SUMMARY One of the current leading HIV cure approaches is the “shock and kill” strategy. This approach takes into account that virus reactivation alone will not likely lead to eradication of the reservoir, and that an additional immunologic effector mechanism will almost certainly be required to eliminate reactivated cells. While cytotoxic T cells have frequently been proposed as potential killers that may be recruited for such a strategy, broadly neutralizing antibodies (bNAbs) can also induce rapid destruction of target cells by directing the cytotoxic and antiviral activity of the innate immune system. This has been widely exploited by the monoclonal antibody therapeutics community in developing improved antibodies for cancer but has not yet been explored for HIV. Antibody Fc-engineering efforts have modified antibodies to ensure that they are able to drive killing of the targets, and not only bind them. Point mutations have been introduced to selectively and specifically drive relevant effector functions, bi- and tetra-specific antibodies have been engineered to broaden and optimize targeting, and natural Fc-optimization strategies via glycan engineering have been utilized to collectively tune and promote more effective Fc-effector function for target cell elimination. In this proposal, we hypothesize that rational antibody engineering will result in functional optimization of bNAbs that will more effectively eliminate the viral reservoir for HIV eradication. Specific Aim 1: Design and down-select a panel of Fc point mutants and/or glycan variants that drive reservoir clearance. Specific Aim 2: Develop a bi- or tetra-specific antibody that drives reservoir eradication. Specific Aim 3: Evaluate the efficacy of the optimized bNAbs for virus eradication in ART-suppressed, SHIV-infected rhesus monkeys.