What drives persistent immune activation/inflammation in cART-treated HIV-1? Giulia Marchetti, MD,...
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Transcript of What drives persistent immune activation/inflammation in cART-treated HIV-1? Giulia Marchetti, MD,...
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
Hammer, S et al. NEJM 1997; Palella, F et al. NEJM 1998
CD4+ HIV-RNA
Full restoration of health upon cART?
Samji et al. ART-Cohort Collaboration. PlosOne 2013
Life expectancy in cART-treated patientsART-Cohort Collaboration
22.937 individuals (82,022 person-year)
At age 20
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 T-lymphocyte 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
Sandler & Douek, Nat Reviews 2012
Brenchley et al. Nat Med 2006
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)
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)
Altered gut tight junctions associate with microbial translocation
0
100
200
300
HIVNegative
HAARTVL < 75
Untreated
P = 0.002
P = 0.001
Pla
sm
a L
PS
(p
g/m
L)
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)
(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/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
Persistent microbial translocation during cART
0
100
200
300
HIVNegative
HAARTVL < 75
Untreated
P = 0.002
P = 0.001P
las
ma
LP
S (
pg
/mL
)
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
Merlini E et al ICI, International Congress of Immunology 2013
35 HIV+ cART-treated
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 T-cell activation, proliferation and apoptosis
Merlini E et al ICI, International Congress of Immunology 2013
35 HIV+ cART-treated
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 cART-
treated HIV?
Altered balance of gut immunoregulatory cells
(e.g. Th17/Th22, gut-homing 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+ cART-treated
Mavigner et al. JCI 2012
Basilissi M ICAR 2015
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
Favre et al Science Transl Med 2010
20 HIV+ cART-treated
Low Th17/Treg ratio is associated to immune activation
Favre et al Science Transl Med 2010
20 HIV+ cART-treated
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 T-cell activation/proliferation
Gianella S et al. J Virol 2015
53 HIV+ cART-treated
cART-treated asymptomatic CMV seminal shedders present higher T-cell expression of PD-1
45 HIV+ cART-treated
Dan J et al. CROI 2015
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+)
Reduction of CD8 T-cell activation by valganciclovir……
Hunt et al., JID, 2011
30 HIV+, 70% cART-treated
……but not valacyclovir
Yi TJ et al., CID, 2013
40 HIV+/HSV2+ cART-treated
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
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
Gonzalez et al et al. J Virol 2009
34 : 14 HCV+/HIV+
cART-treated; 11 HCV+; 9
HIV+ treated
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
Hunt et al. JID 2003; also Greub G Lancet 2000
HCV co-infection is associated to higher T-lymphocyte activation on cART
HCV treatment reduces immune activation ?
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
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)
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
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+ cART-treated
Hatano H et al. JID 2012; also Stone SF HIV Med 2005
….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
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?
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
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
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
Any differences in the effect on immune
activation by diverse cART class?
CD4 231/uL; n=76AZT+ddI or AZT+3TC+ABC or EFV or IDV/r
Rizzardini et al., HIV Clin Trials 2006
Advanz StudyCD4<100/uL; n=65
AZT+3TC+EFV or LPV/r
Mirò et al. AIDS Res and Human Retrov 2010
Advanz 3 StudyCD4<100/uL; n=89
TDF+FTC+ EFV or ATZ/r or LPV/r
Mirò et al. JAIDS, 2015
Immuno StudyCD4<50>250/uL; n=35
TDF+FTC+ EFV or DRV 800mg/r
Tincati et al. under reviewData are presented as
median values
Advanz 3 StudyCD4<100/uL; n=89
TDF+FTC+ EFV or ATZ/r or LPV/r
Mirò et al. JAIDS, 2015
Immuno StudyCD4<50>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
Similar reduction of T-cell activation by different cART class318 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)
Isgro’ et al. CID 2008
Bellistrì et al. PlosOne 2010
Bone marrow alterations upon cART
23 HIV+ cART-treated
cARTcART
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 IL-
7 → Reduced T cell regeneration →
inflammation
Zeng et al. PlosPathogens 2012
Recovery of collagen deposition according to the stage of cART start
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
Tissue fibrosis as driver of immune activation?
Increased CD90+TLR4+ activated myofibroblast in HIV+ duodenal mucosa (a-SMA+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
Asmuth et al. AIDS 2015
+ LPS
+ LPS
Klatt et al. Immunol Rev 2013
Thanks *Dept of Health Sciences- Clinic of Infectious Diseases- Univ of Milan, San Paolo H
Esther MerliniCamilla TincatiElvira S CannizzoGiuseppe AnconaGiusi M BellistrìFrancesca BaiMatteo BasilissiAntonella 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 DisUniv of Milan, L Sacco HStefano Rusconi, Massimo Galli