title: Dysregulated Tim-3 expression on natural killer cells is associated with increased Galectin-9 levels in HIV-1 infection.
abstract: BACKGROUND
  Natural killer (NK) cells constitutively express high levels of Tim-3, an immunoregulatory molecule recently proposed to be a marker for mature and functional NK cells. Whether HIV-1 infection modulates the expression of Tim-3 on NK cells, or the levels of its ligand Galectin-9 (Gal-9), and how signaling through these molecules affects the NK cell response to HIV-1 remains inadequately understood.
  
  
  RESULTS
  We analyzed Tim-3 and Gal-9 expression in a cohort of 85 individuals with early and chronic HIV-1 infection, and in 13 HIV-1 seronegative control subjects. HIV-1 infection was associated with reduced expression of Tim-3 on NK cells, which was normalized by HAART. Plasma concentrations of Gal-9 were higher in HIV-1-infected individuals than in healthy individuals. Interestingly, Gal-9 expression in immune cells was significantly elevated in early infection, with monocytes and dendritic cells displaying the highest expression levels, which correlated with HIV-1 viral loads. In vitro, Gal-9 triggered Tim-3 downregulation on NK cells as well as NK cell activation.
  
  
  CONCLUSIONS
  Our data suggest that high expression levels of Gal-9 during early HIV-1 infection can lead to enhanced NK cell activity, possibly allowing for improved early control of HIV-1. In contrast, persistent Gal-9 production might impair Tim-3 activity and contribute to NK cell dysfunction in chronic HIV-1 infection.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jost
authors.forename: Uriel Y
authors.initials: UY
authors.lastname: Moreno-Nieves
authors.forename: Wilfredo F
authors.initials: WF
authors.lastname: Garcia-Beltran
authors.forename: Keith
authors.initials: K
authors.lastname: Rands
authors.forename: Jeff
authors.initials: J
authors.lastname: Reardon
authors.forename: Ildiko
authors.initials: I
authors.lastname: Toth
authors.forename: Alicja
authors.initials: A
authors.lastname: Piechocka-Trocha
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D003713:Dendritic Cells / Q000276:immunology; D037161:Galectins / Q000097:blood* / Q000235:genetics; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D054884:Host-Pathogen Interactions; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics*; D009000:Monocytes / Q000276:immunology
chemical_list: D044966:Anti-Retroviral Agents; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008565:Membrane Proteins