An engineered antibody-lectin conjugate targeting the HIV glycan shield protects humanized mice against HIV challenge

Enveloped viruses responsible for global health pandemics often display a glycan shield on their surface envelope glycoproteins. In HIV, the glycan shield is formed by clusters of high-mannose glycans and plays essential roles in viral fitness and immune evasion. A few mannose-binding lectins potently inactivate HIV but have not been fully exploited due to poor pharmacokinetics and short serum half-lives. To address this, we engineered an antibody-lectin conjugate comprising the anti-HIV lectin griffithsin (GRFT) to the Fc region of human IgG1, with the aim of extending its serum half-life and augmenting anti-HIV activity by inducing immune effector responses. Engineered mGRFT-Fc produced in bacteria exhibited picomolar anti-HIV activity and an extended serum half-life, and mGRFT-Fc produced in mammalian cells (mGRFT-Fc_glyc) elicited immune effector responses. In HIV-infected CD34⁺-humanized mice, both GRFT and mGRFT-Fc_glyc effectively suppressed viral loads for up to 8 weeks after a single dose. Significantly, mGRFT-Fc_glyc prevented HIV infection by neutralizing HIV and provided sustained protection from break-through infections via Fc-mediated immune effector responses, exhibiting a dual mode of protection. This study demonstrates the successful engineering of a lectin-based biologic and provides early evidence that a glycan-targeting agent alone can confer protection from viral infection in vivo.