Transcript CD4+ T-Cell

Immune Pathogenesis
of HIV
Pathogenesis:
The way that something causes disease.
Immune pathogenesis is how the virus (HIV) interacts with the immune
system, what happens to the immune system and how.
Project Inform
Information,
Inspiration and
Advocacy for People
Living with
HIV/AIDS.
205 13th Street #2001
San Francisco, CA 94103
Website: http://www.projectinform.org
Hotline: 415-558-9051 or 800-822-7422
Project Inform © 2005
1
HIV Disease
 Caused by Human Immunodeficiency Virus (HIV)
 Disables the immune system in many complex
ways
 HIV infects CD4+ (T4) and other immune cells
 CD4+ cells are important immune cells

Key ‘mediator’ of immune responses’

Communicating through chemicals (called ‘cytokines’)
CD4+ cells mediate humoral (antibody) and cellular
immune responses
© Project Inform 2005
2
CD4+ Cells:
Mediators of Immune Responses
Bone Marrow
B-cells
B
B
IL-4
IL-6
IL-10
B
B
IL-2
IL-12
INF-gamma
CD4
Th0
CD4
Th2
CD4
Th1
B
T
B
Humoral
Cellular
• B-Cells
• Antibodies
• Attacks “critters”
outside of Cell
• CD8+ cells, NK cells
• Cell to Cell killing
• Attacks “critters”
inside of cells
(e.g. free virus in blood)
(e.g. HIV infected cells)
T
T
T
T
Thymus
T-cells (e.g. CD4+ and CD8+)
© Project Inform 2005
3
HIV Disease (continued)
 Infected CD4+ cells may die or become dysfunctional
Humoral
Cellular
IL-4
IL-6
IL-10
IL-2
IL-12
INF-g
CD4+ T-Cell




Antigen Presenting Cell
(e.g. dendritic cell, macrophage)
HIV also infects other immune cells (e.g. antigen presenting cells)
Virus reproduces, infecting cells throughout the body
Immune system is gradually weakened
Body loses the ability to fight off infections
© Project Inform 2005
4
HIV Disease (continued)

Co-factors may further weaken the immune system

Other sexually transmitted diseases and active infections
Active infection can increase HIV replication (HIV RNA increases 100 fold+)

Stress
Chemicals released destroys (involutes) thymus and weaken cell walls

Poor nutrition
Early signs of nutritional deficiencies
Deficiencies have similar symptoms as early signs of HIV disease


Lifestyle Factors (e.g. substance use, poor sleeping habits, etc.)
Acquired Immune Deficiency Syndrome (AIDS) is the
advanced stage of HIV disease
© Project Inform 2005
5
1500
and up
CD4+ Cell Ranges
Normal
Range
 Normal Range (500-1500+)
 Predictive Range (below 500)
Changes in CD4+ counts become ‘meaningful’
 Data supports intervention (200 to 350)


Gray Zone For Therapy (350+)

Guidelines suggest either Tx or no Tx
depending on HIV RNA & preference
 Limited data on use of Tx in this range
500
Predictive
Range
 Lowest Range (below 200)

Increased Risk for opportunistic infections
*Note: Trends are most important
*Note: Number does not equal function
© Project Inform 2005
200
100
50
0
Lowest
Range
6
Immunopathogenesis
of HIV Infection
Acute Syndrome
Development of Antibodies (seroconversion)
Early
Early
Intermediate
CD4+ > 500
CD4+ Count
Viral Activity
Intermediate
CD4+ 200-500
Advanced
CD4+ <200
High Burst of
Viral Activity
Infection with HIV
TIME
© Project Inform 2005
Onset of Symptoms
7
Immune Pathogenesis
Population-based information
provides insights into disease,
but each person experiences
HIV disease uniquely
© Project Inform 2005
8
Early Infection/
Acute Syndrome
Development of Antibodies
(seroconversion)
Early
 Burst of viral replication
 Wide distribution of virus
 “Seeding” of virus in lymph tissue

Some believe that this early stage is very
important and may determine the course of
disease in each individual
 Control of virus is probably not only due to
immune response (cellular and humoral) but
also to ‘sequestration’ of virus in lymph tissue
High Burst of
Viral Activity
Infection with HIV
© Project Inform 2005
9
Early Intermediate (CD4+ >500)
Clinical Latency?
 Virus is ‘trapped’ in follicular dendritic cells
(FDC)
 Dendritic cells act as a filter and central
clearing house for ‘antigen presentation’

Early
Intermediate
CD4+ > 500
Unfortunately, HIV collects in large number
and use FDC as a ‘central’ infection center
 CD4+ cells, macrophages and monocytes
become infected when traveling through the
lymph nodes
 Virus levels in lymph tissue are generally much
higher than what is seen in the blood/plasma
© Project Inform 2005
10
Follicular Dendritic Cells
 The “string mops” of the immune system, sweeping up ‘dirt’
that needs to be dealt with
 “Critters” moving through lymph nodes and are ‘caught’ in
FDC network
 CD4+ and other cells also move through lymph nodes to see
what kind of “critters” need to be dealt with
© Project Inform 2005
11
Intermediate (CD4+ 200-500)
 Structure and function of lymph nodes
begin to degrade due to high level of viral
activity
 Beginning to lose follicular dendritic cells
Are “strings” falling off the mop?
 Do FDCs become infected by HIV?
 Do FDCs die for unknown reasons?

Intermediate
CD4+ 200-500
 Clinically: Minor problems begin to worsen
(e.g. herpes, genital warts, thrush), blood
tests begin to show abnormalities.
© Project Inform 2005
12
Lymph Node “Architecture”
Deteriorated lymph node:



FDC are scattered throughout
Cotton ball network is ripped apart
Decrease number of FDCs
Healthy lymph node:



Arranged like an egg
FDC form the yolk in an intricate ‘network’
Network is like a cotton ball
© Project Inform 2005
13
Advanced Disease
Onset of Severe Symptoms
 Complete ‘burn out’ of lymph node centers?

Some studies say no, even in advanced
disease. Much that is not wholly understood
 Loss or dysfunction of many cell types

CD4+ and CD8+ cells, FDC, B cells,
macrophages, others
 Virus levels similar in lymph node and
blood/plasma
 Possible changes in virus (M-tropic to Ttropic, syncitia inducing)
 Immune system more resilient than we
thought
Advanced
CD4+ <200
Onset of Symptoms
© Project Inform 2005
14
Diversity of Immune Cells
 Active vs. Resting cells
 HIV is a retrovirus, and can only reproduce from
activated (e.g. actively replicating) cells
 T-cell receptor diversity
 V-beta repertoire (Variable region of the beta chain
of the T-cell receptor, immunologic alphabet)
 Naïve vs. Memory
 Co-receptor expression (e.g. CKR5, CXCR4)
© Project Inform 2005
15
V-Beta Repertoire
Naïve and Memory Cells

Specificity of cell is dependent on the
composition of the T-cell Receptor (TCR)
 The greater the ‘repertoire’ of TCRs, larger
the diversity of cells and function
P C M F H B
P C M F H B
“Naïve” cells are “rookies” in the immune
system army
 “Memory” cells are “veterans”, which
respond more quickly and potently

© Project Inform 2005
16
Co-receptors
 2 ‘receptors’ are necessary
‘doorways’ for HIV to infect a cell
(CD4+ plus chemokine receptors)
Rantes, MIP1a, MIP1b
SDF1, MDC
 Chemokines (chemicals produced
by immune cells)
block the doorways
 Genetic alterations in receptors
may inhibit HIV from using them to
infect cells (CCR5 32bp-delta)
 NSI virus uses R5; SI virus uses X4
© Project Inform 2005
CKR5
CXCR4
Others...
CD4 receptor
17
Emerging Information
Plasma HIV RNA
CD4+ T cell count
Viral Divergence from “founder strain”
CD4+ cells in GALT
Viral Diversity
Immune activation (esp CD8+ cell activation)
CXCR4 or “X4” virus
Dual tropic – X4/R5 virus
© Project Inform 2005
18
Acute Infection/Early Disease
(Emerging Information)

Within weeks of initial infection:






~75% depletion of “memory” CD4+ cell in gut
Destruction of gut-associated lymphoid tissue
(GALT) “architecture”
~50% loss of total body “memory” CD4+ cells
Initial infection typically with CCR5 or “R5”
type of virus
Virus closely resembles “founder strain”
Virus population not diverse
CD4+ T cell count
Plasma HIV RNA
CD4+ cells in GALT
Viral Divergence from “founder strain”
Immune activation (esp CD8+ cell activation)
Viral Diversity
© Project Inform 2005
19
Early Intermediate and Intermediate
(Emerging Information)





Rising levels of immune activation
(not viral load) predicts rate of
CD4+ cell loss
Continued destruction of GALT
Increased divergence from initial
infecting strain
Increased viral diversity (believed
to be due to escape from cellular
immune responses)
Possible rise of dual tropic virus
Plasma HIV RNA
Viral Divergence from “founder strain”
CD4+ T cell count
Viral Diversity
CD4+ cells in GALT
CXCR4 or “X4” virus
Immune activation (esp CD8+ cell activation)
© Project Inform 2005
Dual tropic – X4/R5 virus
20
Advanced Disease
(Emerging Information)



High levels of immune activation
increasingly believed to be
responsible for immune
deficiency/AIDS
Rise and disappearance of X4 virus
(re-emergence of R5 virus?)
Decrease in viral diversity (possibly
due to loss of CTL, no pressure on
virus to “escape”)
Plasma HIV RNA
Viral Divergence from “founder strain”
CD4+ T cell count
Viral Diversity
CD4+ cells in GALT
CXCR4 or “X4” virus
Immune activation (esp CD8+ cell activation)
© Project Inform 2005
Dual tropic – X4/R5 virus
21
Future Directions
in AIDS Research
Project Inform
Project Inform © 2005
22
Immune Restoration: Rationale




AIDS is a disease of PRIMARY IMMUNE DEFICIENCY
caused by a virus (HIV)
Anti-HIV Therapies alone do not appear to fully
restore the immune system
Strategies that build on advances in anti-HIV therapy
and enhance immune recovery and restoration are
critical
Treatment for the major defect in HIV/AIDS, the
primary immune deficiency/dysfunction
© Project Inform 2005
23
Immune Restoration:
Areas of Focus
Environment
Number
Protection
Function
Bone Marrow
Thymus
Spleen
Lymph tissue
School
Virus
Cell
© Project Inform 2005
24
Addendum Materials:
Immune Pathogenesis
of HIV
Project Inform
Project Inform © 2005
25
The Immune Response
Antigen Presenting cells - Cells of the immune system that bring intruders
to CD4+ T cells. (e.g. macrophages
and dendritic cells
)
CD4+ T-cells (also may be called “T4 helper cells”, “T4 cells”, or less
accurately “T-cells”. CD4+ T cells mediate the immune system response.
CD4+T-cell
CD8+ T-cells - Some CD8+ T cells, when ordered by CD4+ cells will specifically
CD8+ T-cell
B-cell
seek out and destroy infected cells.
B cells - During an immune response B-cells make antibodies.
Antibodies - Antibodies are made by B-cells, they attach to “critters”, marking
them for destruction by the immune system. Antibodies are specific to the “critter”
(bacteria, virus, or other harmful toxins).
© Project Inform 2005
26
Immune Deficiency in HIV Disease
 Decreased number of lymphocytes

Initial decrease then stabilization of CD4+ cell number



Increase in activated CD4+
Depletion of CD4+ naïve cells
Initial increase in CD8+ cell number



Increase in activated CD8+ cells (CD8+CD38+/DR+)
Despite increase CD8+ cell number, poor anti-HIV responses
Decrease in CD8+ naïve cell parallels loss in CD4+
 Impairment of Cell Function

Decreased ability to produce cytokines, respond to antigens,
loss of TCR diversity & APC function, loss of B-cell function
 Increased risk of opportunistic infection
 Impairment of Immune Environment


Damage to immune tissues (LN architecture, FDC Network),
status of thymus
Evidence of immune activation

Increased CD38+/DR+ expression, increased TNF-alpha
© Project Inform 2005
27