title: Impaired gut junctional complexes feature late-treated individuals with suboptimal CD4+ T-cell recovery upon virologically suppressive combination antiretroviral therapy.
abstract: OBJECTIVE
  HIV-infected individuals with incomplete CD4⁺ T-cell recovery upon combination antiretroviral therapy (cART) display high levels of immune activation and microbial translocation. However, whether a link exists between gut damage and poor immunological reconstitution remains unknown.
  
  
  METHODS
  Cross-sectional study of the gastrointestinal tract in late cART-treated HIV-infected individuals: 15 immunological nonresponders (CD4⁺ <350 cells/μl and/or delta CD4⁺ change from baseline <30%); 15 full responders (CD4⁺ >350 cells/μl and/or delta CD4⁺ change from baseline >30%).
  
  
  METHODS
  We assessed gut structure (junctional complex proteins in ileum and colon) and function (small intestine permeability/damage and microbial translocation parameters). The composition of the fecal microbiome and the size of the HIV reservoir in the gut and peripheral blood were investigated as possible mechanisms underlying mucosal impairment.
  
  
  RESULTS
  Markers of intestinal permeability, damage, systemic inflammation, and microbial translocation were comparable in all study individuals, yet the expression of junctional complex proteins in gut biopsies was significantly lower in HIV-infected patients with incomplete CD4⁺ restoration and negatively correlated with markers of CD4⁺ reconstitution. Electron microscopy revealed dilated intercellular spaces in individuals lacking immunological response to cART, yet not in patients displaying CD4⁺ T-cell recovery. Analysis of the fecal microbiome revealed an overall outgrowth of Bacteroides-Prevotella spp. with no differences according to CD4⁺ T-cell reconstitution. Interestingly, HIV reservoirs in peripheral CD4⁺ T cells and intestinal tissue negatively correlated with immune recovery.
  
  
  CONCLUSIONS
  These observations establish gut damage and the size of the HIV reservoir as features of deficient immunological response to cART and provide new elements for interventional strategies in this setting.
authors.affiliation: aClinic of Infectious Diseases bDepartment of Health Sciences, University of Milan cSan Paolo University Hospital, Milan dPathology Unit eMicrobiology Laboratory fBiotechnology Research Centre, Sacred Heart Catholic University, Cremona, Italy gGastroenterology Unit hBiochemistry Laboratory iRoche Innovation Center, Penzberg, Germany jVaccine and Gene Therapy Institute Florida, Port St Lucie, Florida, USA kCentre de Recherche du CHUM et Université de Montréal, Département de Microbiologie, Infectiologie et Immunologie, Montreal, Quebec, Canada.
authors.forename: Camilla
authors.initials: C
authors.lastname: Tincati
authors.forename: Esther
authors.initials: E
authors.lastname: Merlini
authors.forename: Paola
authors.initials: P
authors.lastname: Braidotti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ancona
authors.forename: Federica
authors.initials: F
authors.lastname: Savi
authors.forename: Delfina
authors.initials: D
authors.lastname: Tosi
authors.forename: Elisa
authors.initials: E
authors.lastname: Borghi
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Callegari
authors.forename: Benedetto
authors.initials: B
authors.lastname: Mangiavillano
authors.forename: Alessandra
authors.initials: A
authors.lastname: Barassi
authors.forename: Gaetano
authors.initials: G
authors.lastname: Bulfamante
authors.forename: Antonella
authors.initials: A
authors.lastname: d'Arminio Monforte
authors.forename: Solange
authors.initials: S
authors.lastname: Romagnoli
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chomont
authors.forename: Giulia
authors.initials: G
authors.lastname: Marchetti
mesh_terms: D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D018988:Bacterial Translocation; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003430:Cross-Sectional Studies; D005260:Female; D041981:Gastrointestinal Tract / Q000473:pathology*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D062725:Tight Junction Proteins / Q000032:analysis*
chemical_list: D044966:Anti-Retroviral Agents; D062725:Tight Junction Proteins