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Immune deficiencies
and AIDS
Chapter 15
Self-Test
Questions:
Intro-A1: all
A2: 1 & 2
B1: 1 – 3, 5
B2: 1, 3, 4
B3: all
C: 1 - 5
D: all
E & F: 3
G: all
Immunodeficiencies and HIV
1
What causes immunodeficiencies?
1O vs 2O immunodeficiencies
Examples of 1O
Lymphatic
SCID
DiGeorges
Bare lymphocyte (no MHC)
Agammaglobulinemia
Myeloid
Agranulocytosis
e.g., neutropenia
Nude mouse
Immunodeficiencies and HIV
2
What are causes of 2O Immunodeficiencies?
-- acquired later in life
Malignancies
Nutritional deficiencies
Stress
Age
Drugs
Infections
Immunodeficiencies and HIV
3
What is the structure of HIV?
-- HIV is a ‘retrovirus’
Structure of HIV
Envelope
GP120 receptor
Inner protein layer
Capsid
RNA
RT & integrase enzymes
What cells does HIV infect?
Host cell ligands
CD4
Chemokine receptors
CCR5
CXCR4
Target cells
M-tropic: 1O macrophages (CCR5)
T-tropic: 1O TH cells (CXCR4)
Immunodeficiencies and HIV
4
What genes are present in
the HIV genome?
9 genes, coding for 16 proteins
Functions
Structural
Enzymatic
Regulatory
Precursor proteins
HIV protease
Immunodeficiencies and HIV
5
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 & budding
McGraw-Hill
HIV Life Cycle
Immunodeficiencies and HIV
6
How does HIV
Affect the immune
response?
Why do these responses decline?
Has effects on. . .
TH – 1O target
B-cells
Tc and CTLs
T-cell syncytia
Immunodeficiencies and HIV
7
How does the immunological
response change during the
course of an HIV infection?
1. Acute phase
2. Chronic phase
3. AIDS
Immunodeficiencies and HIV
8
What are the clinical categories
of an HIV infection?
Clinical Presentation
Kaposi
sarcoma
A: typically mild symptoms
B : moderate symptoms
C : severe disease
Immunological Status
1: >= 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
Candidiasis
Immunodeficiencies and HIV
9
Control of viral infections
Antibiotics don’t work
Synthetic drugs
-- treat symptoms
-- slow viral replication
Anti-HIV therapy – 4 classes
Reverse transcriptase inhibitors
1a) nucleotide analogs
e.g., AZT, ddl, ddc, etc
1b) non-analog inhibitors
e.g., nevirapine, etc
2) protease inhibitors
3) Fuzeon
-- newest drug
-- fusion inhibitor
Combinational drug therapy (HAART)
McGraw-Hill
HIV Treatments
Immunodeficiencies and HIV
10
Why is controlling
AIDS in the
developing world so
difficult?
Genetic variability
HIV-1 and HIV-2
HIV-1 Clades
Mode of transmission
C&E mainly heterosexual
Weak health care and
educational systems
Cost of AIDS drugs
Complexity of drug regimen
Immunodeficiencies and HIV
11
Will there be an AIDS
vaccine anytime soon?
Challenges
Antigenic variability
Difficulty getting CTL
and humoral response
Difficulty generating mucosyl-immunity
Use of a live-attenuated vaccine is risky
etc.
“Broadly neutralizing” Abs (Science 333:1593- 2011)
Can passively block infection in primates
Infrequently arise among humans
All studied bind to GP120 CD4 binding site
Require affinity maturation
What’s the implication of this for vaccine production?!!!!
Affinity-matured sequences
from BN-Ab VH chains
Immunodeficiencies and HIV
12