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)

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


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


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


Low Th17/Treg ratio is associated to immune activation

Favre et al Science Transl Med 2010






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


cART-treated asymptomatic CMV seminal shedders present higher T-cell expression of PD-1


Dan J et al. CROI 2015

Vita S et al. CROI 2015

Higher innate immunity markers in HIV/CMV co-infected patients on cART


(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





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 ….


Hatano H et al. JID 2012; also Stone SF HIV Med 2005

….and in tissues


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;


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)





adiposity)

Isgro’ et al. CID 2008

Bellistrì et al. PlosOne 2010

Bone marrow alterations upon cART


cARTcART

Douek et al. Nature 1998





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+)


Pinchuck IV et al. Curr Gatroenterol Rep 2010

LPS stimulation of cultured intestinal myofibroblast from HIV+ patients upregulates pro-fibrotic mediators


+ 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

what drives persistent immune activation/inflammation in cart-treated hiv-1? giulia marchetti, md,...

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