Natural killer cell engineering strategies for HIV cure and reservoir elimination

PURPOSE OF REVIEW: Natural killer (NK) cells are attractive effectors for HIV cure-directed strategies, combining target recognition, antibody-dependent cellular cytotoxicity, and expansion compatibility with scalable allogeneic manufacture. This review evaluates NK cell gene-engineering and NK-boosting approaches as coordinated anti-HIV strategies rather than isolated enhancements. RECENT FINDINGS: HIV-directed NK cell genetic modifications now include fixed CD4-based chimeric antigen receptors (CARs,) a universal adaptor CAR, CD64-engineered antibody-armed NK cells, or added lymph node homing approaches centered on CXCR5, CCR7, or CD62L. Complementary strategies seek to augment NK activity through HIV-specific binders, eCD4-Ig, interleukin (IL)-15-containing TriKEs, or blockade of inhibitory receptors such as NKG2A, TIGIT or KLRG1. However, progress remains uneven as most engineered products are supported only by in vitro or animal studies. Importantly, Env-directed recognition depends on sufficient antigen expression which is often dependent on latency reversal, tissue access remains incompletely validated, and NK checkpoint modulation has not yet been tested clinically in HIV. SUMMARY: A clinically deployable HIV-directed NK cell product or combination therapy will require coordinated strategies addressing target recognition, trafficking, persistence, retained function, and safety. Development milestones should include demonstrable tissue localization, controlled persistence, and safety of engineered NK cells. If met, the goal for future endpoints would be the demonstration of a significant reduction of intact or inducible reservoir and delayed rebound during analytical treatment interruption as progress toward a functional cure for HIV.