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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.

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Presentation on theme: "What drives persistent immune activation/inflammation in cART-treated HIV-1? Giulia Marchetti, MD, PhD Dept of Health Sciences, Clinic of Infectious Diseases."— Presentation transcript:

1 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

2 The revolution of cART Hammer, S et al. NEJM 1997; Palella, F et al. NEJM 1998 CD4+HIV-RNA

3 Full restoration of health upon cART?

4 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

5 Serious non-AIDS events during long-term virologically suppressive cART Tenorio et al. JID 2014

6 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

7 High proportion of activated CD8+ T-cells in HIV Giorgi, J et al. J Immunol 1993

8 CD8 T-cell activation predicts CD4+ T-cell count over time Deeks et al. Blood 2004

9 Shorter survival is associated with T- lymphocyte activation Giorgi, J et al. JID 1999

10 In untreated infection T-cell activation is associated to HIV viral replication Deeks S Blood 2004

11 What happens upon cART?

12 CD8+ T cell activation fails to fully normalize during effective cART Hunt PW, et al. J Infect Dis. 2003;187:1534-1543.

13 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; …..

14 What drives persistent immune activation/inflammation in cART-treated disease?

15 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)

16 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)

17 Gut epithelial barrier dysfunction, microbiome and microbial translocation

18 The GI tract as a site of HIV pathogenesis Sandler & Douek, Nat Reviews 2012 Brenchley et al. Nat Med 2006

19 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)

20 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)

21 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)

22 (Altered) gut tight epithelial barrier as driver of inflammation?

23 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

24 Altered gut microbioma in SIV/HIV Brenchley Nat Med 2006; in humans: Gori et al. JCM 2008

25 Only partial recovery of gut microbioma upon successful cART 50 HIV+ patients before (T0) and after 12 months cART (T12)

26 (Altered) intestinal microbioma as driver of inflammation?

27 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

28 Persistent microbial translocation during cART Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009

29 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

30 Microbial translocation and immune activation: what is the cause what is the effect?

31 Microbial translocation causes immune activation: colocalization of E.coli and IFN-  in colon Estes J et al. PLoS Pathogens 2010

32 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

33 Exogenous LPS administration enhances immune activation and HIV replication Pandrea et al J Immunol 2008; Pandrea et al. Blood 2012

34 Bacterial products drive monocyte expression of thrombosplastin Funderburg N et al Blood 2010

35 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

36 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

37 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

38 Sevelamer treatment reduces MT during early SIVsab infection of PTMs LNs stained for LPS core antigen (brown) Kristoff J, JCI, 2014: 124 (6)

39 Sevelamer treatment reduces immune activation/inflammation during early SIV infection in PTMs Kristoff J, J Clin Invest 2014

40 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?

41 Altered balance of gut immunoregulatory cells (e.g. Th17/Th22, gut- homing T-cells) as driver of inflammation?

42 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

43 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

44 Low Th17/Treg ratio despite cART Favre et al Science Transl Med 2010 20 HIV+ cART- treated

45 Low Th17/Treg ratio is associated to immune activation Favre et al Science Transl Med 2010 20 HIV+ cART- treated

46 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)

47

48 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

49 Naeger D et al. PlosOne 2010

50 cART-treated asymptomatic CMV seminal shedders present higher T- cell activation/proliferation Gianella S et al. J Virol 2015 53 HIV+ cART- treated

51 cART-treated asymptomatic CMV seminal shedders present higher T-cell expression of PD-1 45 HIV+ cART- treated Dan J et al. CROI 2015

52 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+)

53 Reduction of CD8 T-cell activation by valganciclovir…… Hunt et al., JID, 2011 30 HIV+, 70% cART-treated

54 ……but not valacyclovir Yi TJ et al., CID, 2013 40 HIV+/HSV2+ cART-treated

55 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

56 127 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

57 Gonzalez et al et al. J Virol 2009 34 : 14 HCV+/HIV+ cART-treated; 11 HCV+; 9 HIV+ treated

58 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

59 Hunt et al. JID 2003; also Greub G Lancet 2000 HCV co-infection is associated to higher T- lymphocyte activation on cART

60 HCV treatment reduces immune activation ?

61 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

62 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)

63 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

64 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…..

65 Steel A et al. Antiviral Therapy 200.

66 …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

67 ….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

68 ….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

69 Hypothesis: if residual HIV replication sustains immune activation upon cART, then cART intensification should lower immune activation

70 Any benefit by maraviroc intensification? Wilkin et al., JID 2012

71 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

72 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

73 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

74 Any differences in the effect on immune activation by diverse cART class?

75 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

76 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

77 Similar reduction of T-cell activation by different cART class 318 HIV+ starting first cART (170 PI; 128 NNRTI; 20 INI)

78 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)

79 Isgro’ et al. CID 2008 Bellistrì et al. PlosOne 2010 Bone marrow alterations upon cART 23 HIV+ cART- treated cART

80 Douek et al. Nature 1998

81 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)

82 In untreated HIV: hyper-inflamed cytokine milieu → Treg response → TGF-β → collagen deposition → Fibrosis → Reduced IL- 7 → Reduced T cell regeneration → inflammation

83 Zeng et al. PlosPathogens 2012 Recovery of collagen deposition according to the stage of cART start

84 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

85 Tissue fibrosis as driver of immune activation?

86 Increased CD90+TLR4+ activated myofibroblast in HIV+ duodenal mucosa (  - SMA+FAP+) Asmuth et al. AIDS 2015

87 Pinchuck IV et al. Curr Gatroenterol Rep 2010

88 LPS stimulation of cultured intestinal myofibroblast from HIV+ patients upregulates pro-fibrotic mediators Asmuth et al. AIDS 2015 + LPS

89 Klatt et al. Immunol Rev 2013

90 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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