Transcript Immune activation in HIV Causes and Consequences

+
Immune Activation in HIV: Causes & Consequences
Dr Theresa Rossouw
+ Introduction
 HIV-1
most extensively studied pathogen in
history
 Precise
mechanisms of immunodeficiency not
resolved
 Multiple
factors potentially contribute to
disease progression

Immunological, genetic, viral & environmental
 Immune
activation emerging as determinant of
morbidity & mortality
Immune
Activation
in
HIV-1
+
Infection
+ Studying Pathogenesis of HIV
Mainly the host not the virus that
determines whether disease ensues
Chronic Immune Activation:
Animal Models
Non pathogenic
E.g. Sooty
mangabey
Pathogenic
E.g. Rhesus
macaques
High Viraemia
Yes
Yes
MALT CD4 T cell
depletion
Yes
Yes
Immune activation
No
Yes
Peripheral CD4 count
Normal levels
Decline
AIDS
No
Yes
Mechanisms driving immune activation might
hold the key to HIV pathogenesis
+
Causes of Immune Activation
+ Causes of Immune Activation
HIV-1 infection and
replication
Loss of immuno-regulatory
cells
Thymic dysfunction & loss
of regenerative potential
Massive CD4+ T cell
depletion
Viral
reactivation
CMV
replication
Bacterial
translocation
Systemic immune activation
Adaptive and Innate
Production of
HIV proteins
Gp120, nef
Microbial Translocation
Loss of mucosal immune
function
Breakdown of the
mucosal barrier
Translocation of
microbial products e.g.
LPS into the systemic
circulation
Broad immune system
activation
+ Microbial Translocation
 LPS, flagellin
and CpG DNA are toll-like receptor
ligands & activate NOD1&2 (nucleotide-binding
oligomerization domains)
 Direct
stimulation of peripheral macrophages & dendritic
cells  pro inflammatory cytokines
 e.g. TNFα, IL-6 & IL-1β
 Activation & differentiation of lymphocytes & monocytes
 Neutrophils
Pro-inflammatory state
+
 Raised
plasma LPS as indicator of
increased microbial translocation
 Chronic
in vivo stimulation of
monocytes by LPS
 Association
between raised LPS
and immune activation
 Decrease
in LPS upon treatment
with HAART
 Association
between reduction in
LPS and CD4 T-cell reconstitution
with HAART
+ Microbial Translocation Persists
B. cART is only partially
effective in reducing
circulating LPS in Africans
with chronic HIV-1 infection
and low CD4 T cell counts.
Plasma LPS levels were
measured in cART-naive
(n=60) and cART-treated
(n=20) patients (>1 year after
the initiation of a successful
treatment with cART).
Differences between the
various groups were
calculated using the MannWhitney test. **P <.001.
A Complex System of Immune Dysregulation
HIV replication
Role of Smoking
HIV
replication
Smoking
+
Consequences of Immune
Activation & Inflammation
+
Systemic immune
activation
(adaptive & innate)
HIV persistence
Local
inflammation
T cell activation
Immunosenescence
End-organ disease
Lymph node fibrosis
HIV replication
Impaired T-cell
recovery
T-cell
exhaustion
+ Vicious Cycle of Immune
Activation & HIV-1 Replication
T cell activation
HIV replication
promotes immune
activation
 NF Kappa B

Transcription factor
Transcription of integrated virus
Pro-inflammatory
cytokines:
IL1 ; TNF; IL-6
New virions
Infection new targets
Immune activation
promotes HIV
replication
+
Systemic immune
activation
(adaptive & innate)
HIV persistence
Local
inflammation
T cell activation
Immunosenescence
End-organ disease
Lymph node fibrosis
HIV replication
Impaired T-cell
recovery
T-cell
exhaustion
+ Loss of Lymphnode Architecture
 Immune
activation
cause fibrosis of the
lymphatic tissue
damaging its
architecture and
preventing normal T
cell homeostasis
 Impaired
response
against new antigens
 Impaired
ability to
maintain memory
responses
+
Systemic immune
activation
(adaptive & innate)
HIV persistence
Local
inflammation
T cell activation
Immunosenescence
End-organ disease
Lymph node fibrosis
HIV replication
Impaired T-cell
recovery
T-cell
exhaustion
+ Senescence/exhaustion: CD4+ T cells
 Immune
system deals with irreversible exhaustion
of T cells by continuously providing new cells
 BUT
thymus capacity to produce naive T cells and
maintain diversity is reduced
 direct
infection by HIV
 atrophy: ?
suppressive effects of pro-inflammatory
cytokines
 Exhaustion
of primary resources, naive T cells
disappear and highly differentiated oligoclonal
populations accumulate
http://www.natap.org/2010/HIV/021510_01.htm
+ Senescence/exhaustion: CD4+ T cells
Uncontrolled viral replication rapidly depletes the rest
of the CD4+ T cells, which cannot be replenished
Collapse of the immune system
AIDS
+ HIV pathogenesis: comparison to the
ageing immune system
 Several
immunological alterations in HIV are similar
to those associated with ageing e.g.
 T cell renewal
 Progressive enrichment of terminally differentiated
T cells with shortened telomeres
 Thought
to be the consequence of immune activation
over a lifetime  general decline of the immune system
 immunosenescence
?
Accelerated process of immunosenescence and
inflamm-ageing during HIV which participate in the
development of immunodeficiency
+ Other similarities with ageing

HIV+ patients present with several alterations of
physiological functions that usually characterize old age:
  bone mineral content, bone formation rate &
osteoporosis
  atherosclerosis - faster progression than in the general
population
 progressive deterioration of cognitive function
 Frailty
 e.g. unintentional weight loss, general feeling of
exhaustion, weakness
Inflam-ageing
Chronic immune activation & inflammation mediated by
pro-inflammatory cytokines: TNFα, IL-1β and IL-6
+
Systemic immune
activation
(adaptive & innate)
HIV persistence
Local
inflammation
T cell activation
Immunosenescence
End-organ disease
Lymph node fibrosis
HIV replication
Impaired T-cell
recovery
T-cell
exhaustion
+ Viral Persistence
 Relationship
causal or mediated through
other mechanisms?

Unidirectional or bidirectional?
 Residual
low-level viral replication in the setting
of ART may lead to persistently elevated levels of
immune activation
 Increased immune activation may lead to viral
persistence through multiple mechanisms



Increased viral production
Increased number of target cells
Upregulation of negative regulators such as programmed
cell death protein 1 (PD-1)
Strategies to Reduce Immune
+
Activation
Strategy
Example
Enhancing mucosal repair in the gastro- Bovine serum colostrum, micronutrient
intestinal system
supplementation, pro and pre-biotics
Reducing microbial translocation and
endotoxin
Rifaximin, sevelamer carbonate
Intensifying and strengthening HAART
Maraviroc and raltegravir
Treating co-infections
Valgancyclovir, interferon-α and
ribavirin
Reducing activation of plasmacytoid
dendritic cells
chloroquine and hydroxychloroquine
Decreasing TGF-β1 mediated lymph
node fibrosis
pirfenidone, lisinopril
Immune-modulators
HMG CoA reductase inhibitors,
minocycline, selective cyclooxygenase-2 inhibitors, leflunomide
and intravenous immunoglobulin
+ Conclusion
 HIV-1-infected
immune system faces major
difficulties
 Needs
to cope with a massive cellular destruction
of particularly CD4+ T cells, contain HIV-1
replication & other associated pathogens
 HIV-1
induces chronic immune activation with an
accelerated process of immunosenescence &
systemic ageing
 Novel
therapies targeted towards suppressing
immune activation are being investigated
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