Immune activation & Inflammation in HIV infection Laurence WEISS

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

Innate Immunity Inflammation 1 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

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

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

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 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

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

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

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

Nasi, Immunol let 2014

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.

Impact of ART on natural history of HIV disease

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

% 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

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

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

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

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

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