title: Integrative Analysis of Immunological Data to Explore Chronic Immune T-Cell Activation in Successfully Treated HIV Patients.
abstract: OBJECTIVE
  To unravel the complex relationships between cytomegalovirus-induced-, autoimmune-induced responses, microbial translocation and chronic immune activation (CIA) in successfully treated HIV-infected patients and to explore the mediating role of alpha-interferon in these processes.
  
  
  METHODS
  Cross-sectional study nested in the ANRS CO3 Aquitaine Cohort, a prospective hospital-based cohort of HIV-1-infected patients in South-Western France.
  
  
  METHODS
  Patients initiated antiretroviral therapy between 2005 and 2008 and were treated with sustained virological suppression for at least two years. CIA was defined by the percentage of HLA-DR+/CD38+ among CD8+T-cells. Integrative analyses were performed using structural equation modelling (SEM).
  
  
  RESULTS
  The main analysis was performed in 57 HLA-A*0201 positive patients, due to availability of percentages of actin-, vimentin-, lamin-specific CD8+T-cells (HLA-A2-restricted tests) to further characterize autoimmune response. Cytomegalovirus-induced response was assessed by Quantiferon and pp-65 ELISPOT. SEM revealed a direct effect of cytomegalovirus-induced response on CIA (standardized estimate βstd = 0.56, p-value = 0.0004). The effect of autoimmune-induced response on CIA was indirect through alpha-interferon pathway, assessed by expression levels of 5 alpha-interferon-stimulated genes ADAR, ISG15, IFIT1, Mx1 and OAS1 (effect of autoimmune response on alpha-interferon: βstd = 0.36, p-value = 0.0401; effect of alpha-interferon on CIA: βstd = 0.39, p-value = 0.0044). There was no direct effect of autoimmune-induced response on CIA (p-value = 0.3169). Microbial translocation as measured by 16SrDNA and sCD14 in plasma was not associated with CIA. Results were consistent in 142 patients in whom cytomegalovirus and auto-immunity responses were measured by Quantiferon and anti-nuclear antibodies, respectively. All analyses performed in HLA-A*0201 positive patients and in the overall population revealed a significant effect of IFN-α latent variable on CIA.
  
  
  CONCLUSIONS
  The role of cytomegalovirus-induced response on CIA was confirmed as well as the involvement of alpha-interferon on CIA. The indirect effect of auto-immunity response on CIA revealed through the alpha-interferon pathway requires further investigation to confirm the potential role of auto-immunity for CIA in HIV-infected patients.
authors.affiliation: Centre INSERM U1219 Bordeaux Population Health, Bordeaux, France.|Univ. Bordeaux, ISPED, Bordeaux, France.|Service d'Information Médicale, USMR, CHU de Bordeaux - Pôle de Santé Publique, Bordeaux, France.|INRIA, Team SISTM, Bordeaux, France.|Vaccine Research Institute-VRI, Hôpital Henri Mondor, Créteil, France.
authors.forename: Marie-Quitterie
authors.initials: MQ
authors.lastname: Picat
authors.affiliation: Laboratoire d'Immunologie-Immunogénétique, Pôle de Biologie, CHU Bordeaux, Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pellegrin
authors.affiliation: Laboratoire d'Immunologie-Immunogénétique, Pôle de Biologie, CHU Bordeaux, Bordeaux, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Bitard
authors.affiliation: Centre INSERM U1219 Bordeaux Population Health, Bordeaux, France.|Univ. Bordeaux, ISPED, Bordeaux, France.|Service d'Information Médicale, USMR, CHU de Bordeaux - Pôle de Santé Publique, Bordeaux, France.|INRIA, Team SISTM, Bordeaux, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Wittkop
authors.affiliation: Centre INSERM U1219 Bordeaux Population Health, Bordeaux, France.|Univ. Bordeaux, ISPED, Bordeaux, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Proust-Lima
authors.affiliation: Laboratoire de Mathématiques et de leurs Applications, Université de Pau et des Pays de l'Adour, UMR CNRS 5142, Pau, France.|ARC Centre of Excellence for Mathematical and Statistical Frontiers, Queensland University of Technology (QUT), Brisbane, Australia.
authors.forename: Benoît
authors.initials: B
authors.lastname: Liquet
authors.affiliation: Laboratoire d'Immunologie-Immunogénétique, Pôle de Biologie, CHU Bordeaux, Bordeaux, France.|Univ. Bordeaux, Bordeaux, France.|CNRS, UMR 5164, Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Moreau
authors.affiliation: Centre INSERM U1219 Bordeaux Population Health, Bordeaux, France.|Univ. Bordeaux, Bordeaux, France.|Service de Médecine Interne et maladies Infectieuses, CHU de Bordeaux, Bordeaux, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bonnet
authors.affiliation: Laboratoire d'Immunologie-Immunogénétique, Pôle de Biologie, CHU Bordeaux, Bordeaux, France.|Univ. Bordeaux, Bordeaux, France.|CNRS, UMR 5164, Bordeaux, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Blanco
authors.affiliation: Centre INSERM U1219 Bordeaux Population Health, Bordeaux, France.|Univ. Bordeaux, ISPED, Bordeaux, France.|Service d'Information Médicale, USMR, CHU de Bordeaux - Pôle de Santé Publique, Bordeaux, France.|INRIA, Team SISTM, Bordeaux, France.|Vaccine Research Institute-VRI, Hôpital Henri Mondor, Créteil, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Thiébaut
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000465:Algorithms; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003587:Cytomegalovirus; D005260:Female; D005602:France; D015658:HIV Infections / Q000276:immunology* / Q000628:therapy*; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D015999:Multivariate Analysis; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D044966:Anti-Retroviral Agents; D006684:HLA-DR Antigens; D016898:Interferon-alpha; D012336:RNA, Ribosomal, 16S; D051997:ADP-ribosyl Cyclase 1