title: CD4+ T cells with an activated and exhausted phenotype distinguish immunodeficiency during aviremic HIV-2 infection.
abstract: HIV type 2 (HIV-2) represents an attenuated form of HIV, in which many infected individuals remain 'aviremic' without antiretroviral therapy. However, aviremic HIV-2 disease progression exists, and in the current study, we therefore aimed to examine if specific pathological characteristics of CD4 T cells are linked to such outcome.
  
  
  
  HIV-seronegative (n = 25), HIV type 1 (HIV-1) (n = 33), HIV-2 (n = 39, of whom 26 were aviremic), and HIV-1/2 dually (HIV-D) (n = 13)-infected study participants were enrolled from an occupational cohort in Guinea-Bissau.
  
  
  
  CD4 T-cell differentiation, activation, exhaustion, senescence, and transcription factors were assessed by polychromatic flow cytometry. Multidimensional clustering bioinformatic tools were used to identify CD4 T-cell subpopulations linked to infection type and disease stage.
  
  
  
  HIV-2-infected individuals had early and late-differentiated CD4 T-cell clusters with lower activation (CD38HLA-DR) and exhaustion programmed death-1 (PD-1) than HIV-1 and HIV-D-infected individuals. We also noted that aviremic HIV-2-infected individuals possessed fewer individuals. CD4 T cells with pathological signs compared to other HIV-infected groups. Still, compared to HIV-seronegative individuals, aviremic HIV-2-infected individuals had T-bet CD4 T cells that showed elevated immune activation/exhaustion, and particularly the frequencies of PD-1 cells were associated with a suboptimal percentage of CD4 T cells.
  
  
  
  Increased frequencies of CD4 T cells with an activated/exhausted phenotype correlate with exacerbated immunodeficiency in aviremic HIV-2-infected individuals. Thus, these findings encourage studies on the introduction of antiretroviral therapy also to individuals with aviremic HIV-2 infection.
authors.affiliation: aDivision of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden bDepartment of Microbiology, University of Pennsylvania, Philadelphia, PA, USA cCenter for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark dNational Public Health Laboratory, Bissau, Guinea-Bissau eInstituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, Argentina fDepartment of Clinical Sciences Lund gDepartment of Translational Medicine hDepartment of Laboratory Medicine, Lund University, Lund iDepartment of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Buggert
authors.forename: Juliet
authors.initials: J
authors.lastname: Frederiksen
authors.forename: Ole
authors.initials: O
authors.lastname: Lund
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Antonio
authors.initials: A
authors.lastname: Biague
authors.forename: Morten
authors.initials: M
authors.lastname: Nielsen
authors.forename: Johanna
authors.initials: J
authors.lastname: Tauriainen
authors.forename: Hans
authors.initials: H
authors.lastname: Norrgren
authors.forename: Patrik
authors.initials: P
authors.lastname: Medstrand
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsson
authors.forename: Marianne
authors.initials: M
authors.lastname: Jansson
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D015331:Cohort Studies; D005434:Flow Cytometry; D006169:Guinea-Bissau; D015658:HIV Infections / Q000175:diagnosis* / Q000276:immunology / Q000821:virology; D015498:HIV-2 / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D016130:Immunophenotyping; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*