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Early events during acute HIV infection 05/03/12 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 AERES Evaluation - Unit of regulation of retroviral infection
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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
The 6th National Scientific Conference on HIV/AIDS
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
The 6th National Scientific Conference on HIV/AIDS
Despite long-term viral suppression, soluble inflammatory biomarkers remain higher in patients
compared to the general population
Neuhaus JID 2010
The 6th National Scientific Conference on HIV/AIDS
• 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
The 6th National Scientific Conference on HIV/AIDS
Inflammationwith ongoing
viral replicationInflammation
under ARTInflammationHIV- controls
Monocytes
pDCs Innate ImmunityNK
Adaptativeimmunity
The 6th National Scientific Conference on HIV/AIDS
Cardio-VascularDiseases
Cognitive disorders
Inflammation
CANCER
CHRONIC VIRAL
INFECTIONS(HIV)
Osteoporosis
The 6th National Scientific Conference on HIV/AIDS
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)
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-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
The 6th National Scientific Conference on HIV/AIDS
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