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. 2019 Sep 11;20(18):4490. doi: 10.3390/ijms20184490

Figure 1.

Figure 1

Diverse approaches targeting the NKG2D/NKG2DLs axis for ‘shock and kill’ HIV-1 eradication strategy. (1) The ‘shock’ phase relies on the use of LRAs to increase HIV-1 transcription within latently infected CD4+ T cells while ART blocks the spread of newly assembled viral particles. The expression of NKG2DLs is induced by the Vpr and Vif viral proteins and, possibly, by other virus-induced mechanisms. Several LRAs can induce the expression of NKG2DLs and these drugs may cooperate with HIV-1 at NKG2DL upmodulation, sensitizing T cells that exit from latency to recognition and killing by NK cells. On the other hand, due to proteolytic shedding by activated MMPs, sNKG2DL can be released in the extracellular milieu, bind and downregulate NKG2D on NK cells. (2–6) Various approaches to boost the NKG2D-mediated responses of NK cells have been developed and could be applied as an adjuvant NK-cell based immunotherapy to clear T cells harboring reactivated HIV-1: (2) Treatment with an anti-MICA mAb that blocks shedding but not NKG2D recognition resulted in enhanced NK cell-mediated killing by triggering both NKG2D pathway and ADCC [117,118]; (3) adoptive transfer of IL-2-activated NK cells expressing high NKG2D levels reduced the amount of plasma sNKG2DL and improved clearance of NKG2DL+ targets [119]; (4) recombinant NKG2D fused to IL-15 activated NK cell-mediated suppression of NKG2DL+ cells [120,121]; (5) the extracellular domain of NKG2D fused to the Fc of IgG1 optimized for CD16 binding elicits ADCC against NKG2DL+ targets [122,123]; (6) CAR-NK cells engineered to express a NKG2D/CD3ζ/DAP10 recombinant receptor display superior NKG2D-mediated cytotoxic activity [124,125]. LRA, latency-reversing agent; ART, antiretroviral therapy; NKG2DL, NKG2D ligand; sNKG2DL, soluble NKG2D ligand; MMP, matrix methalloprotease; mAb, monoclonal antibody; ADCC, antibody-dependent cellular cytotoxicity; Fc, fragment crystallizable region; CAR, chimeric antigen receptor. Dotted black arrow represents gene expression; solid black arrow represents stimulation.