HIV AND INFLAMMATION: A NEW THREAT

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1 HIV AND INFLAMMATION: A NEW THREAT KAP ANNUAL SCIENTIFIC CONFERENC MAY 2013 DR JOSEPH ALUOCH FRCP,EBS

2 Basic Components of the Immune System Immunology: cells and tissues involved in recognizing and attacking foreign substances in the body e.g. bacteria, viruses, fungi and parasites. Immunity: the condition of being immune. Immunity can be innate or adaptive the result of a previous exposure. Antigen: any substance capable of triggering an immune response.

3 Basic Components of the Immune System Of the white blood cell pool, lymphocytes primarily drive the immune system. Lymphocytes (2 major types which protect host): (1) B cells: formed in bone marrow and produce antibodies after exposure to an antigen. (2) T cells: processed in the thymus (two subtypes) Subtype 1: Regulator cells also known as helper or CD4 cells ( generals in army of immune system which recognize invaders and summon armies of cells to mount a direct attack) Subtype 2: Fighter or effector cells also known as cytotoxic or CD8 cells (bind directly to antigen and kill it)

4 Basic Components of the 2 types of CD4 cells: Immune System (1) Memory cells: those programmed to recognize a specific antigen after it has been previously seen (2) Naïve cells: non-specific responders CD4 cells replicate 100 million times a day. CD4 cells are the target cells of HIV. Bartlett, J.: The Johns Hopkins Hospital 2002 Guide to Medical Care of Patients with HIV Infection

5 Basic Components of the Immune System Lymphatic vessels and nodes: designed to trap and destroy antigen and play a critical role in fighting all infections including HIV Phagocytes: scavengers of the immune system -By digesting/processing antigen, their role is to initiate the immune response by presenting antigen to the lymphocytes. -Serve a secretory function critical to mounting the inflammatory response and regulating immune responses Grimes D. and Grimes R.: AIDS & HIV Infection St. Louis, Mosby, 1994.

6 Differentiating Immune Cells Lymphocytes and other immune cells are classified according to cell-surface molecules designated by a CD ( cluster of differentiation ) number. Human leukocytes have more than 300 CD markers, and an individual cell may carry several of them. Helper T-cells with the CD4 marker, for example, coordinate immune responses, while killer T-cells carrying CD8 attack virus-

7 CD molecules are not simply markers, however, but also have their own functions. Many act as cell surface receptors or ligands (molecules that bind to receptors), often triggering signaling cascades. HIV uses the CD4 receptor as a

8 HIV small virus 9 genes Most extensively studied pathogen HIV-persistence mechanism escapes host immunity -infection and depletion of CD4 411/9/2012 8

9 What Is Inflammation? Inflammation refers to the complex cascade of events that happen when the immune system recognizes a threat and goes into action, including migration and activation of various types of white blood cells (leukocytes) and release of chemical messengers known as cytokines.

10 INFLAMMATION A healthy immune response is key to good health, but ongoing immune activation and inflammation due to a persistent threat such as chronic HIV infection can lead to many different problems throughout the body.

11 HIV inflammation! Fighting a chronic infection like HIV results in Ongoing activation / chronic inflammation Things we used to think were side effects caused by ART alone

12 A growing body of evidence implicates chronic inflammation and immune activation in the development of non-aids conditions, and some experts blame inflammation for what looks like accelerated aging in people with HIV.

13 IMMUNE ACTIVATION AND INFLAMMATION T-Cell Activation:Antigenic stimulation by the virus adaptive immune response.cd8+t Cell. Hiv gene products -induce activation of lymphocytes and macrophages production of pro-inflammatory cytokines and chemokines

14 IMMUNE ACTIVATION Active molecular and cellular processes Cell activation Cell proliferation Cell death Secretion of soluble molecules 411/9/

15 What is different about HIV induced immune activation? In most infectious diseases, [including those in which the pathogen persists indefinitely (eg HCV)], immune activation decreases dramatically after the acute phase Unique to HIV and SIV pathogenic infection, immune activation persists in the chronic phase

16 Chronic Inflammation and Immune Activation Under normal circumstances, the immune response is self-limiting and turns itself off when no longer needed But inflammation can become chronic if the trigger persists or if suppressive control mechanisms do not work

17 HIV and Inflammation Many experts are now convinced that chronic inflammation and immune activation contribute to the higher rates of cardiovascular disease and other non-aids conditions,vasculitis,pah seen in people living with HIV.

18 How does HIV promote inflammation? Viral proteins, including Tat,Nef, Vpr, and gp120, appear to directly trigger immune response, probably by altering cytokine signaling. Two elements of the early innate immune response NF-kB

19 HIV INFECTION A mixture of immune suppression and immune activation.

20 HIV has its foot on the accelerator and the brake at the same time. While latestage HIV/AIDS is indeed characterized by profound immune deficiency, earlier stages are marked by ongoing immune

21 HIV/AIDS: the ultimate paradox Hallmark of AIDS is CD4 T cell loss which is associated with immune deficiency and development of AIDS-related conditions BUT Immune hyperactivation (clinical context= inflammation) is the major driver of HIV pathogenesis, including loss of CD4 T cells

22 HIV infection induces inflamation;shown by elevated inflammatory markers, CD4 count reduced CD8 elevation. CD4/CD8 ratio. changed

23 CD4 T cells role in immunity HIV infection leads to depletion of CD4+T cells Immune activation in HIV-infected individuals Events: Large range of molecular, cellular processes Cell activation proliferation death secretion of soluble molecules 411/9/

24 CAUSES OF IMMUNE ACTIVATION AND INFLAMMATION IN HIV-1 INFECTION Antigenic stimulation direct Indirect via other viruses CMV EBV Microbial translocation 411/9/

25 Microbial translocation Escape of gut bacteria from damaged intestine wall by HIV infection of the gut lymphoid tissue

26 HIV INFECTED INDIVIDUALS Elevated levels of markers of activation and/or apoptosis on CD8+ cell B+ cells NK cells monocytes High levels of pro-inflammatory cytokines; Tumour Necrosis factor alpha (TNFa) Interlukins 6 IL-6 Interlukins 1-beta (1L-1B) 411/9/

27 BIOMARKERS OF INFLAMMATION Biomarkers may not play direct role in immune system but their presence in blood indicate a process of inflammation Several chemical messengers contribute to inflammation Immune dysregulation - chronic inflammation neutophills- lymphocytes Apoptosis programmed cell death or

28 NAME Adiponectin CYTOKINE,MEDIATOR AND BIOMARKERS C-reactive protein (CRP D-dimer Fibrinogen Intercellular adhesion molecule 1 (ICAM-1) FUNCTION Anti-inflammatory adipokine hormone signals increased inflammation Acute phase protein signals increased inflammation Byproduct of blood clot breakdown signals increased coagulation Acute phase protein mediator of blood clotting signals coagulation Cell adhesion molecule enables leukocytes to bind to endothelial lining, signals endothelial dysfunction

29 NAME Interleukin 1 (IL1) Interleukin 4 (IL4) Interleukin 6 (IL6) Interleukin 10 (IL10) Leptin FUNCTION Pro-inflammatory cytokine, signals increased inflammation Anti-inflammatory cytokine Pro-inflammatory cytokine, signals increased inflammation Anti-inflammatory cytokine Pro-Inflammatory adipokine hormone

30 NAME Monocyte chemoattractant protein 1 (MCP-1) Macrophage inflammatory protein 1 (MIP-1) Plasminogen P-selectin FUNCTION Inflammatory chemokine, promotes monocyte migration Inflammatory chemokine, promotes neutrophil migration Acute phase protein, mediator of blood clot breakdown, involved in wound healing Cell adhesion molecule, enables leukocytes to move along endothelial lining,

31 NAME Transforming growth factor-beta (TGFbeta) Tumor necrosis factor-alpha (TNFalpha) Vascular adhesion molecule 1 (VCAM-1) FUNCTION Anti-inflammatory cytokine Pro-inflammatory cytokine, promotes death of cancer cells, signals increased inflammation Cell adhesion molecule, enable leukocytes to bind to endothelial lining, signals endothelial dysfunction

32 immunosenescence Immune activation and inflammation by Hiv stimulation Cell death # cell production Hiv and aging : Age related decline in immune function

33 HIV AND AGING Similar immunological alterations reduction in T-cells cells renewal Progressive enrichment of terminally differentiated T cells general decline in immune system leading to immunosenescence Atherosclorosis Osteoporosis 4/9/

34 NEW PARADIGM Medical complications in HIV attributed not only to detrimental effects of the virus on the immune system but also immune system response to the virus.

35 Paradigm shift A re-conceptualization of the pathogenesis of HIV disease is necessary-- clinical latency is a misperception Inflammation and coagulopathy are important causes of end-organ damage, disease progression and death

36 The Natural History of HIV Infection Clinical Latency? Pantaleo G, et al. N Engl J Me

37 CD4+ cells Count A New Paradigm 1000 Ongoing Morbidity from HIV Opportunistic Diseases Infection Time in Years

38 HIV INFLAMMATION Carotid intima thickness CD8 elevation Increase platelet adhesion HIV antigen from latent pool lymphoid activation old/residual infection Lymphoid dysregulation bacteria translocation 411/9/

39 HIV INFLAMATION AND CVD Atherosclerosis is not merely passive deposit of cholesterol but active inflammatory process. HIV proteins leads to endotholial dysfunction 411/9/

40 CANCER HIV Inflammation Oxidative stress & DNA damage 411/9/

41 Chronic Immune Activation is also associated with non-infectious HIV Complications Accelerated aging Cardiovascular disease Diabetes Bone fragility Cancers Kidney disease Liver Disease

42 MANAGEMENT INFLAMMATION Reduce T-Cell activation Alter production or activity of cytokines and inflammatory mediators changing underlying risks -lifestyle immunomodulators 411/9/

43 TREATMENT OF INFLAMMATION IN HIV Early ART initiation Hydroxychloroquine NSAIDs: Cox inhibitors Co-receptor inhibitors CCRS5 Moraviroc; immunomodulatory effect STATINS Treatment of co-infection CMV HBV HCV Residual viraemia-ratelgravir 411/9/

44 Examples of Ongoing/Planned Clinical Trials in HIV infected Adults To prevent microbial translocation---- Probiotics, Rifaxamine (luminal antibiotic), localized antiinflammatory agents Anti-CD3/costim blockade agents to block T cell activation Anti-vascular endothelial activation modalities Anti TLR signaling e,g. chloroquine Anti-inflammatory -anti-tnfa, anti-il-6, IL-1R antagonists, statins

45 Scenarios and consequences of Inflammation lessons Acute HIV: Inflammation is a necessary component of the host immune response against HIV Chronic untreated HIV: A persistent state of generalized immune activation leading to deleterious outcomes Chronic HIV, ARV treated: immune activation decreases but is not eliminated- it is a cause of disease progression independent of the viral load and CD4+ T cell count ARV treatment initiation: leads to rapid exuberant immune recovery: may cause IRIS in HIV infected children (e.g. BCG, TB and VZV IRIS) and adults

46 ERO URU KAMANO