HIV inhibits early signal transduction events triggered by CD16 cross-linking on NK cells, which are important for antibody-dependent cellular cytotoxicity

Defective NK cell ADCC in whole blood from HIV‐infected patients due to impaired early signaling in response to CD16 surface receptor cross‐linking. Measurement of NK cell cytolytic activity in the setting of chronic viral infection is important for determining viral pathogenicity. Mobilization of LAMP‐1 (CD107a) to the NK cell surface is a surrogate marker for cytotoxic granule release and hence, NK cell cytotoxicity. We have developed a convenient, rapid, whole blood flow cytometric assay for measuring CD107a mobilization in response to CD16 cross‐linking, a surrogate for NK cell ADCC activity ex vivo, which can be performed using small volumes of patient whole blood. Using this assay, we show that CD107a mobilization, in response to CD16 cross‐linking, is triggered in CD56dim but not CD56bright NK cells, requiring Syk/Zap70 tyrosine kinase activity, and that there is a significant correlation between CD107a mobilization and pSyk/Zap70 in response to CD16 cross‐linking. We compared whole blood from treatment‐naïve, HIV‐infected patients with age‐ and sex‐matched HIV‐uninfected control subjects and found a significant reduction in CD16‐dependent pSyk/Zap70 (median=32.7% compared with 67.8%; P=0.0002) and CD107a mobilization (median=9.72% compared with 32.9%; P=0.046) in NK cells. Reduction of both correlated strongly with reduced CD16 surface expression on NK cells of HIV‐infected individuals (P