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بسم الله الرحمن بسم الله الرحمن الرحيمالرحيم

The immunology of The immunology of

HIV infectionHIV infection

In :In :

Medical, health and social Medical, health and social aspects of HIV/AIDSaspects of HIV/AIDS

Sayad B. M.D, MPH

2003

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Entry of HIV to target cells:(1)Entry of HIV to target cells:(1)

Receptors & Ligands Receptors & Ligands HIV receptor and co-receptorsHIV receptor and co-receptors CC-chemokines and chemokin receptorsCC-chemokines and chemokin receptors Chemokine receptors as HIV co-receptors:Chemokine receptors as HIV co-receptors:

CCR5CCR5 CXCR4CXCR4 Others(CCR1,CCR2b,CCR3)Others(CCR1,CCR2b,CCR3)

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Entry of HIV to target cells:(2) Entry of HIV to target cells:(2)

HIV strains and their’s co-receptors:HIV strains and their’s co-receptors: M-tropic strain :CCR5M-tropic strain :CCR5 T-tropic strain: CXCR4T-tropic strain: CXCR4

Natural ligands of CCR5:Natural ligands of CCR5: MIP-1aMIP-1a MIP-1bMIP-1b RANTESRANTES

Natural ligand of CXCR4: Natural ligand of CXCR4: SDF-1SDF-1

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Entry of HIV to target cells:(3)Entry of HIV to target cells:(3)

Answer the questions:Answer the questions:1.What is the result of HIV infection 1.What is the result of HIV infection in the presence of natural ligands of in the presence of natural ligands of HIV co-receptors?HIV co-receptors?

2.Can we use chemokins as a 2.Can we use chemokins as a treatment in HIV infections?treatment in HIV infections?

3.What is the result of CCR5 defect?3.What is the result of CCR5 defect?

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Entry of HIV to target cells:(4)Entry of HIV to target cells:(4)

HIV co-receptor defects:HIV co-receptor defects: CCR5-delete 32CCR5-delete 32 CCR5-delete 32/m303CCR5-delete 32/m303 CCR2 defectCCR2 defect SDF-1 3’ASDF-1 3’A

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Entry of HIV to target cells:(5)Entry of HIV to target cells:(5)

Expression of HIV-coreceptors:Expression of HIV-coreceptors:For example CCR5:For example CCR5:

Upregulation:Upregulation: with IL-2with IL-2 Downregulation:Downregulation: with CD3,CD28 with CD3,CD28

stimulationstimulation

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Entry of HIV to target cells:(6)Entry of HIV to target cells:(6)

New therapeutic strategies:New therapeutic strategies:Chemokine analoguesChemokine analoguesMolecular genetic approachMolecular genetic approach

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Immune responses to HIV:Immune responses to HIV:

Immune responses is severe and Immune responses is severe and universaluniversal

Some responses maybe harmful Some responses maybe harmful to the hostto the host

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Immune dysfunction during Immune dysfunction during HIVinfection:HIVinfection:

CD4+ TcellsCD4+ Tcells CD8+ TcellsCD8+ Tcells Monocytes-macrophagesMonocytes-macrophages Dendritic cellsDendritic cells B lymphocytesB lymphocytes NeutrophilsNeutrophils Natural killer cellsNatural killer cells

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CD4+ Tcells dysfunction:CD4+ Tcells dysfunction: Direct mechanisms:Direct mechanisms:

Accumulation of unintegrated viral DNAAccumulation of unintegrated viral DNA Interference with cellular RNA processingInterference with cellular RNA processing Intracellular gp120 autofusion eventsIntracellular gp120 autofusion events Viral buddingViral budding Elimination of HIV infected cellsElimination of HIV infected cells

Indirect mechanisms:Indirect mechanisms: Syncytium formationSyncytium formation AutoimminityAutoimminity Superantigenetic stimulationSuperantigenetic stimulation Innocent by stander killingInnocent by stander killing ApoptosisApoptosis

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CD8+ Tcells:CD8+ Tcells:

Roles in defense against HIV infectionRoles in defense against HIV infection Dysregulation of CD8+ Tcell numbersDysregulation of CD8+ Tcell numbers Cytotoxicity dysfunctionCytotoxicity dysfunction Abnormal phenotypes:Abnormal phenotypes:

HLA-DR with CD38HLA-DR with CD38 HLA-Drwithout CD38HLA-Drwithout CD38

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Monocytes-Macrophages:Monocytes-Macrophages:

Roles in the immunophathogenesis of HIVRoles in the immunophathogenesis of HIV Decreased MHC-II expressionDecreased MHC-II expression Decreased IL-12 secretionDecreased IL-12 secretion Increased IL-10 secretionIncreased IL-10 secretion Defects in the ADCCDefects in the ADCC Abnormal Ag uptakeAbnormal Ag uptake Abnormal oxidative burstAbnormal oxidative burst Abnormal chemotaxisAbnormal chemotaxis

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B cells:B cells:

HypergammaglobulinemiaHypergammaglobulinemia B cells hyperactivationB cells hyperactivation Decreased ability to response to AgDecreased ability to response to Ag Decreasd HLA-DR ExpressionDecreasd HLA-DR Expression Secretion of TNF-a and IL-6Secretion of TNF-a and IL-6

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Neutrophils:Neutrophils:

Increased in NBT reductionIncreased in NBT reduction Increased oxydative capacity with GM-CSFIncreased oxydative capacity with GM-CSF Increased actin polimerizationIncreased actin polimerization Increased HIncreased H22OO22 production production Increased oxygen radical productionIncreased oxygen radical production Decreased opsonization activityDecreased opsonization activity Accelerated apoptosisAccelerated apoptosis Overproduction of TNF-a ,IL-6Overproduction of TNF-a ,IL-6

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Natural Killer Cells:Natural Killer Cells:

Roles in defense against HIV:Roles in defense against HIV: ADCCADCC Secretion of inhibtory chemokinesSecretion of inhibtory chemokines

Decreased CD16+/CD56+ subpapulationDecreased CD16+/CD56+ subpapulation Decreased ability of killing targetsDecreased ability of killing targets

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Dendritic cells:Dendritic cells:

Roles in defense against HIVRoles in defense against HIV Impair the ability to activate TcellsImpair the ability to activate Tcells

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Manifestations of an activated Manifestations of an activated immune system in HIV:immune system in HIV:

Hyperactivation of BcellsHyperactivation of Bcells HypergammaglobulinemiaHypergammaglobulinemia Spuntaneous lymphocytic proliferationSpuntaneous lymphocytic proliferation Activation of monocytes with cytokinesActivation of monocytes with cytokines Increased activation markers on TcellsIncreased activation markers on Tcells Follicular hyperplasiaFollicular hyperplasia AutoimmunityAutoimmunity

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Cytokines and HIV infection:Cytokines and HIV infection:

Cytokines that cause increased replication:Cytokines that cause increased replication: TNF-a,TNF-b-, G-CSF, GM-CSFTNF-a,TNF-b-, G-CSF, GM-CSF IL-1b, IL-2, IL-3, IL-6IL-1b, IL-2, IL-3, IL-6 IL-7, IL-12, IL-15IL-7, IL-12, IL-15

Cytokines that cause decreased replication:Cytokines that cause decreased replication: INF-a, INF-b, IL-16INF-a, INF-b, IL-16

Cytokines that cause increased or decreased Cytokines that cause increased or decreased replication:replication:

IL-4, IL-10, IL-13IL-4, IL-10, IL-13 INF-Y TGF-bINF-Y TGF-b

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Cytokines and therapeutic Cytokines and therapeutic interventions: interventions:

TNF inhibition with pentoxyfyllineTNF inhibition with pentoxyfylline IL-2 plus HAART for increase CD4+T cellsIL-2 plus HAART for increase CD4+T cells IL-2 plus IL-16 for expansion of CD4+T cellsIL-2 plus IL-16 for expansion of CD4+T cells

2020

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