The study investigates the potential of bispecific antibodies (bAbs) targeting the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16) to enhance HIV-1-specific natural killer (NK) cell activity and eliminate latently infected CD4+ T cells. Two single-chain bAbs, PG16-Db and 3BNC117-Db, were designed based on broadly neutralizing antibodies (bNAbs) PG16 and 3BNC117, respectively. These bAbs were shown to robustly activate HIV-1-specific NK cells and promote their-mediated lysis of infected cells. In vitro, these bAbs significantly reduced the number of intact provirus+ CD4+ T cells, both in the presence and absence of latency reversal agents (LRAs). In humanized mice, 3BNC117-Db treatment enhanced NK cell activity and reduced the frequency of intact provirus+ CD4+ T cells, suggesting its potential as a therapeutic for HIV-1 reservoir clearance. The study highlights the promise of bAbs in enhancing NK cell-mediated elimination of HIV-1-infected cells and warrants further evaluation as a therapeutic strategy.The study investigates the potential of bispecific antibodies (bAbs) targeting the HIV-1 envelope protein (Env) and the human type III Fcγ receptor (CD16) to enhance HIV-1-specific natural killer (NK) cell activity and eliminate latently infected CD4+ T cells. Two single-chain bAbs, PG16-Db and 3BNC117-Db, were designed based on broadly neutralizing antibodies (bNAbs) PG16 and 3BNC117, respectively. These bAbs were shown to robustly activate HIV-1-specific NK cells and promote their-mediated lysis of infected cells. In vitro, these bAbs significantly reduced the number of intact provirus+ CD4+ T cells, both in the presence and absence of latency reversal agents (LRAs). In humanized mice, 3BNC117-Db treatment enhanced NK cell activity and reduced the frequency of intact provirus+ CD4+ T cells, suggesting its potential as a therapeutic for HIV-1 reservoir clearance. The study highlights the promise of bAbs in enhancing NK cell-mediated elimination of HIV-1-infected cells and warrants further evaluation as a therapeutic strategy.