Bidirectional interactions between HIV-1 broadly neutralizing antibodies and natural killer cells in antibody development and effector phases: a systematic review

Broadly neutralizing antibodies (bNAbs) are increasingly investigated for HIV-1 prevention and treatment. bNAbs have both direct neutralizing activity and Fc-dependent effector functions. Natural killer (NK) cells are important Fc-dependent effectors, but their interactions with bNAbs remain incompletely understood. This systematic review evaluated the bidirectional relationship between NK cells and HIV-1 bNAbs, focusing on natural bNAb development and interactions involving mature bNAbs. Following PRISMA 2020, PubMed, Web of Science, and Embase were searched from inception through August 10, 2026. A total of 40 studies met the eligibility criteria. Findings were synthesized narratively because of substantial heterogeneity. Evidence on the role of NK cells in bNAb development was limited and mainly observational. NK cell subset distribution, RAB11FIP5 expression, degranulation, and cytokine responses were associated with neutralization breadth, without establishing causality. Evidence was stronger for the effector phase. bNAbs induced NK cell degranulation and cytokine production and mediated NK cell-dependent killing of infected cells. These responses varied among bNAbs and were influenced by antibody properties, NK cell subset and differentiation phenotype, and viral, target cell, microenvironmental, and experimental factors. Enhanced NK cell activity did not necessarily translate into greater protection in vivo . The evidence provides stronger support for NK cell effector responses involving mature bNAbs, whereas a causal role for NK cells in natural bNAb development remains unestablished. Future studies should clarify whether NK cells causally influence bNAb development and under what conditions NK cell engagement provides additional antiviral benefit beyond direct neutralization. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420261378840.