Transcript CD4 and HIV - Chulabhorn Research Institute

CD4 and HIV
by
Tan Swee Huang
AIT UEEM
ED19.98 Bioengineering and Environmental Health
Outline
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Life Cycle of HIV
Major Target Cells for HIV
Cell surface receptors for HIV
CD4
CD4- gp120 Interactions
Theories of Immune System cell Loss
in HIV infection
• Challenges Ahead
Life Cycle of HIV
Steps in Viral Replication
1. Attachment/Entry
2. Reverse Transcription & DNA
Synthesis
3. Transport to Nucleus
4. Integration
5. Viral Transcription
6. Viral Protein Synthesis
7. Assembly of Virus
8. Release of Virus
9. Maturation
Major Target Cells for HIV
• Infection
– CD4+ T-Lymphocytes
– CD4+ monocytes and macrophages
(inclu. microglia)
– CD4+ Dendritic cells (inclu.
Langerhans cells)
Major Target Cells for HIV
• Attachment/Presentation
– Folicular dendritic cells in lymph
nodes
– M cells on Peuyer’s patches
– Galactosylcerebroside positive cells
in brain and gut
Cell surface receptors for HIV
(Attachment, Entry, Fusion)
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CD4 differentiation antigen
Galactosylcerebroside glycolipid
LFA-1 Adhesion receptor
Fc receptors
Complement receptors
Proteinases (?)
CD4
• Cluster Designation 4
• Expressed on T-helper lymphocytes
– signaling other cells in immune system
– healthy: 800~1200 CD4+ T cells/mm3
– AIDS: < 200 CD4+ T cells/mm3
• less densely on macrophages, dendritic
cell* and microglial cells
CD4 - gp 120 Interaction
• Virus peptide approaches CD4
• Virus docking
• conformational changes (proteolytic
cleavage of V3 loop exposes the
fudigenc domain of gp41)
• fusion of virion envelope
Theories of Immune System
cell Loss in HIV infection
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Direct cell killing
Syncytia formation
Apoptosis
Innocent bystanders
Anergy
Superantigens
Damage to Precursor cells
Challenges Ahead
• Role of CD8+ T cells
– attack and killed infected cells
– secrete soluble factors that suppress
HIV replication (e.g. RANTES, MIP-1alpha,
MIP-1 beta)
Challenges Ahead
• Blocking gp 120 binding to CD4
– problem: cause hemorrhaging
• Secondary receptor for fusion (fusion
cofactor/fusin)
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new target for anti-HIV drug (JM3100)
first true animal model for HIV infection
not effective on macrophages infection
function unknown
Challenges Ahead
• Antibodies to V3-loop on gp 120
– differ from macrophages to lymphocytes
• 5~10% patients show no symptoms & stable
CD4+ T cell counts
– chemokines(?)
– genetic