RT Journal Article
SR Electronic
T1 Nanobody-mediated Complement Activation to Kill HIV-infected Cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.09.495439
DO 10.1101/2022.06.09.495439
A1 Maria Lange Pedersen
A1 Dennis Vestergaard Pedersen
A1 Mikael Becher Lykkegaard Winkler
A1 Heidi Gytz Olesen
A1 Ole Schmeltz Søgaard
A1 Lars Østergaard
A1 Nick Stub Laursen
A1 Anna Halling Folkmar Andersen
A1 Martin Tolstrup
YR 2022
UL http://biorxiv.org/content/early/2022/06/11/2022.06.09.495439.abstract
AB The 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.