1. 1 بسم الله الرحمن الرحيم The immunology of HIV infection In : Medical, health and social aspects of HIV/AIDS Sayad B. M.D, MPH 2003

2. 2 Entry of HIV to target cells:(1) Receptors & Ligands Receptors & Ligands HIV receptor and co-receptors HIV receptor and co-receptors CC-chemokines and chemokin receptors CC-chemokines and chemokin receptors Chemokine receptors as HIV co-receptors: Chemokine receptors as HIV co-receptors: CCR5 CCR5 CXCR4 CXCR4 Others(CCR1,CCR2b,CCR3) Others(CCR1,CCR2b,CCR3)

3. 3 Entry of HIV to target cells:(2) HIV strains and their’s co-receptors: HIV strains and their’s co-receptors: M-tropic strain :CCR5 M-tropic strain :CCR5 T-tropic strain: CXCR4 T-tropic strain: CXCR4 Natural ligands of CCR5: Natural ligands of CCR5: MIP-1a MIP-1a MIP-1b MIP-1b RANTES RANTES Natural ligand of CXCR4: Natural ligand of CXCR4: SDF-1 SDF-1

4. 4 Entry of HIV to target cells:(3) Answer the questions: Answer the questions: 1.What is the result of HIV infection in the presence of natural ligands of HIV co-receptors? 2.Can we use chemokins as a treatment in HIV infections? 3.What is the result of CCR5 defect?

5. 5 Entry of HIV to target cells:(4) HIV co-receptor defects: HIV co-receptor defects: CCR5-delete 32 CCR5-delete 32 CCR5-delete 32/m303 CCR5-delete 32/m303 CCR2 defect CCR2 defect SDF-1 3’A SDF-1 3’A

6. 6 Entry of HIV to target cells:(5) Expression of HIV-coreceptors: Expression of HIV-coreceptors: For example CCR5: For example CCR5: Upregulation:with IL-2 Upregulation:with IL-2 Downregulation:with CD3,CD28 stimulation Downregulation:with CD3,CD28 stimulation

7. 7 Entry of HIV to target cells:(6) New therapeutic strategies: New therapeutic strategies: Chemokine analogues Chemokine analogues Molecular genetic approach Molecular genetic approach

8. 8 Immune responses to HIV: Immune responses is severe and universal Immune responses is severe and universal Some responses maybe harmful to the host Some responses maybe harmful to the host

9. 9 Immune dysfunction during HIVinfection: CD4+ Tcells CD4+ Tcells CD8+ Tcells CD8+ Tcells Monocytes-macrophages Monocytes-macrophages Dendritic cells Dendritic cells B lymphocytes B lymphocytes Neutrophils Neutrophils Natural killer cells Natural killer cells

10. 10 CD4+ Tcells dysfunction: Direct mechanisms: Direct mechanisms: Accumulation of unintegrated viral DNA Accumulation of unintegrated viral DNA Interference with cellular RNA processing Interference with cellular RNA processing Intracellular gp120 autofusion events Intracellular gp120 autofusion events Viral budding Viral budding Elimination of HIV infected cells Elimination of HIV infected cells Indirect mechanisms: Indirect mechanisms: Syncytium formation Syncytium formation Autoimminity Autoimminity Superantigenetic stimulation Superantigenetic stimulation Innocent by stander killing Innocent by stander killing Apoptosis Apoptosis

11. 11 CD8+ Tcells: Roles in defense against HIV infection Roles in defense against HIV infection Dysregulation of CD8+ Tcell numbers Dysregulation of CD8+ Tcell numbers Cytotoxicity dysfunction Cytotoxicity dysfunction Abnormal phenotypes: Abnormal phenotypes: HLA-DR with CD38 HLA-DR with CD38 HLA-Drwithout CD38 HLA-Drwithout CD38

12. 12 Monocytes-Macrophages: Roles in the immunophathogenesis of HIV Roles in the immunophathogenesis of HIV Decreased MHC-II expression Decreased MHC-II expression Decreased IL-12 secretion Decreased IL-12 secretion Increased IL-10 secretion Increased IL-10 secretion Defects in the ADCC Defects in the ADCC Abnormal Ag uptake Abnormal Ag uptake Abnormal oxidative burst Abnormal oxidative burst Abnormal chemotaxis Abnormal chemotaxis

13. 13 B cells: Hypergammaglobulinemia Hypergammaglobulinemia B cells hyperactivation B cells hyperactivation Decreased ability to response to Ag Decreased ability to response to Ag Decreasd HLA-DR Expression Decreasd HLA-DR Expression Secretion of TNF-a and IL-6 Secretion of TNF-a and IL-6

14. 14 Neutrophils: Increased in NBT reduction Increased in NBT reduction Increased oxydative capacity with GM-CSF Increased oxydative capacity with GM-CSF Increased actin polimerization Increased actin polimerization Increased H 2 O 2 production Increased H 2 O 2 production Increased oxygen radical production Increased oxygen radical production Decreased opsonization activity Decreased opsonization activity Accelerated apoptosis Accelerated apoptosis Overproduction of TNF-a,IL-6 Overproduction of TNF-a,IL-6

15. 15 Natural Killer Cells: Roles in defense against HIV: Roles in defense against HIV: ADCC ADCC Secretion of inhibtory chemokines Secretion of inhibtory chemokines Decreased CD16+/CD56+ subpapulation Decreased CD16+/CD56+ subpapulation Decreased ability of killing targets Decreased ability of killing targets

16. 16 Dendritic cells: Roles in defense against HIV Roles in defense against HIV Impair the ability to activate Tcells Impair the ability to activate Tcells

17. 17 Manifestations of an activated immune system in HIV: Hyperactivation of Bcells Hyperactivation of Bcells Hypergammaglobulinemia Hypergammaglobulinemia Spuntaneous lymphocytic proliferation Spuntaneous lymphocytic proliferation Activation of monocytes with cytokines Activation of monocytes with cytokines Increased activation markers on Tcells Increased activation markers on Tcells Follicular hyperplasia Follicular hyperplasia Autoimmunity Autoimmunity

18. 18 Cytokines and HIV infection: Cytokines that cause increased replication: Cytokines that cause increased replication: TNF-a,TNF-b-, G-CSF, GM-CSF TNF-a,TNF-b-, G-CSF, GM-CSF IL-1b, IL-2, IL-3, IL-6 IL-1b, IL-2, IL-3, IL-6 IL-7, IL-12, IL-15 IL-7, IL-12, IL-15 Cytokines that cause decreased replication: Cytokines that cause decreased replication: INF-a, INF-b, IL-16 INF-a, INF-b, IL-16 Cytokines that cause increased or decreased replication: Cytokines that cause increased or decreased replication: IL-4, IL-10, IL-13 IL-4, IL-10, IL-13 INF-Y TGF-b INF-Y TGF-b

19. 19 Cytokines and therapeutic interventions: TNF inhibition with pentoxyfylline TNF inhibition with pentoxyfylline IL-2 plus HAART for increase CD4+T cells IL-2 plus HAART for increase CD4+T cells IL-2 plus IL-16 for expansion of CD4+T cells IL-2 plus IL-16 for expansion of CD4+T cells

20. 20 شاد باشيـــد