Immune activation & Inflammation in HIV infection

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


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


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


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


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


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


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


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


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

compared to the general population

Neuhaus JID 2010


• 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


Inflammationwith ongoing

viral replicationInflammation

under ARTInflammationHIV- controls

Monocytes

pDCs Innate ImmunityNK

Adaptativeimmunity


Cardio-VascularDiseases

Cognitive disorders

Inflammation

CANCER

CHRONIC VIRAL

INFECTIONS(HIV)

Osteoporosis


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)


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


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


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

Documents

Immune activation & Inflammation in HIV infection