MHC class I chain-related protein A shedding in chronic HIV-1 infection is associated with profound NK cell dysfunction.
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.
Nolting
Anne
A
Ragon Institute of Massachusetts General Hospital, Harvard University, Boston, MA, USA.
Dugast
Anne-Sophie
AS
Rihn
Suzannah
S
Luteijn
Rutger
R
Carrington
Mary F
MF
Kane
Katherine
K
Jost
Stephanie
S
Toth
Ildiko
I
Nagami
Ellen
E
Faetkenheuer
Gerd
G
Hartmann
Pia
P
Altfeld
Marcus
M
Alter
Galit
G
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
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