2. CD4 and HIV Tan Swee Huang AIT UEEM by ED19.98 Bioengineering and Environmental Health

3. 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

4. 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

5. Major Target Cells for HIV Infection –CD4+ T-Lymphocytes –CD4+ monocytes and macrophages (inclu. microglia) –CD4+ Dendritic cells (inclu. Langerhans cells)

6. 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

7. Cell surface receptors for HIV (Attachment, Entry, Fusion) CD4 differentiation antigen Galactosylcerebroside glycolipid LFA-1 Adhesion receptor Fc receptors Complement receptors Proteinases (?)

8. CD4 Cluster Designation 4 Expressed on T-helper lymphocytes –signaling other cells in immune system –healthy: 800~1200 CD4+ T cells/mm 3 –AIDS: < 200 CD4+ T cells/mm 3 less densely on macrophages, dendritic cell* and microglial cells

9. 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

10. Theories of Immune System cell Loss in HIV infection Direct cell killing Syncytia formation Apoptosis Innocent bystanders Anergy Superantigens Damage to Precursor cells

11. 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 )

12. Challenges Ahead Blocking gp 120 binding to CD4 –p–problem: cause hemorrhaging Secondary receptor for fusion (fusion cofactor/fusin) –n–new target for anti-HIV drug (JM3100) –f–first true animal model for HIV infection –n–not effective on macrophages infection –f–function unknown

13. 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