Immunodeficiencies 1

HIV and AIDSChapter 15

Self-Test Questions:Intro-A1: allA2: 1 & 2B1: 1 – 3, 5B2: 1, 3, 4B3: allC: 1 - 5D: allE & F: 3G: all

Immunodeficiencies and Cancer 2

What causes immunodeficiencies?

1O vs 2O immunodeficiencies

Examples of 1O

LymphaticSCIDDiGeorgesBare lymphocyte (no MHC)Agammaglobulinemia

MyeloidAgranulocytosis e.g., neutropenia

Nude mouse

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What are causes of 2O Immunodeficiencies?-- acquired later in life

Malignancies

Nutritional deficiencies

Stress

Age

Drugs

Infections

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What is the structure of HIV?-- HIV is a ‘retrovirus’

Structure of HIVEnvelope

GP120 receptorInner protein layerCapsidRNART & integrase enzymes

What cells does HIV infect?Host cell ligands

CD4Chemokine receptors

CCR5CXCR4

Target cellsM-tropic: 1O macrophages (CCR5)T-tropic: 1O TH cells (CXCR4)

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What genes are present in the HIV genome?

9 genes, coding for 16 proteins

FunctionsStructuralEnzymaticRegulatory

Precursor proteins

HIV protease

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How does HIV infect cells and replicate?

Infection

Receptor binding & membrane fusion

Capsid entry & dissociation

Release of RNA & enzymes-- Reverse Transcription

Provirus integration in host DNA-- integrase activity

Replication

Provirus activation

Protein and RNA synthesis-- protease activity

Virion self-assembly & buddingMcGraw-Hill

HIV Life Cycle

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How does HIVAffect the immune response?

Has effects on. . .TH – 1O targetB-cellsTc and CTLs

T-cell syncytia

Why do these responses decline?

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How does the immunological response change during the course of an HIV infection?

1. Acute phase

2. Chronic phase

3. AIDS

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What are the clinical categories of an HIV infection?

Clinical PresentationA: typically mild symptoms

B : moderate symptoms

C : severe disease

Immunological Status1: >= 500 TH cells /μl blood

2: 200 – 499 /μl

3: < 200/μl

AIDS diagnosis• HIV+• < 200 TH cells /μl blood• 1 or more AIDS associated diseases

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Clinical course of HIV infection

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Control of viral infections

Antibiotics don’t work

Synthetic drugs-- treat symptoms-- slow viral replication

Anti-HIV therapy – 4 classes

Reverse transcriptase inhibitors1a) nucleotide analogs

e.g., AZT, ddl, ddc, etc1b) non-analog inhibitors

e.g., nevirapine, etc2) protease inhibitors

3) Fuzeon -- newest drug-- fusion inhibitor

Combinational drug therapy (HAART)

McGraw-Hill HIV Treatments

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Why is controlling AIDS in the developing world so difficult?

Genetic variabilityHIV-1 and HIV-2 HIV-1 Clades

Mode of transmissionC&E mainly heterosexual

Weak health care and educational systems

Cost of AIDS drugs

Complexity of drug regimen

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Will there be an AIDS vaccine anytime soon?

Current strategiesDNA vaccinesVector based vaccines

Recent “success” with combined vaccine

ChallengesAntigenic variabilityDifficulty getting CTL and humoral responseDifficulty generating mucosyl-immunity Use of a live-attenuated vaccine is riskyEtc.