THE 6TH NATIONAL SCIENTIFIC CONFERENCE ON HIV/AIDS

Immune activation & Inflammation in HIV infection

Laurence WEISS

Early events during acute HIV infection

Chronic infection

Intestinal CCR5+ CD4+ T memory cells

Inflammation & immune activation

CD4 count(blood)

Viral load

2-3 weeks 3-10 weeks > 6months

Generalized immune activation

set points

HIV-specific CD8 T cells

(predictive of progression)

Viral reservoirs & replication

Acute infection

The 6th National Scientific Conference on HIV/AIDS

InnateInnateImmunitImmunit

yyHIVOther viruses (CMV, HCV...)Bacterial products (LPS…)

Adaptiveimmunity

T-cell activation

1 2 3 4 5 60

IL-6 CRP

Haptoglobin

1-glycoprotein acid

APP

Activation mono/MActivation mono/M,, DCs, NK…DCs, NK…

The 6th National Scientific Conference on HIV/AIDSD’après Mc Michael Nat Rev Immunol 2010

Cytokine storm following HIV infection

The 6th National Scientific Conference on HIV/AIDS

Deeks, Blood 2004

T-cell and innate immune activation set points during early HIV infection predict subsequent CD4 cell decline

CD38-MFIon CD8 T cells

Time (weeks)

prop

ortio

n w

ith C

D4 >

350

68 recently HIV-infected adults before ART

CD8 T-cell activation set point

Baseline M6

plas

ma

IL-1

RA(lo

g pg

/mL)

IL-1RA

plas

ma

sCD1

4(n

g/m

L)Baseline M6

sCD14

Time to a CD4 T-cell count <350 cells/mm3

Chevalier, Plos Path 2013

plasma IL-1RA at baseline(log pg/mL)

% C

D38

+ HLA

-DR

+

CD

8 T

cells

at M

6

Innate immune activation set point

The 6th National Scientific Conference on HIV/AIDS

Chronic Immune activation in HIV infection

• Monocyte/macrophages

• B lymphocytes Polyclonal or oligoclonal hypergammaglobulinemia

• CD4 and CD8 T lymphocytes

CD8 T-cell activation : predictive of disease progression in untreated patients independent of plasma viral load and CD4 cell counts (Giorgi et al, JID 99; JAIDS 99; Leng et al, J.AIDS 2001; Hazenberg et al, AIDS 2003)

Potential mechanisms driving immune activation

HIV infection - Viral replication

CD4 cell loss↘mucosal CD4+CCR5+ ; ↘ Th17

Microbialtranslocation

Viral reactivation (CMV, HCV..)

HIV protein productiongp120, Nef

Innate and adaptive immune responses

against HIV

T-CELLACTIVATION

Adapted from Appay, 2008

Reduced intestinal barrier integrity

Hom

eostatic response

Monocyte activation

The 6th National Scientific Conference on HIV/AIDS

Th17CCR5+CCR6+

Integrity of mucosal barriers(intestinal epithelium)

Control of bacterial and fungal infections

IL-17

Recruitment of PMNs

IL-22

Proliferation of enterocytes+ defensins production

Depletion of mucosal Th17 cells: microbial translocation and Immune activation

Preferential target of HIV

Epple, Gastroenterology 2010; Brenchley, Blood 2008; Cecchinato,Mucosal Immunol 2008; El Hed, JID 2010

The 6th National Scientific Conference on HIV/AIDS

NHPChimpanzees

SMAGM

AsymptomaticAsymptomatic

NHP Macaques

AIDSAIDS

HUMANS

Parameter Natural hostsSIV-AGM

Non-natural hostsHIV/SIV mac

Viral loadBlood, gut

+++ +++

Chronic Immune activation + +++Depletion of mucosal CD4 T

cells++ +++

Preserved mucosal barrier integrity

+ -

Preferential depletion of mucosal Th 17 cells

- +

Paiardini, Curr Opin HIV AIDS 2010

The 6th National Scientific Conference on HIV/AIDS

Favre Plos path 2009

% C

D38

+ HLA

-DR

+

CD

8 T

cells

at M

6

log Th17/Treg ratio at baseline

Chevalier Plos Path 2013

Loss of the Th17/treg balance in pathogenic infection correlates with systemic T-cell activation

Th17 depletion correlated with MT and T cell activation in the chronic phase of HIV disease

The 6th National Scientific Conference on HIV/AIDSNasi, Immunol let 2014

The 6th National Scientific Conference on HIV/AIDS

Biomarker levels associated with mortality in RCT

• All-cause mortality: higher for patients with CD4> 350 randomly assigned to CD4-guided interruption of ART (DC) than continuous ART (VS)

• Most common causes of death: non AIDS-malignancy, CVD

• Baseline IL-6, hsCRP and D-dimer associated with all cause mortality

• Baseline IL-6, D-dimer and hsCRP: significantly related to CVD

• In the PHIDISA trial (South Africa), elevated pre-ART levels of hsCRP, IL-6 and D-dimer: strongly associated with early mortality after ART initiation Ledwaba,

PlosOne 2012

Kuller Plos Medicine 2008Rodger JID 2008Duprez PlosOne 2012

SMART

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Impact of ART on natural history of HIV disease

The 6th National Scientific Conference on HIV/AIDSHunt, JID, 2003Hunt, JID 2008

Persistence of residual chronic T-cell activation in ART-treated patients

n = 30 HIV+ with CV < 75 c/mL

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Despite long-term viral suppression, soluble inflammatory biomarkers remain higher in patients

compared to the general population

Neuhaus JID 2010

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• Nested case-control study in SMART• 74 DCs + 120 CV events + 100 AIDS events (20 NA) / N= 5472• 2 controls/case• Most patients under ART with VL < 400 cp/mL• Baseline plasma sCD14, IFABP, LPS, EndoCAB

SCD14: marker of monocyte activation (acute phase protein) not necessarily indicative of microbial translocation

Sandler, JID 2011

Plasma levels of sCD14: independent predictor of mortality in the SMART study

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Inflammationwith ongoing

viral replicationInflammation

under ARTInflammationHIV- controls

Monocytes

pDCs Innate ImmunityNK

Adaptativeimmunity

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Cardio-VascularDiseases

Cognitive disorders

Inflammation

CANCER

CHRONIC VIRAL

INFECTIONS(HIV)

Osteoporosis

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Inflammation predicts disease in treated HIV infection, as it

does in the general population

• Mortality (Kuller, PLoS Med, 2008, Sandler JID 2011, Tien JAIDS 2011)

• Cardiovascular Disease (Baker, CROI 2013)

• Lymphoma (Breen, Cancer Epi Bio Prev, 2010)

• Venous Thromboembolism (Musselwhite, AIDS, 2011)

• Type II Diabetes (Brown, Diabetes Care, 2010)

• Cognitive Dysfunction (Burdo AIDS 2012)

• Frailty (Erlandson, JID 2013)

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Soluble markers of inflammation & coagulation, but not T-Cell activation, predict non-AIDS defining events during suppressive ART

• Case-control study of ALLRT subjects (ACTG studies) (ART-naïve at BL and ART-suppressed during FU)

• Cases : non-AIDS death, MI, stroke, non-AIDS cancer, or serious non-AIDS bacterial infection

• Controls (2 - 3/case)

• Greater CD4 change at yr 1 associated with a decreased risk for non-AIDS event (OR per 100 cells increase= 0.81, p= 0.007)

• High T-cell activation: not consistently associated with a non-AIDS-related event

• Higher IL-6,sCD14, sTNFR-I, sTNFR-II, and D-dimer prior to ART independently associated with non AIDS events

Tenorio CROI 2013

The 6th National Scientific Conference on HIV/AIDS

Soluble markers of inflammation & coagulation, but not T-Cell activation, predict non-AIDS defining events during suppressive ART

• Case-control study of ALLRT subjects (ACTG studies) (ART-naïve at BL and ART-suppressed during FU)

• Cases : non-accidental non-AIDS death, MI, stroke, non-AIDS cancer, or serious non-AIDS bacterial infection

• Controls (2 - 3/case)

• Greater CD4 change at yr 1 associated with a decreased risk of non-AIDS event (OR per 100 cells increase= 0.81, p= 0.007)

• High T-cell activation: not consistently associated with a non-AIDS-related event

• Higher IL-6,sCD14, sTNFR-I, sTNFR-II, and D-dimer prior to ART independently associated with non AIDS event

Tenorio CROI 2013

Role of immune activation in HIV persistence

Klatt, Immunol rev 2013

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Suboptimal CD4 T-cell gains

HIV persistence

Comorbidities (Accelerated atherosclerosis, arterial inflammation, cognitive

disorders, chronic renal disease, osteoporosis: « Inflam-Aging » , cancers)

↗ Risk of mortality

Persistent Inflammation

under ART

The 6th National Scientific Conference on HIV/AIDSAll the patients included in the studies

Hôpital Européen G. PompidouChristophe PikettyMaria ManeaErika Bourzam

Hôpital Saint-AntoinePierre-Marie GirardPauline CampaNelly Desplanques

Hôpital TenonLaurence SlamaGilles Pialoux CHU Carémeau Nîmes

Jean-Philippe LavigneCatherine Dunyach

Mathieu ChevalierGaël PetitjeanCéline DidierDaniel Scott-AlgaraFrançoise Barré-Sinoussi

INSERM U 1018Laurence MeyerChristiane DeveauFeriel Tibaoui

Acknowledgments

U943Dominique CostagliolaLambert Assoumou

the ANRS 116 SALTO study groupEA 3620 Christine Rouzioux