HIV-1 Lifecycle (Assembly and Maturation)

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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
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
3
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.
4
Human Immunodeficiency Virus
5
HIV-1 Particle
6
HIV Life Cycle
7
HIV Life Cycle
Reverse
Transcriptase
HIV
RNA
RNA
Protease
RNA
RNA
RNA
RNA
DNA
RNA
RNA
RNA
CD4 T -Lymphocyte
Proviral
DNA
8
HIV Variability
9
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.
10
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.
11
Immunology
12
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
13
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 1000
CD8
500
Percent
55% WBC
30%
Lymphocytes
Basophils
Eosinophils
Monocytes
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.
17
Natural History of
HIV Infection
18
Natural History of HIV-1 Infection
Acute
Retroviral
Syndrome
1-12 weeks
Clinical
AIDS
Latency
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 (HIVspecific antibodies).
• Development of cellular immunity (HIV-specific
CD4 and CD8 cells).
22
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
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
25
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.
26
Relative Control of HIV-1:
Viral Set Points
Predictor for:
- Disease progression
- Risk of transmission
Year 1
27
AIDS
1-12 weeks
6-10 years
1-2 years
28
29
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
31
CD4 count
Viral load
Variability of Response to HIV Infection
Typical Progressor
Viral load
CD4 count
Time
Time
Rapid Progressor
32
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).
33
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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