TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4(+) T cells

OBJECTIVES: During chronic human immunodeficiency virus (HIV)‐1 infection, inhibitory molecules upregulated on lymphocytes contribute to effector cell dysfunction and immune exhaustion. People living with HIV (PLWH) are at greater risk for age‐related morbidities, an issue magnified by human cytomegalovirus (CMV) coinfection. As CMV infection modifies natural killer (NK) cell properties and NK cells contribute to protection against HIV‐1 infection, we considered the role of T‐cell immunoreceptor with immunoglobulin and intracellular tyrosine inhibitory motif domains (TIGIT) in NK cell‐based HIV‐1 immunotherapy and elimination strategies. METHODS: We measured TIGIT expression on immune cell subsets of 95 PLWH and assessed its impact on NK cell function, including elimination of autologous CD4(+) T cells infected through reactivation of endogenous HIV‐1. RESULTS: TIGIT was expressed on CD4(+) T cells, CD8(+) T cells and NK cells from PLWH. Although TIGIT levels on T cells correlated with HIV‐1 disease progression, the extent of TIGIT expression on NK cells more closely paralleled adaptation to CMV. TIGIT interacts with its predominant ligand, poliovirus receptor (PVR), to inhibit effector cell functions. Circulating CD4(+) T cells from PLWH more frequently expressed PVR than HIV‐seronegative controls, and PVR expression was enriched in CD4(+) T cells replicating HIV‐1 ex vivo. Treatment with anti‐TIGIT monoclonal antibodies increased NK cell HIV‐1‐specific antibody‐dependent cytotoxicity in vitro and ex vivo. CONCLUSION: Blocking TIGIT may be an effective strategy to invigorate antibody‐dependent NK cell activity against HIV‐1 activated in cellular reservoirs for cure or treatment strategies.