title: Impaired natural killer cell responses are associated with loss of the highly activated NKG2A(+)CD57(+)CD56(dim) subset in HIV-1 subtype D infection in Uganda.
abstract: OBJECTIVE
  Of the predominant HIV-1 subtypes in Uganda, subtype D infection confers a worse prognosis. HIV-1 infection causes perturbations to natural killer (NK) cells, and yet these cells can exert immune pressure on the virus and influence clinical outcome. Here, we studied NK cell activation and function in Ugandans with chronic untreated HIV-1 subtype D infection in comparison to uninfected community matched controls.
  
  
  METHODS
  Cryopreserved peripheral blood mononuclear cells (PBMCs) from 42 HIV-infected individuals and 28 HIV-negative controls were analysed using eight-colour flow cytometry. NK cell surface expression of CD16, CD56, CD57, HLA-DR and NKG2A were used to investigate activation, maturation and differentiation status. NK cell function was evaluated by measuring interferon-gamma (IFNγ) production in response to K562 cells, or interleukin (IL)-12 and IL-18.
  
  
  RESULTS
  CD56(dim) NK cells from HIV-infected individuals produced less IFNγ in response to IL-12 and IL-18 than did CD56(dim) NK cells from uninfected controls. Infected individuals had lower levels of CD56(dim) NK cells coexpressing the differentiation markers NKG2A and CD57 than controls. In addition, their NKG2A(+)CD57(+) CD56(dim) NK cells displayed elevated activation levels as assessed by HLA-DR expression. Cytokine-induced IFNγ production correlated directly with coexpression of CD57 and NKG2A on CD56(dim) NK cells.
  
  
  CONCLUSIONS
  HIV-1 subtype D infection is associated with impaired NK cell responsiveness to cytokines, decline of the NKG2A(+)CD57(+) CD56(dim) NK cell subset, as well as elevated activation in this subset. These alterations within the NK cell compartment may contribute to immunopathogenesis of HIV-1 subtype D infection in Ugandans.
authors: aMakerere University Walter Reed Project, Kampala, Uganda bCenter for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden cUS Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring dHenry M. Jackson Foundation for the Advancement of Military Medicine eLaboratory of Immunoregulation, Division of Intramural Research, NIAID, NIH, Bethesda fSchool of Medicine, Johns Hopkins University, Baltimore, Maryland, USA gSchool of Public Health, Makerere University College of Health Sciences, Kampala hRakai Health Sciences Program, Uganda Virus Research Institute, Entebbe iFaculty of Medicine, Makerere University College of Health Sciences, Kampala, Uganda jBloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Prossy
authors: P
authors: Naluyima
authors: Michael A
authors: MA
authors: Eller
authors: Oliver
authors: O
authors: Laeyendecker
authors: Thomas C
authors: TC
authors: Quinn
authors: David
authors: D
authors: Serwadda
authors: Nelson K
authors: NK
authors: Sewankambo
authors: Ronald H
authors: RH
authors: Gray
authors: Nelson L
authors: NL
authors: Michael
authors: Fred
authors: F
authors: Wabwire-Mangen
authors: Merlin L
authors: ML
authors: Robb
authors: Johan K
authors: JK
authors: Sandberg
mesh_terms: D000954:Antigens, Surface / Q000032:analysis*; D015331:Cohort Studies; D005838:Genotype; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D014454:Uganda
chemical_list: D000954:Antigens, Surface; D007371:Interferon-gamma