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CD4-binding led to prepositioning of the bsAb at the site of viral fusion, enhancing its neutralization potency and achieving 95% breadth (IC80 &lt; 5 \u03bcg\/mL) against a panel of 119 pseudotyped, multiclade HIV-1 viruses. In the current study, we engineered a bsAb against NHR that also targets CCR5, one of two HIV-1 coreceptors on T cells. This optimized bsAb design further improves neutralization potency and achieves 100% neutralization breadth against the 119-member pseudotyped virus panel, including those resistant to CD4-binding iMab\/D5_AR. Considering that nearly all initial HIV-1 infections occur via CCR5-tropic viruses, we expect our redesigned bsAb targeting CCR5 to be an effective prophylactic agent. 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