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Transcript
+ 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 + References Ambrose Z, Kewal-Ramani VN, Bieniasz PD, Hatziioannou T. HIV/AIDS: in search of an animal model. TRENDS in Biotechnology Vol.25:8. Colson AE, John PE, Bartlett G, McGovern BH. Primary HIV-1 infection: Pathogenesis; epidemiology and clinical manifestations. Up to date 2009 Stebbing J, Gazzard B, Douek DC. Where Does HIV Live? N Engl J Med 2004;350:1872-80. Dybul M, Connors M, Fauci AS. Chapter 116 – The Immunology of Human Immunodeficiency Virus Infection. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett's principles and practice of Infectious diseases. 5th ed. New York: Elsevier/Churchill Livingstone; 2005. Haynes BF. Gut microbes out of control in HIV infection. Nature Medicine. 2006:1351-1352. Kuritzkes DR, Walker BD. Chapter 58 HIV-1: Pathogenesis, Clinical Manifestations, and Treatment. In: Knipe, David M, Howley PM, editors. Fields Virology. 5th ed. Lippincott Williams & Wilkins. 2007. p2188-2209. Mackay CR. Immunology: Dual personality of memory T cells. Nature 1999; 401:659-660. References + Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 2008; 231-241. Bartlett JG, Hirsch MS, McGovern BH. The stages and natural history of HIV infection. Up to date 2009. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Medicine 2006;12:1365-1371. Cadogan M, Dalgleish AG.HIV immunopathogenesis and strategies for intervention. Lancet Infect Dis 2008;8: 675–84. Derdeyn CA, Silvestri G.Viral and host factors in the pathogenesis of HIV infection. Current Opinion in Immunology 2005;17:366–373. Smith SM. The pathogenesis of HIV infection: stupid may not be so dumb after all. Retrovirology 2006;3:60. Picker LJ; Watkins DI. HIV pathogenesis: the first cut is the deepest. Nature Immunology 2005;6:430-432. References + Richman DD, Margolis DM, Delaney M et al. The Challenge of Finding a Cure for HIV Infection. Science. March 2009; 323. Rychert JA, Rosenberg ES, Bartlett JG, McGovern BH. Immunology of HIV-1 infection. Up to date January 2009. Lederman MM, Offord RE, Hartley O. Microbicides and other topical strategies to prevent vaginal transmission of HIV. Nature Reviews Immunology 2006: 6:371-382. Johnston MI, Fauci AS. An HIV Vaccine-Evolving Concepts. N Engl J Med 2007;356:2073-81. Silvestri G, Paiardini M, Pandrea I, Lederman MM, Sodora DL. Understanding the benign nature of SIV infection in natural hosts. J Clin Invest 2007:117:3148–3154. Forsman A, Weiss RA. Why is HIV a pathogen? Trends in Microbiology 16;12: 555560. De Silva TI, Cotten M, Rowland-Jones SL. Review: HIV-2: the forgotten AIDS virus. + References Haase AT. Perils at mucosal front lines for HIV and SIV and their hosts. Nature Review Immunology 2005;5:783-792. Saez-Cirion A , Pancino G, Sinet M,Venet A, Lambotte O.HIV controllers: how do they tame the virus? Review Trends in Immunology 28;12:532-540 Haynes BF. Gut microbes out of control in HIV infection. Nature Medicine 2006;12:13511352 Paiardini M, Frank I, Pandrea I et al. Mucosal Immune Dysfunction in AIDS Pathogenesis. AIDS Reviews 2008;10; 36-46. Wu L, Kewal-Ramani VN. Dendritic-cell interactions with HIV: infection and viral dissemination. Nature Reviews Immunology 2006;6:859-868 Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nature Medicine 2006;12: 289295. Wild chimpanzees get AIDS-like illness. Nature News. Accessed: 23 July 2009. http://www.nature.com/news/2009/090722/full/news.2009.711.html.