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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 The revolution of cART CD4+ HIV-RNA Hammer, S et al. NEJM 1997; Palella, F et al. NEJM 1998 Full restoration of health upon cART? Life expectancy in cART-treated patients ART-Cohort Collaboration 22.937 individuals (82,022 personyear) At age 20 Samji et al. ART-Cohort Collaboration. PlosOne 2013 Serious non-AIDS events during long-term virologically suppressive cART Tenorio et al. JID 2014 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 High proportion of activated CD8+ T-cells in HIV Giorgi, J et al. J Immunol 1993 CD8 T-cell activation predicts CD4+ T-cell count over time Deeks et al. Blood 2004 Shorter survival is associated with Tlymphocyte activation Giorgi, J et al. JID 1999 In untreated infection T-cell activation is associated to HIV viral replication Deeks S Blood 2004 What happens upon cART? CD8+ T cell activation fails to fully normalize during effective cART Hunt PW, et al. J Infect Dis. 2003;187:1534-1543. 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; ….. What drives persistent immune activation/inflammation in cART-treated disease? 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) 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) Gut epithelial barrier dysfunction, microbiome and microbial translocation The GI tract as a site of HIV pathogenesis Brenchley et al. Nat Med 2006 Sandler & Douek, Nat Reviews 2012 Persistent Depletion of CD4+ T cells in the GI Tract despite Normalization in the Peripheral Blood 54 HIV+ patients (acute) Mehandru S, Plos Med 2006 Persistent damage to the gut tight epithelial barrier despite cART Chung; Plos. Path. 2014; (see also Somsouk AIDS 2015) HIV negative HIV+ cART-treated Tincati C et al. CROI 2014 Chung et al. Plos. Path. 2014; (see also Somsouk AIDS 2015) Plasma LPS (pg/mL) Altered gut tight junctions associate with microbial translocation P = 0.001 300 P = 0.002 200 100 0 HIV Negative HAART VL < 75 Untreated Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009 (Altered) gut tight epithelial barrier as driver of inflammation? 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 Altered gut microbioma in SIV/HIV Brenchley Nat Med 2006; in humans: Gori et al. JCM 2008 Only partial recovery of gut microbioma upon successful cART 50 HIV+ patients before (T0) and after 12 months cART (T12) (Altered) intestinal microbioma as driver of inflammation? Greater representation of proinflammatory/inflammationthriving class-level bacteria Correlation between gut microbioma and systemic immune activation Ellis et al. JAIDS 2011, also Dillon et al. Mucosal Immunol 2014 Plasma LPS (pg/mL) Persistent microbial translocation during cART P = 0.001 300 P = 0.002 200 100 0 HIV Negative HAART VL < 75 Untreated Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009 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 Microbial translocation and immune activation: what is the cause what is the effect? Microbial translocation causes immune activation: colocalization of E.coli and IFN-a in colon Estes J et al. PLoS Pathogens 2010 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 Exogenous LPS administration enhances immune activation and HIV replication Pandrea et al J Immunol 2008; Pandrea et al. Blood 2012 Bacterial products drive monocyte expression of thrombosplastin Funderburg N et al Blood 2010 In vitro LPS stimulation of monocyte-derived macrophages: cytokine/chemokine expression of genes involved in the TLR pathway 35 HIV+ cARTtreated Merlini E et al ICI, International Congress of Immunology 2013 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 In vitro LPS stimulation on PBMC: CD4 and CD8 Tcell activation, proliferation and apoptosis 35 HIV+ cARTtreated Merlini E et al ICI, International Congress of Immunology 2013 Sevelamer treatment reduces MT during early SIVsab infection of PTMs LNs stained for LPS core antigen (brown) Kristoff J, JCI, 2014: 124 (6) Sevelamer treatment reduces immune activation/inflammation during early SIV infection in PTMs Kristoff J, J Clin Invest 2014 Sevelamer does not reduce LPS and sCD14 in chronic early-stage untreated HIV Sandler N, J Infect Dis 2014 Should we test sevelamer in cARTtreated HIV? Altered balance of gut immunoregulatory cells (e.g. Th17/Th22, guthoming T-cells) as driver of inflammation? Only partial recovery of gut-homing T-cells upon cART 20 HIV+ before and at 12 months cART 20 HIV+ cARTtreated Basilissi M ICAR 2015 Mavigner et al. JCI 2012 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 Low Th17/Treg ratio despite cART 20 HIV+ cARTtreated Favre et al Science Transl Med 2010 Low Th17/Treg ratio is associated to immune activation 20 HIV+ cARTtreated Favre et al Science Transl Med 2010 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) 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 Naeger D et al. PlosOne 2010 cART-treated asymptomatic CMV seminal shedders present higher Tcell activation/proliferation 53 HIV+ cARTtreated Gianella S et al. J Virol 2015 cART-treated asymptomatic CMV seminal shedders present higher T-cell expression of PD-1 45 HIV+ cARTtreated Dan J et al. CROI 2015 Higher innate immunity markers in HIV/CMV co-infected patients on cART p=0.018 sCD163 ng/ml 2500 2000 1500 1000 500 0 HIV/CMV - Fig. 1A HIV/CMV + Serostatus 69 HIV+ cARTtreated (46/69 CMV Ab+) Vita S et al. CROI 2015 Reduction of CD8 T-cell activation by valganciclovir…… 30 HIV+, 70% cART-treated Hunt et al., JID, 2011 ……but not valacyclovir 40 HIV+/HSV2+ cART-treated Yi TJ et al., CID, 2013 *ARR, 3.87 *ARR, 3.15 *ARR, 2.68 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) 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 34 : 14 HCV+/HIV+ cART-treated; 11 HCV+; 9 HIV+ treated Gonzalez et al et al. J Virol 2009 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 HCV co-infection is associated to higher Tlymphocyte activation on cART Hunt et al. JID 2003; also Greub G Lancet 2000 HCV treatment reduces immune activation ? Reduction of T-cell activation by anti-HCV treatment 356 HIV+ cART-treated : 130 HCV coinfected Gonzalez et al et al. J Virol 2009; also Massanella M et al. Antiviral Therapy 2010 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) Despite cART, HIV viremia persists indefinitely at very low level Adapted from Deeks S – International Congress on Drug Therapy in HIV Infection, Glasgow UK 2-6 Nov 2014 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….. Steel A et al. Antiviral Therapy 200. …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 ….Immune activation (and senescence) does associate with cell-associated HIV-DNA/RNA in peripheral blood …. 190 HIV+ cARTtreated Hatano H et al. JID 2012; also Stone SF HIV Med 2005 ….and in tissues 23 HIV+ cARTtreated Sheth PM et al. Mucosal Immuno 2008; also Yukl SA JID 2010; d’Ettorre G et al. Curr HIV Res 2011 Hypothesis: if residual HIV replication sustains immune activation upon cART, then cART intensification should lower immune activation Any benefit by maraviroc intensification? Wilkin et al., JID 2012 Any benefit by maraviroc intensification? 45 HIV+ cART-treated with low CD4+ immune recovery Hunt et al., Blood, 2013 97 HIV+ cARTtreated with low CD4+ immune recovery Rusconi et al., PLOSOne, 2013 Any benefit by integrase inhibitors intensification? 30 HIV+ cART-treated with low CD4+ immune recovery Peripheral blood Gut Hatano H et al., JID, 2011; also Hatano H et al JAIDS 2012 Raltegravir induced a specific reduction of CD38 expression in CD8 T cells 69 HIV+ cART-treated Buzon MJ et al. Nat Med 2010; Massanella et al., AIDS, 2012; also Vallejo A et al. AIDS 2012 Any differences in the effect on immune activation by diverse cART class? 1 * 1.0 0.5 0.0 60 40 20 10 80 60 40 20 60 ID Vr EF V Vr * * * 40 * 20 EF V LP V/ r 40 * * 30 T0 20 T12 10 0 D R V/ r EF V A TZ /r 50 LP V/ r 0 EF V Tincati et al. under review B 20 ID * % CD8+CD38+DR+ * %CD8+CD38+HLADR+ Immuno Study CD4<50>250/uL; n=35 TDF+FTC+ EFV or DRV 800mg/r A 30 0 Mirò et al. JAIDS, 2015 * 0 EF V 100 C r ID V/ EF V C B 80 0 % CD8+CD38+ Advanz 3 Study CD4<100/uL; n=89 TDF+FTC+ EFV or ATZ/r or LPV/r 5 AT Z/ r Mirò et al. AIDS Res and Human Retrov 2010 10 40 CD8+CD38+DR+, % %CD8+CD38+ Advanz Study CD4<100/uL; n=65 AZT+3TC+EFV or LPV/r A * 100 * 15 0 r ID V/ B A EF V 0 1.5 * * 20 ID V/ r 2 25 EF V 3 2.0 %CD8+CD38+R0+ 4 C Rizzardini et al., HIV Clin Trials 2006 * %CD8+CD25+ 5 % CD8+DRII+ CD4 231/uL; n=76 AZT+ddI or AZT+3TC+ ABC or EFV or IDV/r Data are presented as median values hs RCP D-Dimer 0.3 400 mg/dL 200 100 pg/mL 2 LP V/ r 2 Data are presented as median values D R V/ r 0 D R V/ r T12 3 1 EF V A TZ /r LP V/ r T0 * 4 4 10 0 EF V LP V/ r A TZ /r * * * 5 sCD14 ug/mL pg/mL /r 1 5 0 See also: McComsey, AIDS, 2012 2 IL-6 8 * 15 EF V Tincati et al. under review 20 0 EF V 0 6 LP V EF V 5 Immuno Study CD4<50>250/uL, n=35 TDF+FTC+ EFV or DRV 800mg/r * 3 * TNF-a sCD14 * EF V IL-6 ug/mL 10 LP V/ r EF V A TZ /r 0.0 160 120 80 40 pg/mL Mirò et al. JAIDS, 2015 0 0.1 A TZ /r Advanz 3 Study CD4<100/uL; n=89 TDF+FTC+ EFV or ATZ/r or LPV/r 0.2 A TZ /r ng/mL 300 Similar reduction of T-cell activation by different cART class 318 HIV+ starting first cART (170 PI; 128 NNRTI; 20 INI) 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) Bone marrow alterations upon cART cART cART 23 HIV+ cARTtreated Isgro’ et al. CID 2008 Bellistrì et al. PlosOne 2010 Douek et al. Nature 1998 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) In untreated HIV: hyper-inflamed cytokine milieu → Treg response → TGF-β → collagen deposition → Fibrosis → Reduced IL7 → Reduced T cell regeneration → inflammation Recovery of collagen deposition according to the stage of cART start Zeng et al. PlosPathogens 2012 Collagen deposition in lymphoid tissues before cART substantially impacts the dynamics of Tlymphocyte reconstitution LN Schaker et al. JID 2002 GUT Asmuth et al. AIDS 2015 Zeng et al. PlosPathogens 2012 Tissue fibrosis as driver of immune activation? Increased CD90+TLR4+ activated myofibroblast in HIV+ duodenal mucosa (aSMA+FAP+) Asmuth et al. AIDS 2015 Pinchuck IV et al. Curr Gatroenterol Rep 2010 LPS stimulation of cultured intestinal myofibroblast from HIV+ patients upregulates pro-fibrotic mediators + LPS + LPS Asmuth et al. AIDS 2015 Klatt et al. Immunol Rev 2013 Thanks *Dept of Health SciencesClinic of Infectious DiseasesUniv 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 SciencesPathology DeptUniv of Milan, S Paolo Ho Delfina Tosi, Solange Romagnoli (now Roche Diagnostics, Germany) *Clinic of Infect Dis Univ of Milan, L Sacco H Stefano Rusconi, Massimo Galli Alessandro Cozzi-Lepri, Miriam Lichtner, Antonella d’Arminio Monforte