COMPETING INTEREST OF FINANCIAL VALUE

Transcription

1 BHIVA AUTUMN CONFERENCE 2013 Including CHIVA Parallel Sessions Dr Daniel Douek Vaccine Research Center, National Institute of Health, Bethesda, Maryland, USA COMPETING INTEREST OF FINANCIAL VALUE > 1,000: Speaker Name Statement Dr Daniel Douek None Date November November 2013, Queen Elizabeth II Conference Centre, London

2 The Surfaces of Infection Normal Cervix Normal Intestinal Mucosa CD4 T cell Low density of available CD4 T cell targets Majority of CD4 T cells in the body

3 Transmission And Local Propagation Transmission at Cervix Transmission at Intestinal Mucosa Infected founder population Recruitment and infection of new CD4 T cell targets Infection of resident CD4 T cell targets

4 Window of Therapeutic Opportunity Transmission at Cervix Transmission at Intestinal Mucosa Infected founder population Recruitment and infection of new CD4 T cell targets Infection of resident CD4 T cell targets

5 Damage to the GI Tract in Acute Infection HIV - Acute HIV + Massive loss of mucosal CD4 T cells in acute infection Majority of loss is from lamina propria Accounts for loss of majority of memory CD4 T cells

6 Maintenance of Mucosal Integrity Th17 CD4 T cells are critical to the maintenance of mucosal epithelium, barrier function and immunity Brenchley JM, et al. Blood 2008 Th17 cells are preferentially lost from the GI tract

7 Consequences of Epithelial Barrier Damage Loss of tight junctions Mucus Microbial products Enterocyte apoptosis CD4 T cell loss Healthy Gut Tight epithelial junctions, mucus Anti-microbial peptides Secreted antibodies Phagocytes, neutrophils, T cells Cross-talk between microbes and epithelial cells and immune cells HIV-Infected Gut Massive loss of CD4 T cells Preferential loss of Th17 cells Enteropathy 2-10x increased permeability Translocation of microbial products

8 What We Talk About When We Talk About Immune Activation As virus load decreases, immune activation persists Innate Cells: activation of Macrophages and Dendritic Cells Cytokines, chemokines: IFNa, TNF, IL-1, IL-6, IL-8, IL-15, IL-10 Acute phase proteins: Serum Amyloid A, C-Reactive Protein Coagulation: D-dimers, Tissue Factor Fibrosis: Matrix Metalloproteinase activation, collagen deposition Microbial sensors: Lipopolysaccharide Binding Protein, soluble CD14 Adaptive T cells: increased turnover, exhaustion, low thymic output, virus reservoir B cells: increased turnover, exhaustion, hypergammaglobulinemia Frequency of activated T cells is a strong predictor of disease progression

9 ART and T Cell Immune Activation Hunt, et al. J Infect Dis. 2003, 2008 and unpublished observations T cell activation declines during long-term ART, but remains elevated and is associated with poor CD4 T cell reconstitution

10 Causes Of Chronic Immune Activation HIV-induced activation of innate immune system (Bhardwaj) When virus load decreases after acute phase, immune activation remains elevated Virus load alone is a poor predictor disease progression (Rodriguez JAMA 2006) Immune activation predicts disease progression independent of viral load (Giorgi, Deeks etc.) Elite controllers who progress have increased activated CD38 + T cells (Hunt JID 2008) When virus load is suppressed with ART immune activation persists and predicts progression Increased antigen load, bacterial overgrowth, herpes viruses (Deeks, Hunt) Immunologic and structural damage to gut, increased mucosal permeability, translocation of inflammatory microbial products into systemic circulation

11 The Gut and Immune Activation Microbial Translocation: translocation of gut-derived microbial products to systemic circulation without overt bacteremia Graft vs. host disease Inflammatory bowel disease Liver disease Pancreatitis Surgery Alcohol NSAIDS Measures of microbial translocation correlate with systemic immune activation and are predictive of clinical outcome Can microbial translocation across gut mucosal surface cause systemic immune activation in HIV infection?

12 20m l Microbial Translocation in HIV Infection Plasma LPS and bacterial 16S rdna levels are indicators of microbial translocation Increased plasma LPS and bacterial 16S rdna levels in HIV + individuals indicate microbial translocation

13 LPS and Systemic Immune Activation Plasma LPS correlates with CD8 T cell activation and plasma IFNa Other factors in addition to LPS directly and indirectly stimulating adaptive and innate immune systems (peptidoglycan, bacterial DNA..)

14 Microbial Translocation and Immune Activation 1. Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12, (2006). 2. Anselmi, A. et al. Immune reconstitution in human immunodeficiency virus type 1-infected children with different virological responses to anti-retroviral therapy. Clin Exp Immunol 150, (2007). 3. Hunt, P. W. et al. Relationship between T Cell Activation and CD4(+) T Cell Count in HIV-Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy. J Infect Dis 197, (2008). 4. Marchetti, G. et al. Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS 22, (2008). 5. Ancuta, P. et al. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS ONE 3, e2516 (2008). 6. Balagopal, A. et al. Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C. Gastroenterology (2008). 7. Baroncelli, S. et al. Microbial translocation is associated with residual viral replication in HAART-treated HIV+ subjects with <50copies/ml HIV-1 RNA. J Clin Virol 46, (2009). 8. Papasavvas, E. et al. Delayed loss of control of plasma lipopolysaccharide levels after therapy interruption in chronically HIV-1-infected patients. AIDS 23, (2009). 9. Gregson, J. N. et al. Elevated plasma lipopolysaccharide is not sufficient to drive natural killer cell activation in HIV-1-infected individuals. AIDS 23, (2009). 10. Jiang, W. et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 199, (2009). 11. Cassol, E. et al. Persistent Microbial Translocation and Immune Activation in HIV-1-Infected South Africans Receiving Combination Antiretroviral Therapy. J Infect Dis (2010). 12. Arias, J. F., Nishihara, R., Bala, M. & Ikuta, K. High systemic levels of IL--10, IL--22 and CRP in Indian patients are associated with low in vitro replication of HIV-1 subtype C viruses. Retrovirology 7, 15 (2010). 13. Ciccone, E. J. et al. Cycling of gut mucosal CD4+ T cells decreases after prolonged anti-retroviral therapy and is associated with plasma LPS levels. Mucosal Immunol 3, (2010). 14. Estes, J. D. et al. Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog 6, e (2010). 15. Favre, D. et al. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2, 32r-336 (2010). 16. Funderburg, N. T. et al. Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood 115, (2010). 17. Harris, L. D. et al. Mechanisms underlying {gamma}{delta} T-cell subset perturbations in SIV-infected Asian rhesus macaques. Blood 116, (2010). 18. Kamat, A., Ancuta, P., Blumberg, R. S. & Gabuzda, D. Serological markers for inflammatory bowel disease in AIDS patients with evidence of microbial translocation. PLoS One 5, e15533 (2010). 19. Klatt, N. R. Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in absence of SIV infection. M Imm 3, (2010). 20. Leinert, C. et al. Microbial translocation in simian immunodeficiency virus (SIV)-infected rhesus monkeys (Macaca mulatta). J Med Primatol 39, (2010). 21. Massanella, M. et al. CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART. AIDS 24, (2010). 22. Nowroozalizadeh, S. et al. Microbial translocation correlates with the severity of both HIV-1 and HIV-2 infections. J Infect Dis 201, (2010). 23. Piconi, S. et al. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. AIDS 24, (2010). 24. Rajasuriar, R. et al. Biological determinants of immune reconstitution in HIV-infected patients receiving antiretroviral therapy: the role of IL-7 and IL-7Ra and microbial translocation. J I Dis 202, (2010). 25. Rempel, H., Sun, B., Calosing, C., Pillai, S. K. & Pulliam, L. Interferon-alpha drives monocyte gene expression in chronic unsuppressed HIV-1 infection. Aids 24, (2010). 26. Said, E. A. et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med 16, (2010). 27. Smith, A. J., Schacker, T. W., Reilly, C. S. & Haase, A. T. A role for syndecan-1 and claudin-2 in microbial translocation during HIV-1 infection. J Acquir Immune Defic Syndr 55, (2010). 28. Troseid, M. et al. Elevated plasma levels of LPS and high mobility group box-1 protein are associated with high viral load in HIV-1 infection: reduction by 2-year antiretroviral therapy. AIDS 24, (2010). 29. Wallet, M. A. et al. Microbial translocation induces persistent macrophage activation unrelated to HIV-1 levels or T-cell activation following therapy. AIDS 24, (2010). 30. Abdurahman, S. et al. Elevated Flagellin-specific Antibodies during HIV-1 Infection. CROI 313, (2011). 31. Funderburg, N. et al. Delayed Reduction in CD4 T Cell Turnover following Viral Control Correlates with Markers of Microbial Translocation in Treatment-naïve Patients Receiving RAL-based ART. CROI 318, (2011). 32. Pilakka-Kanthikeel, S. et al. Microbial Translocation Is Increased in HIV-infected Children on ART and Is Independent of Viral Replication and Immune Activation. CROI 728, (2011). 33. Sandler, N. G. et al. Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection. J Infect Dis (2011). 34. Shive, C. et al. Immunologic Failure Despite Suppressive ART Is Related to Increased Inflammation and Evidence of Microbial Translocation. CROI 320, (2011). 35. And so on A number of studies have confirmed the observations of raised measures of microbial translocation and their association with immune activation and disease progression independent of VL

15 LPS Causes Immune Activation In Vivo LPS-stimulated monocytes secrete scd14 and shed surface CD14 Raised plasma scd14 indicates chronic in vivo stimulation of monocyte/macrophages by LPS The host response to microbial translocation

16 Microbial Translocation and Disease Progression Strategies for Management of Antiretroviral Therapy (SMART) 5,472 HIV+ subjects at 318 sites in 33 countries CD4+ T cells > 350 cells/mm 3 at enrollment >80% on ART Antiretroviral strategy Viral suppression (VS): Continuous use of ART Drug conservation (DC): Defer treatment until CD4+ T cells < 250 cells/mm 3 Continue treatment until CD4+ T cells > 350 cells/mm 3 85 subjects died, 124 had cardiovascular events, 96 had opportunistic diseases increased in DC arm Odds Ratio of death 1.8 in DC arm IL-6, C-reactive protein and D-dimer were associated with mortality In 700 subjects, we evaluated baseline levels of: Lipopolysaccharide (LPS) Soluble CD14 (scd14) LPS core antigen-specific antibody (EndoCAb) Intestinal fatty acid binding protein (I-FABP) plasma marker of enterocyte apoptosis Each case was matched with 2 controls on age, sex, location, date of enrollment

17 Microbial Translocation and Enterocyte Damage Biomarkers indicate microbial translocation, LPS bioactivity and enterocyte damage in treated and untreated subjects

18 LPS Levels and Disease Progression Raised plasma LPS levels predict PB CD4 T cell decline, independently of viremia, in subjects with high plasma scd14

19 scd14 Levels and Mortality > <2.07 x10 6 pg/ml scd14: OR of Death by Quartile Adjusted for IL-6, D-dimer, CRP, SAA and virus load Univariate Sandler JID OR (95% CI) Baseline scd14 is a significant independent predictor of death from AIDS and non-aids events

20 Markers of Inflammation and GI Dysfunction Predict Mortality Microbial translocation Hunt, CROI 2013 Inflammation Coagulation T cells %CD38 + DR + %CD57 + DR + Odds of Mortality (4 th vs 1 st Quartile) (Independent of CD4 count and virus load) Markers of inflammation and gut barrier dysfunction predict mortality independently of CD4 count and virus load

21 Microbial Translocation in HBV and HCV Infections Possible reasons for microbial translocation: Altered hepatic architecture Kupffer cell dysfunction Intestinal permeability Bacterial overgrowth Measured plasma LPS, scd14, I-FABP and IL-6 in 84 subjects with varying degrees of liver fibrosis due to infection with HBV or HCV

22 Microbial Translocation in Hepatitis Increased levels of I-FABP, LPS, scd14 and IL-6 indicate enterocyte damage, microbial translocation and LPS bioactivity

23 Hepatic Inflammation, Fibrosis and Regeneration scd14 correlates with markers of inflammation, fibrosis and regeneration

24 Progression to End-Stage Liver Disease Plasma scd14 levels predict poor clinical outcome

25 gut CD4 depletion enteropathy HIV Tem Tem Tem Tcm Tem Tcm immune activation

26 immune deficiency gut CD4 depletion enteropathy HIV Tem Tem Tcm immune activation CMV??? low thymic output LT fibrosis T/B cell dysfunction non-aids morbidity and mortality inflammation tissue damage coagulopathy

27 immune deficiency gut CD4 depletion enteropathy ART HIV Tem Tem Tem Tcm Tem Tcm immune activation CMV??? non-aids morbidity and mortality low thymic output LT fibrosis T/B cell dysfunction inflammation tissue damage coagulopathy

28 Therapeutic Interventions in Development Chemokine receptor inhibitors: maraviroc, TB-652 Anti-infective therapy: CMV, EBV, HSV, HCV/HBV Microbial translocation: sevelamer, colostrum, rifaximin Enhance T cell renewal: Growth Hormone, IL-7 Anti-fibrotic drugs: pirfenidone, ACEi, ARBs, KGF Anti-aging: caloric restriction, sirtuin activators, vit. D, omega-3 fatty acids, rapamycin, diet, exercise (not recommended by me) Anti-inflammatory drugs: Chloroquine, Hydroxychloroquine Minocycline NSAIDs (COX-2i, aspirin) Statins Methotrexate Anakinra (IL-1Ra) Thalidomide, lenalidomide, pentoxyfylline (weak TNF inhibitors) Biologics (TNF inhibitors, IL-6 inhibitors, anti-ifna, anti-pd1) Anti-coagulants: - warfarin, dabigatran, aspirin, clopidogrel Combination therapy may be necessary

29 LPS fold increase Therapeutic Interventions in Studies DR + CD38 + CD4 T cells %CD4 T cells in colon Sevelamer: Pandrea, CROI 2013 Probiotics: Klatt, et al. JCI, 2013 ARV + Probiotic ARV Bovine Colostrum: Asmuth, Douek et al, AIDS 2013 scd14 µg/ml P=0.740 P=0.008 D0 D28 W12 D-dimer mg/l 1.5 % mucosal CD4 + T cells P <0.001 P=0.031 P= P=0.078P= D0 BaselineD21 W12 W12 HIV- % mucosal CD8 + T cells P< P=0.042 P< IL-7: 60 INSPIRE2 team, Sereti et al, submitted Baseline W12 HIV-

30 U. Minn Tim Schacker Ashley Haase NCI Frederick Jake Estes CWRU Mike Lederman UCSF Steve Deeks Peter Hunt Many Thanks To NIH VRC Netanya Sandler Annelys Roque Molly Perkins Brenna Hill Srinivas Rao Mario Roederer LMM Jason Brenchley OHSU Louis Picker U. Penn Guido Silvestri Mirko Paiardini U. Pitt Cristian Apetrei Ivona Pandrea SBRI Don Sodora Rush Alan Landay H. Bicetre Olivier Lambotte CC Irini Sereti NIDDK Theo Heller Chris Koh The INSIGHT Team Money NIH Intramural Program Bill and Melinda Gates Foundation NIH Office of AIDS Research