Antiviral activity of non-neutralizing antibodies during steady-state HIV-1 infection in humanized mice

Fc-mediated effector functions of monoclonal antibodies can contribute to antiviral immunity, yet their quantitative impact for non-neutralizing antibodies (nnAbs) in HIV-1 infection remains poorly defined. Here, we directly measured the in vivo antiviral activity of two HIV-1 envelope glycoprotein-specific nnAbs, 7B2 (gp41-directed) and A32 (gp120-directed), during steady-state infection in humanized mice to compare the antiviral effects of wild-type nnAbs and their Fc-Null variants. Both nnAbs significantly increased the rate of plasma viral load decay, across multiple HIV-1 strains. Fc-dependent activity was evident when nnAbs were administered alongside a neutralizing anchor antibody and, to a lesser extent, when given by itself. These findings provide direct quantitative evidence that nnAbs can accelerate viral clearance in vivo through Fc-dependent mechanisms. Our results highlight the potential clinical relevance of nnAbs in antibody-based therapies and inform vaccine studies that aim to elicit protective antibody responses against HIV-1.