HIV tri-specific killer engagers directly enhance NK cell function and safely expand NK cells in vivo.

An HIV cure remains elusive, and many individuals develop comorbidities; therefore, new synergistic strategies to combat HIV are needed. Enhanced natural killer (NK) cell function associates with HIV elite control, primarily through antibody-dependent cellular cytotoxicity (ADCC). We generated tri-specific killer engagers (TriKEs) to enhance NK cell responses against HIV-infected cells. HIV TriKEs, one using the VRC01/07 antibody domains (VRC TriKE) and one using the CD4 ectodomain 1 (CD4 TriKE), promote NK cell function and killing of HIV target cells. NK cells expressing both CD38 and CD57 are major mediators of this function. We performed a dose-escalation study in SIV-uninfected rhesus macaques to assess the safety and pharmacodynamics of our CD4 TriKE. The TriKE is safe and effective at expanding peripheral and lymphoid NK cells in vivo. These findings support TriKEs as a promising safe immunotherapy to recognize and kill HIV-infected cells, with potential for combination cure strategies.