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HIV Pathogenesis: Immune
Activation & Inflammation
HIV Research Catalyst Forum, April 21
2010
HIV Research Catalyst Forum April 21, 2010
What is Immune Activation?
• Normally a transient phenomenon, as with the flu or any
other acute infection
• All the signs of activation happen, but only for a week or
two
• Pathogen is then cleared or controlled, and activation
subsides back to baseline
• In HIV infection, activation subsides, but not back to
baseline (even in most elite controllers)
• Immune activation as measured by CD38 expression on
CD8 T cells is the strongest predictor of the pace of
disease progression
HIV Research Catalyst Forum April 21, 2010
T-Cell Development
• T cells are produced in the bone marrow then
travel to an organ called the thymus that’s just
behind your breastbone.
• In the thymus, the T-cell acquires a “CD”
surface marker that governs what type of Tcell it will be.
• The two major T-cell types are:
– CD4 helper T-cell.
– CD8 T-cells, including cytotoxic T-lymphocytes (CTLs) or killer Tcells.
HIV Research Catalyst Forum April 21, 2010
T-Cell Development
• Both CD4 and CD8 T-cells have a docking bay type
structure called a "T-cell receptor" (TCR) that can
dock with protein fragments called epitopes (from
pathogens or other sources)
• TCRs are generated in the thymus in a sort of fruit
machine process that gives each T-cell one out of 25
million or so possible TCRs.
• A newly made T-cell leaves the thymus to patrol
around the body looking for an epitope that fits its
TCR. At this stage the T-cell is called “naïve.”
HIV Research Catalyst Forum April 21, 2010
The Immune Response to Infection
• On first exposure to a virus, incoming particles
are taken up by the sentries of the immune
system, dendritic cells (DC)
• DCs can recognize pathogen-associated
molecular patterns (PAMPs) shared by many
different types of pathogens via toll-like
receptors (TLRs)
• DCs become activated (switched on) which
causes them to migrate from the site of
exposure to lymph nodes
HIV Research Catalyst Forum April 21, 2010
The Immune Response to Infection
• DCs break the pathogen down into protein fragments
(called epitopes) which are then displayed on the
outer surface by specialized molecules
• Class II HLA (also known as MHC) molecules present
epitopes to CD4 T cells
• Class I HLA molecules present epitopes to CD8 T cells
• In both cases recognition occurs via the docking bay
structure on the outside of the cell, the T cell receptor
(TCR)
HIV Research Catalyst Forum April 21, 2010
HIV Research Catalyst Forum April 21, 2010
The Immune Response to Infection
• T cells travel through lymph nodes on
string-like pathways made of fibroblastic
reticular cells (FRC), these pathways form
a complex traffic system with crossroads,
junctions and dead ends
• DCs hang out at crossroads like salesmen
trying to interest T cells in the epitopes
they have on offer
HIV Research Catalyst Forum April 21, 2010
Getting Activated
• A passing T cell that recognizes an epitope will engage in
a prolonged embrace with the DC and eventually
become activated
Video of DC
(green) and T cell
(red) interactions in
a mouse lymph
node, before and
after injection of an
antigen. Note how
the red T cells only
contact DC briefly
until antigen is
present, then
prolonged contacts
can be seen.
Celli et al. Immunity. 27:625-634
HIV Research Catalyst Forum April 21, 2010
Getting Activated
• Activated T cells divide >15 times, generating a
swarm of T cells specific for the same pathogen
epitope
• Dividing T cells switch on genes for making
important signaling and antiviral proteins
(chemokines & cytokines)
• Inflammatory cyokines and rapid T cell
expansion contribute to the symptoms during
acute infection (fever, malaise, swollen lymph
nodes)
HIV Research Catalyst Forum April 21, 2010
T Cell Subsets
• Different T cell subsets engage in different tasks,
typically defined by production of particular
cytokines
• CD4 T cells
– Type 1 (Th1): help CD8 T cells kill infected cells
– Type 2 (Th2): support production of antibodies by B
cells
– Regulatory (Treg): release immune-suppressive
cytokines to dampen the immune response
– Th17: Recently discovered subset involved in
responses to extracellular bacteria and autoimmunity
HIV Research Catalyst Forum April 21, 2010
T Cell Subsets
• CD8 T cells
– Recognize infected cells displaying pathogen
fragments on their surface
– Release cell-killing substances (perforin,
granzyme B) that puncture the cell wall and
destroy the infected cell
The CD8 T cell is the
smaller cell at the bottom
of the image that
punctures a larger
influenza virus-infected
cell and destroys it.
HIV Research Catalyst Forum April 21, 2010
Resolution & Memory
• When the infection is controlled, the majority of the
newly-produced pathogen-specific “effector” T cells are
no longer needed and die in a process called activationinduced cell death (AICD)
• Importantly, a subset of pathogen-specific T cell and B
cells survive and these are described as “memory” cells
• Memory cells have enhanced functionality compared to
naive cells and are often able prevent re-infection (with
cleared pathogens) or control a pathogen that remains in
the body (e.g. CMV, EBV, herpes zoster)
HIV Research Catalyst Forum April 21, 2010
Wherry & Ahmed, J. Virology, 78;11:5535-5545
HIV Research Catalyst Forum April 21, 2010
T-Cell Pools
The thymus
produces
around ~10100 million
new naïve
T-cells every
day
Naïve T-cells that hadn’t
responded to anything
die to make room for
the fresh naïve T-cells
Naïve T-cell pool size
= ~100 billion
Memory T-cell pool size
= ~200-300 billion
Naïve T cells that
meet a matching antigen
leave a legacy of
memory cells which
join the memory pool
An existing memory
cell dies to make
room for the new
HIV Research Catalyst Forum April 21, 2010
Acute HIV infection
• Transient (typically) loss of CD4 T cells from
blood, significant loss of CD4 T cells from gut
• High viral load
• High levels of immune activation
• Increased CD8 T cell counts & skewing of
CD4:CD8 ratio
HIV Research Catalyst Forum April 21, 2010
Acute HIV infection
• HIV-specific immune responses become detectable in
2-3 weeks
• Decline in viral load occurs in parallel with emergence
of HIV-specific memory CD8 T cell response but is
rarely fully controlled
• Evidence of HIV-specific memory T cell dysfunction
emerges early (HIV infection of developing CD4
responses may be the culprit)
• Neutralizing antibodies are not generated for several
months and are rarely able to neutralize
contemporaneous virus
HIV Research Catalyst Forum April 21, 2010
HIV Infects Developing Memory CD4 T Cells
CD127 aka IL-7R is
a marker for T cells
destined to become
long-term memory
cells
HIV Research Catalyst Forum April 21, 2010
Zaunders et al
J. Virology,
80:20:10162-10172
Chronic HIV Infection
• Immune activation persists
• Immune responses to HIV become
progressively more diverse
– as the virus replicates, mutant forms arise and
these induce new immune responses (from the
naïve T cell and B cell pools)
– effective immune responses pressure the virus
to mutate in ways that prevent recognition,
somewhat similar to the way HIV mutations can
impair drug effectiveness (“immune escape”)
HIV Research Catalyst Forum April 21, 2010
Chronic HIV Infection
• T cells become exhausted & senescent
– lose the capacity to proliferate (copy themselves)
– sequential loss of cytokine production capacity: IL2>TNFalpha>interferon gamma
– Express exhaustion markers (PD-1, Tim-3)
– lose the CD28 co-stimulatory molecule, leading to an
accumulation of CD28- T cells (also seen in aging)
– Shortened telomeres
– Dysfunctional HIV-specific CD4 and CD8 T cells
accumulate
HIV Research Catalyst Forum April 21, 2010
Parallels with Aging
•
•
•
•
•
Decreased thymic output
Decreased naive CD4 and CD8 T cell numbers
Decreased response to vaccinations
Skewed CD4:CD8 ratio
Narrowing of the T cell repertoire, particularly in
CMV+ (memory pool gets crowded)
• Increased numbers of CD28- CD8 T cells (associated
with morbidity & mortality)
• Increased levels of inflammatory cytokines
(“inflammaging”)
HIV Research Catalyst Forum April 21, 2010
The Immune Activation Suspects
• Ongoing HIV replication: production of viral
antigens and possibly also via viral HIV RNA
stimulating toll-like receptors 7 & 8
• Microbial translocation - leaking of normally
harmless bacteria from the gut into the
circulation, leading to increased levels of bacterial
DNA and LPS in the bloodstream (also seen in
idiopathic CD4 T cell lymphopenia, but it doesn’t
cause CD8 T cell activation in that setting)
HIV Research Catalyst Forum April 21, 2010
The Immune Activation Suspects
• Co-infections
– hepatitis C co-infection associated with increased
CD8 T cell activation
– CMV: treatment with anti-CMV drug valganciclovir
reduced CD8 T cell activation but did not increase
CD4 T cell counts
– Other herpesviruses (Epstein-Barr Virus, Herpes
Simplex Virus types 1+2)
• Loss of T cells leads to “homeostatic”
proliferation
HIV Research Catalyst Forum April 21, 2010
Impact of Virus Suppression
• Immune activation declines rapidly
• CD4 T cell increases: redistribution of cells
trapped in lymph tissue, proliferation of
functional cells, production of new naive T cells
from the thymus (slowest aspect of recovery)
• CD8 T cell numbers decrease
• Memory T cell responses to opportunistic
pathogens improve
HIV Research Catalyst Forum April 21, 2010
Factors Associated with Poor CD4 Recovery
•
•
•
•
•
•
Low CD4 T cell nadir
Low naive/memory T cell ratio
Age
Immune activation
Microbial translocation
Hepatitis C co-infection (some conflicting data,
largest studies find no significant effect)
• Lymphoid tissue fibrosis
HIV Research Catalyst Forum April 21, 2010
Long Term CD4 Recovery – ACTG 384
• Strata:
– 1 (0–50)
– 2 (51–200)
– 3 (201–350)
– 4 (351–500)
– 5 (1500)
HIV Research Catalyst Forum April 21, 2010
Long Term CD4 Recovery – ACTG 384
HIV Research Catalyst Forum April 21, 2010
Poor CD4 Recovery & Clinical Risk
HIV Research Catalyst Forum April 21, 2010
CD4 Boosting Therapies?
• IL-2: Increased numbers but no clinical benefit
(functionality?)
• IL-7: Less toxic (so far), significant CD4 T cell
increases, contribution of thymus to T cell
increases still uncertain
• Human Growth Hormone (HGH): Increased
naive T cells & thymic output, significantly
reduced CD4 and CD8 T cell activation, but not
ideal (lower doses?)
HIV Research Catalyst Forum April 21, 2010
Other Immune-Based Approaches
• CCR5 inhibitors e.g. maraviroc – multiple trials for
poor CD4 recovery
• Anti-PD1 antibodies – phase I for cancer
• TLR7/9 inhibitors/agonists (chloroquine, Dynavax
oligonucleotides) – ongoing ACTG trial of chloroquine
vs. immune activation
HIV Research Catalyst Forum April 21, 2010
Other Immune-Based Approaches
• Rapamycin
• Anti-CMV treatments – study in press
• Flagyl-based antibiotics – one small recent study
reported combination antibiotic treatment for H.
Pylori improved CD4 recovery
• Rheumatoid arthritis/inflammatory bowel disease
treatments (IL-1 receptor antagonists, minocycline,
leflonomide)
• Anti-CTLA-4 – ongoing studies in cancer
HIV Research Catalyst Forum April 21, 2010
Tx Vaccines & Gene Therapies
• Therapeutic vaccines
• Better gut CD4 T cell recovery associated with HIVspecific CD4 T cell responses in the gut
• Therapeutic immunization reported to decrease
CD8 T cell activation
• Genetically modified immunity
• E.g. Carl June is extracting CD4 T cells, deleting the
CCR5 gene, expanding & reinfusing in hopes of
creating HIV-resistant HIV-specific T cells
HIV Research Catalyst Forum April 21, 2010
Advocacy Issues
• The generally dismal and scattershot IBT pipeline
• Lack of trials or any other options for people with
poor CD4 T cell recovery
• Uncertainty about how to reduce
activation/inflammation
• Administrative obstacles to translational (benchto-bedside) research
• Lack of a systematic, coordinated research plan
HIV Research Catalyst Forum April 21, 2010