title: Plasma IP-10 Is Increased in Immunological NonResponders and Associated With Activated Regulatory T Cells and Persisting Low CD4 Counts.
abstract: To explore immune mechanisms and identify biomarkers associated with an inadequate immune recovery in patients with HIV with efficient antiretroviral therapy.
  
  
  
  A cross-sectional study of 67 HIV-infected patients on antiretroviral therapy for ≥24 months with HIV RNA ≤20 copies per milliliter; 41 were defined as immunological nonresponders (INR) (CD4 < 400 cells per microliter) and 26 as immunological responders (CD4 > 600 cells per microliter). CD4 counts were also registered 2 years after inclusion.
  
  
  
  Cytokines, soluble markers of microbial translocation, and tryptophan catabolites were measured in plasma by multiplex assay, ELISA, or mass spectrometry. T-cell activation, differentiation, and regulatory T cells (Tregs) were analyzed by flow cytometry in 2 subgroups with comparable nadir CD4 counts.
  
  
  
  Plasma interferon-inducible protein-10 (IP-10) levels were higher (P < 0.05), the T cells were more activated (CD38HLA-DR) (P < 0.05), the naive/effector memory T-cell ratio was lower (P < 0.01) and the proportion of resting Tregs (CD4CD45RAFoxP3) was reduced (P < 0.001) in INR patients compared with immunological responders. INR patients with CD4 counts ≤300 cells per microliter also demonstrated a higher fraction of activated Tregs (aTreg) (CD4CD147CD25) (P < 0.05). In the INR group, the aTreg percentages correlated with plasma IP-10 levels and inversely with CD4 counts (both P < 0.01). IP-10 levels (P < 0.05) and kynurenine/tryptophan ratio (P < 0.01) were negatively associated with the CD4 count 2 years after inclusion.
  
  
  
  Patients with HIV with inadequate CD4 responses had higher levels of IP-10, more activated and differentiated T-cell phenotypes, as well as aTreg, compared with patients with satisfactory CD4 gain. High IP-10 levels were also associated with lower CD4 counts after 2 years.
authors.affiliation: *Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway;†Department of Infectious Diseases, Institute of Clinical Medicine, University of Oslo, Oslo, Norway;‡Centre for Molecular Medicine Norway, Nordic EMBL Partnership, Oslo University Hospital, University of Oslo, Oslo, Norway;§Biotechnology Centre, University of Oslo, Oslo, Norway;‖K.G. Jebsen Centre for Inflammation Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway;¶Department of Immunology, Oslo University Hospital, Oslo, Norway;#Research Laboratory, Nordland Hospital, Bodø, Norway;**Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Norway;††Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway;‡‡Department of Clinical Science, University of Bergen, Bergen, Norway;§§Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway;‖‖Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; and¶¶Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Stiksrud
authors.forename: Kristina Berg
authors.initials: KB
authors.lastname: Lorvik
authors.forename: Dag
authors.initials: D
authors.lastname: Kvale
authors.forename: Tom Eirik
authors.initials: TE
authors.lastname: Mollnes
authors.forename: Per Magne
authors.initials: PM
authors.lastname: Ueland
authors.forename: Marius
authors.initials: M
authors.lastname: Trøseid
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dyrhol-Riise
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D018791:CD4 Lymphocyte Count; D054357:Chemokine CXCL10 / Q000097:blood*; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10