastern

Asia:

7 million

Western Europe:540,000

Sub - Saharan Africa:

25.3 million:

B

B

C

BC

C,E

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

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HIV Life Cycle

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CD4

HIV Life Cycle

DNA

RNA

Reverse Transcriptase

RNA

HIVRNA

Protease

CD4 T -Lymphocyte

RNA

Proviral DNA

RNA

RNA

RNA

RNA

RNA

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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

Adaptive Immunity

Plasma cells CD4 cells CD8 cells

B-Lymphocytes T-Lymphocytes-Skin, mucosa-Cells White blood cells Macrophages

-Complement

High Specificity/ Memory Cells

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Helper Function of CD4 Cells

B Lymphocyte

T helper cell (CD4)Macrophage

Antibody secreting (plasma) cell

Infected cell

Cytotoxic T Lymphocyte (CD8)

Killed

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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

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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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AIDS Clinical

Latency

Acute Retroviral Syndrome

Natural History of HIV-1 Infection

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

Vir

al L

oad

C

D4

cou

nt

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Acute Retroviral Syndrome

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

Vir

al L

oad

CD

4 co

un

t

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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).

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Acute HIV-1 Infection

Viral load

CD4 cell count

0 3 6 12 weeks after HIV infection

HIV-antibodies

V

iral

Lo

ad

CD

4 co

un

t

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Clinical Latency

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

Vir

al L

oad

C

D4

cou

nt

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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.).

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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

Year 1

Vir

al lo

ad

Predictor for:- Disease progression- Risk of transmission

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AIDS

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

Vir

al L

oad

C

D4

cou

nt

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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

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Typical Progressor

Rapid Progressor

Vir

al l

oad

Vir

al l

oad

CD

4 co

un

tC

D4

cou

nt

Variability of Response to HIV Infection

Time

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%.

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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

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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.