title: MHC class I chain-related protein A shedding in chronic HIV-1 infection is associated with profound NK cell dysfunction.
abstract: Natural killer (NK) cells play a critical role in host defense against viral infections. However chronic HIV-1 infection is associated with an accumulation of dysfunctional NK cells, that poorly control viral replication. The underlying mechanisms for this NK cell mediated dysfunction are not understood. Certain tumors evade NK cell mediated detection by dampening NK cell activity through the downregulation of NKG2D, via the release of soluble NKG2D-ligands, resulting in a potent suppression of NK cell function. Here we show that chronic HIV-1 infection is associated with a specific defect in NKG2D-mediated NK cell activation, due to reduced expression and transcription of NKG2D. Reduced NKG2D expression was associated with elevated levels of the soluble form of the NKG2D-ligand, MICA, in patient sera, likely released by HIV+CD4+ T cells. Thus, like tumors, HIV-1 may indirectly suppress NK cell recognition of HIV-1-infected CD4+ T cells by enhancing NKG2D-ligand secretion into the serum resulting in a profound impairment of NK cell function.
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Harvard University, Boston, MA, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Nolting
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Dugast
authors.forename: Suzannah
authors.initials: S
authors.lastname: Rihn
authors.forename: Rutger
authors.initials: R
authors.lastname: Luteijn
authors.forename: Mary F
authors.initials: MF
authors.lastname: Carrington
authors.forename: Katherine
authors.initials: K
authors.lastname: Kane
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jost
authors.forename: Ildiko
authors.initials: I
authors.lastname: Toth
authors.forename: Ellen
authors.initials: E
authors.lastname: Nagami
authors.forename: Gerd
authors.initials: G
authors.lastname: Faetkenheuer
authors.forename: Pia
authors.initials: P
authors.lastname: Hartmann
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
mesh_terms: D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D016022:Case-Control Studies; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D015658:HIV Infections / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015497:HIV-1; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D020782:Matrix Metalloproteinases