title: Antiretroviral therapy suppressed participants with low CD4+ T-cell counts segregate according to opposite immunological phenotypes.
abstract: The failure to increase CD4 T-cell counts in some antiretroviral therapy suppressed participants (immunodiscordance) has been related to perturbed CD4 T-cell homeostasis and impacts clinical evolution.
  
  
  
  We evaluated different definitions of immunodiscordance based on CD4 T-cell counts (cutoff) or CD4 T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 antiretroviral therapy suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals.
  
  
  
  Cutoff definition of CD4 cell count 400 cells/μl performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4 T cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated participants into three distinct subgroups with distinct production, programmed cell-death protein-1 (PD-1) expression, activation and death of T cells. Surprisingly, a nonnegligible number of immunodiscordant participants (22%) showed high frequency of recent thymic emigrants and low CD4 T-cell activation and death, very similar to immunoconcordant participants. Notably, human leukocyte antigen - antigen D related (HLA-DR) PD-1 and CD45RA expression in CD4 T cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4 values were maintained in these participants over time.
  
  
  
  A cutoff value of CD4 T-cell count 400 cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup classification may help clinicians to delineate diverse approaches that may be needed to boost CD4 T-cell recovery.
authors.affiliation: aUniversity of California San Diego, La Jolla, California, USAbInstitut de Recerca de la Sida IrsiCaixa-HIVACAT, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, UAB, BadalonacUniversitat de Vic - Universitat Central de Catalunya, BarcelonadFundació Lluita contra la SIDA, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, SpaineDepartment of Microbiology, Infectiology and Immunology, Université de Montréal, Faculté de MédecinefCentre de Recherche du CHUM, Montréal, Québec, Canada.
authors.forename: Josué
authors.initials: J
authors.lastname: Pérez-Santiago
authors.forename: Dan
authors.initials: D
authors.lastname: Ouchi
authors.forename: Victor
authors.initials: V
authors.lastname: Urrea
authors.forename: Jorge
authors.initials: J
authors.lastname: Carrillo
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cabrera
authors.forename: Jordi
authors.initials: J
authors.lastname: Villà-Freixa
authors.forename: Jordi
authors.initials: J
authors.lastname: Puig
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
authors.forename: Eugènia
authors.initials: E
authors.lastname: Negredo
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Marta
authors.initials: M
authors.lastname: Massanella
authors.forename: Julià
authors.initials: J
authors.lastname: Blanco
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D000074243:Immune Reconstitution; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D000072230:Sustained Virologic Response; D016896:Treatment Outcome
chemical_list: D044966:Anti-Retroviral Agents