Nanobody-mediated Complement Activation to Kill HIV-infected Cells

Author:

Pedersen Maria LangeORCID,Pedersen Dennis Vestergaard,Lykkegaard Winkler Mikael Becher,Olesen Heidi Gytz,Søgaard Ole SchmeltzORCID,Østergaard Lars,Laursen Nick Stub,Andersen Anna Halling FolkmarORCID,Tolstrup MartinORCID

Abstract

AbstractThe complement system which is part of the innate immune response against invading pathogens, represents a powerful mechanism for killing of infected cells. Utilizing direct complement recruitment for complement-mediated elimination of HIV-1-infected cells is underexplored. We developed a novel therapeutic modality to direct complement activity to the surface of HIV-1-infected cells. This bispecific complement engager (BiCE) is comprised of a nanobody recruiting the complement-initiating protein C1q, and single-chain variable fragments of broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope (Env) protein. Here, we show that two anti-HIV BiCEs targeting the V3 loop and the CD4 binding site, respectively, increase C3 deposition and mediate complement-dependent cytotoxicity (CDC) of HIV-1 Env expressing Raji cells. Furthermore, anti-HIV BiCEs trigger complement activation on primary CD4 T cells infected with laboratory-adapted HIV-1 strain and facilitates elimination of HIV-1-infected cells over time. In summary, we present a novel approach to direct complement deposition to the surface of HIV-1-infected cells leading to complement-mediated killing of these cells.

Publisher

Cold Spring Harbor Laboratory

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