Matrix metalloprotease inhibitors restore impaired NK cell-mediated antibody-dependent cellular cytotoxicity in human immunodeficiency virus type 1 infection.
Increasing evidence suggests that NK cells not only are critical in the initial host defense against pathogens but also may contribute to continued protection from human immunodeficiency virus type 1 (HIV-1) disease progression. NK cell cytolysis can be induced directly through diverse receptor families or can be induced indirectly through Fc receptors by antibodies mediating antibody-dependent cellular cytotoxicity (ADCC). ADCC has been implicated in both protection from simian immunodeficiency virus infection and slower progression of HIV-1 disease. ADCC activity declines with advancing infection, and yet the underlying mechanism for this dysfunction has not been defined, nor has it been determined whether the activity can be reconstituted. Here we demonstrate that NK cell-mediated ADCC is severely compromised in chronic HIV infection. The potency of ADCC function was directly correlated with baseline Fc gammaRIIIa receptor (CD16) expression on NK cells. CD16 expression was negatively influenced by elevated expression of a group of enzymes, the matrix metalloproteinases (MMPs), normally involved in tissue/receptor remodeling. Inhibition of MMPs resulted in increased CD16 expression and augmented ADCC activity in response to antibody-coated target cells. These data suggest that MMP inhibitors may improve NK cell-mediated ADCC, which may provide subjects with an opportunity to harness the cytolytic power of NK cells through naturally occurring nonneutralizing HIV-specific antibodies.
Liu
Qingquan
Q
Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Sun
Yongtao
Y
Rihn
Suzannah
S
Nolting
Anne
A
Tsoukas
Peter Nicholas
PN
Jost
Stephanie
S
Cohen
Kristen
K
Walker
Bruce
B
Alter
Galit
G
D000328:Adult; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D005260:Female; D058851:GPI-Linked Proteins; D015870:Gene Expression; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis*; D008875:Middle Aged; D017452:Receptors, IgG / Q000096:biosynthesis
C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D015483:HIV Antibodies; D017452:Receptors, IgG; D020782:Matrix Metalloproteinases