Soluble ligands for the NKG2D receptor are released during HIV-1 infection and impair NKG2D expression and cytotoxicity of NK cells

In humans, the interaction of the natural killer group 2 member D (NKG2D)-activating receptor on natural killer (NK) and CD8+ T cells with its major histocompatibility complex class I-related chain (MIC) and UL16 binding protein (ULBP) ligands (NKG2DLs) promotes recognition and elimination of stressed cells, such as tumor or infected cells. Here, we investigated the capacity of HIV-1 to modulate NKG2DL expression and escape NGK2D-mediated immunosurveillance. In CD4+ T lymphocytes, both cell surface expression and release of MICA, MICB, and ULBP2 were up-regulated >2-fold by HIV-1 infection. In HIV-infected CD4+ T lymphocytes or Jurkat T-cell lines, increased shedding of soluble NKG2DLs (sNKG2DLs) was impaired by a matrix metalloproteinase inhibitor (MMPI). Moreover, naive HIV+ patients displayed increased plasma sMICA and sULBP2 levels and reduced NKG2D expression on NK and CD8+ T cells compared to patients receiving highly active antiretroviral therapy (HAART) or healthy donors. In individual patients, H...