Monovalent 2F5 and 3BNC117 promote recognition and elimination of HIV-1-infected CD4+ T cells

Broadly neutralizing antibodies (bNAbs) target HIV-1 envelope and could induce the elimination of infected CD4 ⁺ T cells through antibody-dependent cell-mediated cytotoxicity (ADCC), which has been demonstrated as an important strategy in AIDS functional cure. However, epitopes confined to narrow spaces are often poorly recognized by bNAbs, leading to insufficient cytotoxicity and limited clearance of HIV-1-infected CD4 ⁺ T cells. In this study, we engineered monovalent forms of 2F5, 4E10 and 3BNC117 with optimized Fc regions. Our results demonstrate that monovalent 2F5 and 3BNC117 exhibit enhanced antigen recognition and improved clearance of HIV-1-infected CD4 ⁺ T cells via ADCC. Structural analyses revealed that these monovalent antibodies form additional hydrogen bonds with the HIV-1 gp145 glycoprotein, particularly through their Fc regions. These findings highlight the potential of leveraging monovalent bNAbs as a strategic approach to facilitate the clearance of HIV-1-infected CD4 ⁺ T cells.