+

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

+ References

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+ References

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+References

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+References

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