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CD4 and HIV by Tan Swee Huang AIT UEEM ED19.98 Bioengineering and Environmental Health Outline • • • • • • 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) • • • • • • 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 • • • • • • • 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) – – – – 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