title: HIV infection deregulates Tim-3 expression on innate cells: combination antiretroviral therapy results in partial restoration.
abstract: BACKGROUND
  The Tim-3 receptor has been implicated as a negative regulator of adaptive immune responses and has been linked to T-cell dysfunction in chronic viral infections, such as HIV. Blocking Tim-3 has been proposed as a potential therapeutic intervention in HIV infection. However, a more detailed characterization of Tim-3 expression in the presence of HIV is required before such strategies can be considered.
  
  
  METHODS
  In this study, we investigate Tim-3 expression on innate immune cell subsets in chronic HIV-infected individuals pretherapy and posttherapy.
  
  
  RESULTS
  We report that, pretherapy, HIV infection is associated with elevated levels of Tim-3 on resting innate lymphocytes (NK, NKT, and γδ T cells), but not resting monocytes. In the absence of HIV infection, stimulation with an inflammatory stimulus resulted in decreased Tim-3 on monocytes and increased Tim-3 on NK, NKT, and γδ T cells. However, innate cells from HIV-infected donors were significantly less responsive to stimulation. Six months of combination antiretroviral therapy (cART) restored Tim-3 levels on resting NK cells but not NKT or γδ T cells. The responses of all subsets to inflammatory stimuli were restored to some extent with cART but only reached HIV-negative control levels in monocytes and NK cells.
  
  
  CONCLUSIONS
  These results demonstrate that, during HIV infection, Tim-3 expression on innate cells is dysregulated and that this dysregulation is only partially restored after 6 months of cART. Our findings suggest that Tim-3 is differentially regulated on innate immune effector cells, and have direct implications for strategies designed to block Tim-3-ligand interactions.
authors: SAR Laboratories, Sandra Rotman Centre for Global Health, UHN-Toronto General Hospital, Toronto, ON, Canada.
authors: Constance A M
authors: CA
authors: Finney
authors: Kodjo
authors: K
authors: Ayi
authors: James D
authors: JD
authors: Wasmuth
authors: Prameet M
authors: PM
authors: Sheth
authors: Rupert
authors: R
authors: Kaul
authors: Mona
authors: M
authors: Loutfy
authors: Kevin C
authors: KC
authors: Kain
authors: Lena
authors: L
authors: Serghides
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000954:Antigens, Surface / Q000096:biosynthesis; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D019002:CD56 Antigen / Q000096:biosynthesis; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007249:Inflammation; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D008565:Membrane Proteins / Q000096:biosynthesis*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D000954:Antigens, Surface; D019002:CD56 Antigen; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta