Transcript HIV-1 Lifecycle (Assembly and Maturation)

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:
920,000
Western Europe:
540,000
Northern Africa &
Middle East:
400,000
Caribbean:
390,000
Latin America:
1.4 million
:
B
C
Eastern Europe &
Central Asia:
700,000
C
C,E
Eastern Asia & the
Pacific: 640,000
Southern &
Southeastern
Asia:
7 million
Sub - Saharan Africa:
25.3 million
Source: WHO/UNAIDS (data as of December, 2000)
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
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HIV-1 Particle
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HIV Life Cycle
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HIV Life Cycle
Reverse
Transcriptase
HIV
RNA
RNA
Protease
RNA
RNA
RNA
RNA
DNA
RNA
RNA
RNA
CD4 T -Lymphocyte
Proviral
DNA
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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)
Adaptive
Immunity
Innate
Immunity
-Skin, mucosa
-Cells
B-Lymphocytes
T-Lymphocytes
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
(plasma) cell
Killed
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White Blood Cell Distribution
Absolute/Total
cells/uL
Neutrophils
4000
Lymphocytes CD4 1000
CD8
500
Percent
55% WBC
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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Natural History of HIV-1 Infection
Acute
Retroviral
Syndrome
1-12 weeks
Clinical
AIDS
Latency
6-10 years
1-2 years
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Acute Retroviral Syndrome
1-12 weeks
8-10 years
1-2 years
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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 (HIVspecific 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 infection23
Clinical Latency
1-12 weeks
6-10 years
1-2 years
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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
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zoster, etc.).
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
Year 1
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AIDS
1-12 weeks
6-10 years
1-2 years
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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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CD4 count
Viral load
Variability of Response to HIV Infection
Typical Progressor
Viral load
CD4 count
Time
Time
Rapid Progressor
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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.
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