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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 - PowerPoint PPT Presentation
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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
Mechanisms driving immune activation might hold the key to HIV pathogenesis
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
Chronic Immune Activation:Animal Models
+
Causes of Immune Activation
+HIV-1 infection and
replication
Massive CD4+ T cell depletion
Loss of immuno-regulatory cells
Thymic dysfunction & loss of regenerative potential
Bacterial translocation
Viral reactivation
Production of HIV proteinsGp120, nef
Systemic immune activationAdaptive and Innate
Causes of Immune Activation
CMV replication
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
+ 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 weremeasured 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 Mann-Whitney test. **P <.001.
HIV replication
A Complex System of Immune Dysregulation
HIV replication
Smoking
Role of Smoking
+
Consequences of Immune Activation & Inflammation
+Systemic immune
activation(adaptive & innate)
HIV persistence T cell activation
HIV replicationImmuno-senescence
End-organ disease
Local inflammation
Lymph node fibrosis
Impaired T-cell recovery
T-cell exhaustion
+ Vicious Cycle of Immune Activation & HIV-1 Replication
T cell activation
NF Kappa B Transcription factor
Transcription of integrated virus
New virions
Infection new targets
HIV replication promotes immune activation
Immune activation promotes HIV replication
Pro-inflammatory cytokines:IL1 ; TNF; IL-6
+Systemic immune
activation(adaptive & innate)
HIV persistence T cell activation
HIV replicationImmuno-senescence
End-organ disease
Local inflammation
Lymph node fibrosis
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 T cell activation
HIV replicationImmuno-senescence
End-organ disease
Local inflammation
Lymph node fibrosis
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
+
Uncontrolled viral replication rapidly depletes the rest of the CD4+ T cells, which cannot be replenished
Senescence/exhaustion: CD4+ T cells
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-ageingChronic immune activation & inflammation mediated by pro-inflammatory cytokines: TNFα, IL-1β and IL-6
+Systemic immune
activation(adaptive & innate)
HIV persistence T cell activation
HIV replicationImmuno-senescence
End-organ disease
Local inflammation
Lymph node fibrosis
Impaired T-cell recovery
T-cell exhaustion
+ Viral PersistenceRelationship 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-intestinal system
Bovine serum colostrum, micronutrient 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 cyclo-oxygenase-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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