Transcript HIV-1 Lifecycle (Assembly and Maturation)
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
28
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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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