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What drives persistent immune activation/inflammation in cART-treated HIV-1? Giulia Marchetti, MD, PhD Dept of Health Sciences, Clinic of Infectious Diseases - University of Milan, San Paolo Hospital, Italy
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The revolution of cART Hammer, S et al. NEJM 1997; Palella, F et al. NEJM 1998 CD4+HIV-RNA
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Full restoration of health upon cART?
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Samji et al. ART-Cohort Collaboration. PlosOne 2013 Life expectancy in cART-treated patients ART-Cohort Collaboration 22.937 individuals (82,022 person- year) At age 20
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Serious non-AIDS events during long-term virologically suppressive cART Tenorio et al. JID 2014
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HIV as an inflammatory disease Acute HIV associated with rapid/intense release of pro-inflammatory cytokines (IL-6, IP-10, TNF-a) and dramatic increase of activated innate immune cells T-, B-cells Chronic HIV: T-cell activation steady state
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High proportion of activated CD8+ T-cells in HIV Giorgi, J et al. J Immunol 1993
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CD8 T-cell activation predicts CD4+ T-cell count over time Deeks et al. Blood 2004
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Shorter survival is associated with T- lymphocyte activation Giorgi, J et al. JID 1999
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In untreated infection T-cell activation is associated to HIV viral replication Deeks S Blood 2004
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What happens upon cART?
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CD8+ T cell activation fails to fully normalize during effective cART Hunt PW, et al. J Infect Dis. 2003;187:1534-1543.
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Chronic inflammation is a much more important determinant of mortality in treated HIV Kuller L PLOS Medicine 2008; also Hunt et al. AIDS 2011; Lok et al, AIDS 2013; Hunt et al. JID 2014; Tenorio et al JID 2014; …..
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What drives persistent immune activation/inflammation in cART-treated disease?
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Gut epithelial barrier dysfunction, microbiome and microbial translocation Co-infections (CMV et al….) Residual HIV replication Thymic dysfunction and residual defects in adaptive immune responses Lack of immunoregulatory responses- Lymphoid fibrosis Co-morbid conditions (metabolic syndrome, central adiposity)
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What drives persistent immune activation/inflammation in cART-treated disease? Gut epithelial barrier dysfunction, microbiome and microbial translocation Co-infections (CMV et al….) Residual HIV replication Thymic dysfunction and residual defects in adaptive immune responses Lack of immunoregulatory responses- Lymphoid fibrosis Co-morbid conditions (metabolic syndrome, central adiposity)
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Gut epithelial barrier dysfunction, microbiome and microbial translocation
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The GI tract as a site of HIV pathogenesis Sandler & Douek, Nat Reviews 2012 Brenchley et al. Nat Med 2006
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Persistent Depletion of CD4+ T cells in the GI Tract despite Normalization in the Peripheral Blood Mehandru S, Plos Med 2006 54 HIV+ patients (acute)
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Persistent damage to the gut tight epithelial barrier despite cART HIV negative HIV+ cART-treated Tincati C et al. CROI 2014 Chung; Plos. Path. 2014; (see also Somsouk AIDS 2015)
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Altered gut tight junctions associate with microbial translocation Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009 Chung et al. Plos. Path. 2014; (see also Somsouk AIDS 2015)
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(Altered) gut tight epithelial barrier as driver of inflammation?
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Altered gut tight junctions associate with immune activation Chung et al Plos. Path. 2014; (see also Somsouk AIDS 2015) Tincati C et al. CROI 2014
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Altered gut microbioma in SIV/HIV Brenchley Nat Med 2006; in humans: Gori et al. JCM 2008
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Only partial recovery of gut microbioma upon successful cART 50 HIV+ patients before (T0) and after 12 months cART (T12)
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(Altered) intestinal microbioma as driver of inflammation?
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Greater representation of proinflammatory/inflammation- thriving class-level bacteria Correlation between gut microbioma and systemic immune activation Ellis et al. JAIDS 2011, also Dillon et al. Mucosal Immunol 2014
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Persistent microbial translocation during cART Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009
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Microbial translocation hampers CD4+ T-cell recovery upon cART Marchetti G et al. AIDS 2008; Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009
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Microbial translocation and immune activation: what is the cause what is the effect?
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Microbial translocation causes immune activation: colocalization of E.coli and IFN- in colon Estes J et al. PLoS Pathogens 2010
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Microbial translocation is associated to immune activation Brenchley J et al. Nat Med 2006 Marchetti G et al. AIDS 2008; Jiang et al. J Infect Dis 2009
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Exogenous LPS administration enhances immune activation and HIV replication Pandrea et al J Immunol 2008; Pandrea et al. Blood 2012
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Bacterial products drive monocyte expression of thrombosplastin Funderburg N et al Blood 2010
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In vitro LPS stimulation of monocyte-derived macrophages: cytokine/chemokine expression of genes involved in the TLR pathway Merlini E et al ICI, International Congress of Immunology 2013 35 HIV+ cART- treated
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Stimulation of peripheral blood cells by TLR ligands increases expression of CD38 on CD4+ and CD8+ T-lymphocytes - HIV-negative Funderburg N et al. PLoS One 2008
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In vitro LPS stimulation on PBMC: CD4 and CD8 T- cell activation, proliferation and apoptosis Merlini E et al ICI, International Congress of Immunology 2013 35 HIV+ cART- treated
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Sevelamer treatment reduces MT during early SIVsab infection of PTMs LNs stained for LPS core antigen (brown) Kristoff J, JCI, 2014: 124 (6)
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Sevelamer treatment reduces immune activation/inflammation during early SIV infection in PTMs Kristoff J, J Clin Invest 2014
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Sevelamer does not reduce LPS and sCD14 in chronic early-stage untreated HIV Sandler N, J Infect Dis 2014 Should we test sevelamer in cART- treated HIV?
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Altered balance of gut immunoregulatory cells (e.g. Th17/Th22, gut- homing T-cells) as driver of inflammation?
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Only partial recovery of gut-homing T-cells upon cART 20 HIV+ before and at 12 months cART 20 HIV+ cART- treated Mavigner et al. JCI 2012 Basilissi M ICAR 2015
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Only partial recovery of gut-homing and Th17/Th22 T-cells upon cART 20 HIV+ before and at 12 months cART Basilissi M ICAR 2015
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Low Th17/Treg ratio despite cART Favre et al Science Transl Med 2010 20 HIV+ cART- treated
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Low Th17/Treg ratio is associated to immune activation Favre et al Science Transl Med 2010 20 HIV+ cART- treated
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What drives persistent immune activation/inflammation in cART-treated disease? Gut epithelial barrier dysfunction, microbiome and microbial translocation Co-infections (CMV et al….) Residual HIV replication Thymic dysfunction and residual defects in adaptive immune responses Lack of immunoregulatory responses- Lymphoid fibrosis Co-morbid conditions (metabolic syndrome, central adiposity)
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Higher non-AIDS morbidity/mortality in HIV+/CMV-Ab+ patients 6111 HIV+ (5119 CMV-Ab+), 12% cART-treated Lichtner M et al. J Infect Dis 2015
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Naeger D et al. PlosOne 2010
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cART-treated asymptomatic CMV seminal shedders present higher T- cell activation/proliferation Gianella S et al. J Virol 2015 53 HIV+ cART- treated
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cART-treated asymptomatic CMV seminal shedders present higher T-cell expression of PD-1 45 HIV+ cART- treated Dan J et al. CROI 2015
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Vita S et al. CROI 2015 Higher innate immunity markers in HIV/CMV co-infected patients on cART 69 HIV+ cART- treated (46/69 CMV Ab+)
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Reduction of CD8 T-cell activation by valganciclovir…… Hunt et al., JID, 2011 30 HIV+, 70% cART-treated
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……but not valacyclovir Yi TJ et al., CID, 2013 40 HIV+/HSV2+ cART-treated
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HCV coinfection was associated with increased risk of developing an ADI (adjusted relative rate [ARR], 2.61; 95% confidence interval [CI], 1.88–3.61) *ARR, 3.15 *ARR, 3.87 *ARR, 2.68
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127 HIV-infected hepatitis viruses co-infected patients (118 HCV, 9 HBV) - ART naïve, CD4 cell count >200/μl - known date of prior HIV neg/pos tests →immune activation (IA): IL-6,TNFα →microbial translocation (MT): LPS, sCD14
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Gonzalez et al et al. J Virol 2009 34 : 14 HCV+/HIV+ cART-treated; 11 HCV+; 9 HIV+ treated
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Hampered T-cell dynamics in HIV/HCV co-infected patients 356 HIV+ cART- treated : 130 HCV co-infected Zaegel-Fauchel O et al. AIDS 2015
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Hunt et al. JID 2003; also Greub G Lancet 2000 HCV co-infection is associated to higher T- lymphocyte activation on cART
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HCV treatment reduces immune activation ?
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Reduction of T-cell activation by anti-HCV treatment Gonzalez et al et al. J Virol 2009; also Massanella M et al. Antiviral Therapy 2010 356 HIV+ cART-treated : 130 HCV co- infected
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What drives persistent immune activation/inflammation in cART-treated disease? Gut epithelial barrier dysfunction, microbiome and microbial translocation Co-infections (CMV et al….) Residual HIV replication Thymic dysfunction and residual defects in adaptive immune responses Lack of immunoregulatory responses- Lymphoid fibrosis Co-morbid conditions (metabolic syndrome, central adiposity)
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Adapted from Deeks S – International Congress on Drug Therapy in HIV Infection, Glasgow UK 2-6 Nov 2014 Despite cART, HIV viremia persists indefinitely at very low level
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Immune activation does not correlate with residual plasma viremia…… Case: 123 HIV+ cART-treated with transient low level viremia (>50 <400 cp/ml) Control: HIV+ cART-treated RNA<50cp/ml Taiwo B et al. JAIDS 2013; also Chun TW et al. JID 2011 (including C-reactive protein, D-dimer, IL-6, soluble TNF receptor I); Steel A et al. Antiviral Therapy 2007…..
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Steel A et al. Antiviral Therapy 200.
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…but may associate with residual plasma viremia in the setting of poor immune recovery on cART…. Mauvigner M et al. PlosOne 2009 Marchetti G et al. AIDS 2006
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….Immune activation (and senescence) does associate with cell-associated HIV-DNA/RNA in peripheral blood …. 190 HIV+ cART- treated Hatano H et al. JID 2012; also Stone SF HIV Med 2005
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….and in tissues 23 HIV+ cART- treated Sheth PM et al. Mucosal Immuno 2008; also Yukl SA JID 2010; d’Ettorre G et al. Curr HIV Res 2011
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Hypothesis: if residual HIV replication sustains immune activation upon cART, then cART intensification should lower immune activation
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Any benefit by maraviroc intensification? Wilkin et al., JID 2012
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Any benefit by maraviroc intensification? Hunt et al., Blood, 2013 Rusconi et al., PLOSOne, 2013 97 HIV+ cART- treated with low CD4+ immune recovery 45 HIV+ cART-treated with low CD4+ immune recovery
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Any benefit by integrase inhibitors intensification? 30 HIV+ cART-treated with low CD4+ immune recovery Hatano H et al., JID, 2011; also Hatano H et al JAIDS 2012 Peripheral blood Gut
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Raltegravir induced a specific reduction of CD38 expression in CD8 T cells Massanella et al., AIDS, 2012; also Vallejo A et al. AIDS 2012 Buzon MJ et al. Nat Med 2010; 69 HIV+ cART-treated
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Any differences in the effect on immune activation by diverse cART class?
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CD4 231/uL; n=76 AZT+ddI or AZT+3TC+ ABC or EFV or IDV/r Rizzardini et al., HIV Clin Trials 2006 Advanz Study CD4<100/uL; n=65 AZT+3TC+EFV or LPV/r Mirò et al. AIDS Res and Human Retrov 2010 Advanz 3 Study CD4<100/uL; n=89 TDF+FTC+ EFV or ATZ/r or LPV/r Mirò et al. JAIDS, 2015 Immuno Study CD4 250/uL; n=35 TDF+FTC+ EFV or DRV 800mg/r Tincati et al. under review Data are presented as median values
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Advanz 3 Study CD4<100/uL; n=89 TDF+FTC+ EFV or ATZ/r or LPV/r Mirò et al. JAIDS, 2015 Immuno Study CD4 250/uL, n=35 TDF+FTC+ EFV or DRV 800mg/r Tincati et al. under review Data are presented as median values See also: McComsey, AIDS, 2012
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Similar reduction of T-cell activation by different cART class 318 HIV+ starting first cART (170 PI; 128 NNRTI; 20 INI)
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What drives persistent immune activation/inflammation in cART-treated disease? Gut epithelial barrier dysfunction, microbiome and microbial translocation Co-infections (CMV et al….) Residual HIV replication Thymic dysfunction and residual defects in adaptive immune responses Lack of immunoregulatory responses- Lymphoid fibrosis Co-morbid conditions (metabolic syndrome, central adiposity)
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Isgro’ et al. CID 2008 Bellistrì et al. PlosOne 2010 Bone marrow alterations upon cART 23 HIV+ cART- treated cART
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Douek et al. Nature 1998
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What drives persistent immune activation/inflammation in cART-treated disease? Gut epithelial barrier dysfunction, microbiome and microbial translocation Co-infections (CMV et al….) Residual HIV replication Thymic dysfunction and residual defects in adaptive immune responses Lack of immunoregulatory responses- Lymphoid fibrosis Co-morbid conditions (metabolic syndrome, central adiposity)
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In untreated HIV: hyper-inflamed cytokine milieu → Treg response → TGF-β → collagen deposition → Fibrosis → Reduced IL- 7 → Reduced T cell regeneration → inflammation
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Zeng et al. PlosPathogens 2012 Recovery of collagen deposition according to the stage of cART start
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Schaker et al. JID 2002 Collagen deposition in lymphoid tissues before cART substantially impacts the dynamics of T- lymphocyte reconstitution Zeng et al. PlosPathogens 2012 LN Asmuth et al. AIDS 2015 GUT
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Tissue fibrosis as driver of immune activation?
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Increased CD90+TLR4+ activated myofibroblast in HIV+ duodenal mucosa ( - SMA+FAP+) Asmuth et al. AIDS 2015
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Pinchuck IV et al. Curr Gatroenterol Rep 2010
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LPS stimulation of cultured intestinal myofibroblast from HIV+ patients upregulates pro-fibrotic mediators Asmuth et al. AIDS 2015 + LPS
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Klatt et al. Immunol Rev 2013
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Thanks *Dept of Health Sciences- Clinic of Infectious Diseases- Univ of Milan, San Paolo H Esther Merlini Camilla Tincati Elvira S Cannizzo Giuseppe Ancona Giusi M Bellistrì Francesca Bai Matteo Basilissi Antonella d’Arminio Monforte ***all the patients and staff *Dept of Health Sciences- Pathology Dept- Univ of Milan, S Paolo Ho Delfina Tosi, Solange Romagnoli (now Roche Diagnostics, Germany) Alessandro Cozzi-Lepri, Miriam Lichtner, Antonella d’Arminio Monforte *Clinic of Infect Dis Univ of Milan, L Sacco H Stefano Rusconi, Massimo Galli
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