Immune Activation in HIV: Causes & Consequences

1. Immune Activation in HIV: Causes & Consequences Dr Theresa Rossouw

2. 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

3. Immune Activation in HIV-1 Infection

4. Studying Pathogenesis of HIV Mainly the host not the virus that determines whether disease ensues

5. Mechanisms driving immune activation might hold the key to HIV pathogenesis Chronic Immune Activation: Animal Models

6. Causes of Immune Activation

7. 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 Production of HIV proteins Gp120, nef CMV replication Viral reactivation Bacterial translocation Systemic immune activation Adaptive and Innate

8. 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

9. 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

10. 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

11. 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 Mann-Whitney test. **P <.001.

12. A Complex System of Immune Dysregulation HIV replication

13. Role of Smoking HIV replication Smoking

14. Consequences of Immune Activation & Inflammation

15. Systemic immune activation (adaptive & innate) T cell activation HIV persistence Lymph node fibrosis Local inflammation Immuno- senescence HIV replication Impaired T-cell recovery T-cell exhaustion End-organ disease

16. Vicious Cycle of Immune Activation & HIV-1 Replication T cell activation HIV replication promotes immune activation • NF Kappa B • Transcription factor Immune activation promotes HIV replication Transcription of integrated virus New virions Pro-inflammatory cytokines: IL1 ; TNF; IL-6 Infection new targets

17. Systemic immune activation (adaptive & innate) T cell activation HIV persistence Lymph node fibrosis Local inflammation Immuno- senescence HIV replication Impaired T-cell recovery T-cell exhaustion End-organ disease

18. 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

19. Systemic immune activation (adaptive & innate) T cell activation HIV persistence Lymph node fibrosis Local inflammation Immuno- senescence HIV replication Impaired T-cell recovery T-cell exhaustion End-organ disease

20. 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

21. http://www.natap.org/2010/HIV/021510_01.htm

22. 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

23. 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

24. 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

26. Systemic immune activation (adaptive & innate) T cell activation HIV persistence Lymph node fibrosis Local inflammation Immuno- senescence HIV replication Impaired T-cell recovery T-cell exhaustion End-organ disease

27. 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)

28. Strategies to Reduce Immune Activation

29. 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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