1. Immune activation & Inflammation in HIV infection
Laurence WEISS

2. 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

3. Innate Immunity Inflammation1 2 3 4 5 6
IL-6
CRP
Haptoglobin
a1-glycoprotein acid
APP
Proinflammatory cytokine network
COAGULATION
TISSUE
FACTOR
 D-dimer
Innate
Immunity
Inflammation
Activation mono/M,
DCs, NK…
Adaptive
immunity
HIV
Other viruses (CMV, HCV...)
Bacterial products (LPS…)
T-cell activation

4. Cytokine storm following HIV infection
D’après Mc Michael Nat Rev Immunol 2010

5. CD8 T-cell activation set point Innate immune activation set point
T-cell and innate immune activation set points during early HIV infection predict subsequent CD4 cell decline
68 recently HIV-infected adults before ART
CD38-MFI
on CD8 T cells
Time (weeks)
proportion with CD4 > 350
CD8 T-cell activation set point
Time to a CD4 T-cell count <350 cells/mm3
Deeks, Blood 2004
Innate immune activation set point
plasma IL-1RA at baseline
(log pg/mL)
% CD38+HLA-DR+
CD8 T cells at M6
Baseline M6
plasma IL-1RA
(log pg/mL)
IL-1RA
plasma sCD14
(ng/mL)
Baseline M6
sCD14
Chevalier, Plos Path 2013

6. 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)

7. Potential mechanisms driving immune activation
HIV infection - Viral replication
CD4 cell loss ↘mucosal CD4+CCR5+ ; ↘ Th17
Innate and adaptive immune responses against HIV
HIV protein production gp120, Nef
Reduced intestinal
barrier integrity
Homeostatic response
Viral reactivation
(CMV, HCV..)
Microbial
translocation
Monocyte activation
T-CELL
ACTIVATION
Adapted from Appay, 2008

8. Depletion of mucosal Th17 cells: microbial translocation and Immune activation
CCR5+CCR6+
Preferential target of HIV
IL-22
IL-17
Proliferation of enterocytes
+ defensins production
Recruitment of PMNs
Integrity of mucosal barriers
(intestinal epithelium)
Control of bacterial and
fungal infections
Epple, Gastroenterology 2010; Brenchley, Blood 2008; Cecchinato,Mucosal Immunol 2008; El Hed, JID 2010

9. Chronic Immune activation
NHP
Chimpanzees SM
AGM
Asymptomatic
NHP Macaques
AIDS
HUMANS
Parameter
Natural hosts
SIV-AGM
Non-natural hosts
HIV/SIV mac
Viral load
Blood, 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

10. log Th17/Treg ratio at baseline
Loss of the Th17/treg balance in pathogenic infection correlates with systemic T-cell activation
% CD38+HLA-DR+
CD8 T cells at M6
log Th17/Treg ratio at baseline
Favre Plos path 2009
Chevalier Plos Path 2013
Th17 depletion correlated with MT and T cell activation in the chronic phase of HIV disease

11. Nasi, Immunol let 2014

12. Biomarker levels associated with mortality in RCT
SMART
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 2008
Rodger JID 2008
Duprez PlosOne 2012
SMART more than 5 thousands patients
Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels.

13. Impact of ART on natural history of HIV disease

14. Persistence of residual chronic T-cell activation in ART-treated patients
n = 30 HIV+ with CV < 75 c/mL
Hunt, JID, 2003
Hunt, JID 2008

15. % Diff. from General Population (MESA)
Despite long-term viral suppression, soluble inflammatory biomarkers remain higher in patients compared to the general population
% Diff. from General Population (MESA)
Neuhaus JID 2010

16. Plasma levels of sCD14: independent predictor of mortality in the SMART study
Nested case-control study in SMART
74 DCs CV events 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

17. Inflammation with ongoing viral replication under ART
HIV- controls
Monocytes pDCs Innate Immunity NK
Adaptative
immunity

18. Inflammation CHRONIC VIRAL INFECTIONS (HIV) CANCER Cardio- Vascular
Diseases
Osteoporosis
Cognitive
disorders

19. 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)

20. 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

21. 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

22. Role of immune activation in HIV persistence
Klatt, Immunol rev 2013

23. 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

24. All the patients included in the studies
Acknowledgments
Mathieu Chevalier
Gaël Petitjean
Céline Didier
Daniel Scott-Algara
Françoise Barré-Sinoussi
Hôpital Européen G. Pompidou
Christophe Piketty
Maria Manea
Erika Bourzam
Hôpital Saint-Antoine
Pierre-Marie Girard
Pauline Campa
Nelly Desplanques
Hôpital Tenon
Laurence Slama
Gilles Pialoux
INSERM U 1018
Laurence Meyer
Christiane Deveau
Feriel Tibaoui
CHU Carémeau Nîmes
Jean-Philippe Lavigne
Catherine Dunyach
U943
Dominique Costagliola
Lambert Assoumou
EA 3620 Christine Rouzioux
the ANRS 116 SALTO study group
All the patients included in the studies