TY - JOUR
T1 - Revisiting an IgG Fc Loss-of-Function Experiment
T2 - The Role of Complement in HIV Broadly Neutralizing Antibody b12 Activity
AU - Goldberg, Benjamin S.
AU - Kaku, Chengzi I.
AU - Dufloo, Jérémy
AU - Bruel, Timothée
AU - Schwartz, Olivier
AU - Spencer, David A.
AU - Hessell, Ann J.
AU - Ackerman, Margaret E.
N1 - Funding Information:
The following reagents were obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: vector pcDNA3.1 containing human immunodeficiency virus type 1 (HIV-1) strain YU-2 gp140D683(2/GCN4) in pcDNA3.1 (catalog number ARP-12133), contributed by Joseph Sodroski, and HIV-1 VRC01 monoclonal antibody heavy and light chain expression vectors (catalog numbers ARP-12035 and ARP-12036), contributed by John Mascola. Heavy and light chain nucleotide sequences for 10-1074 were generously provided by Hugo Mouquet and Marina Caskey. AT-2 inactivated virions were kindly provided by Jeff Liffson (NIH/Leidos). This work was supported by the National Institutes of Health NIAID and NIGMS under grants R01AI131975 (M.E.A.) and R01AI129801 (A.J.H.). Work in the O.S. lab is funded by the Institut Pasteur, the Urgence COVID-19 Fundraising Campaign of the Institut Pasteur, the Fondation pour la Recherche Médicale (FRM), ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, and IDISCOVR. J.D. is supported by a grant from the French Ministry of Higher Education and Research. We report no conflicts of interest.
Funding Information:
This work was supported by the National Institutes of Health NIAID and NIGMS under grants R01AI131975 (M.E.A.) and R01AI129801 (A.J.H.). Work in the O.S. lab is funded by the Institut Pasteur, the Urgence COVID-19 Fundraising Campaign of the Institut Pasteur, the Fondation pour la Recherche Médicale (FRM), ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, and IDISCOVR. J.D. is supported by a grant from the French Ministry of Higher Education and Research. We report no conflicts of interest.
Publisher Copyright:
Copyright © 2021 Goldberg et al.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - The role of the complement system in HIV-1 immunity and pathogenesis is multifaceted, and an improved understanding of complement activities mediated by HIV-1-specific antibodies has the potential to inform and advance clinical development efforts. A seminal nonhuman primate challenge experiment suggested that complement was dispensable for the protective effect of the early broadly neutralizing antibody (bnAb) b12, but recent experiments have raised questions about the breadth of circumstances under which this conclusion may hold. Here, we reassess the original observation using Fc variants of IgG1 b12 that enhance complement activity and report that complement fixation on recombinant antigen, virions, and cells and complement-dependent viral and cellular lysis in vitro vary among bnAbs. Specifically, while the clinically significant V3 glycan-specific bnAb 10-1074 demonstrates activity, we found that b12 does not meaningfully activate the classical complement cascade. Consistent with avid engagement by C1q and its complex system of regulatory factors, these results suggest that complement-mediated antibody activities demonstrate a high degree of context dependence and motivate revisiting the role of complement in antibody-mediated prevention of HIV-1 infection by next-generation bnAbs in new translational studies in animal models. IMPORTANCE Given the suboptimal outcome of VRC01 antibody-mediated prevention of HIV-1 infection in its first field trial, means to improve diverse antiviral activities in vivo have renewed importance. This work revisits a loss-of-function experiment that investigated the mechanism of action of b12, a similar antibody, and finds that the reason why complement-mediated antiviral activities were not observed to contribute to protection may be the inherent lack of activity of wild-type b12, raising the prospect that this mechanism may contribute in the context of other HIV-specific antibodies.
AB - The role of the complement system in HIV-1 immunity and pathogenesis is multifaceted, and an improved understanding of complement activities mediated by HIV-1-specific antibodies has the potential to inform and advance clinical development efforts. A seminal nonhuman primate challenge experiment suggested that complement was dispensable for the protective effect of the early broadly neutralizing antibody (bnAb) b12, but recent experiments have raised questions about the breadth of circumstances under which this conclusion may hold. Here, we reassess the original observation using Fc variants of IgG1 b12 that enhance complement activity and report that complement fixation on recombinant antigen, virions, and cells and complement-dependent viral and cellular lysis in vitro vary among bnAbs. Specifically, while the clinically significant V3 glycan-specific bnAb 10-1074 demonstrates activity, we found that b12 does not meaningfully activate the classical complement cascade. Consistent with avid engagement by C1q and its complex system of regulatory factors, these results suggest that complement-mediated antibody activities demonstrate a high degree of context dependence and motivate revisiting the role of complement in antibody-mediated prevention of HIV-1 infection by next-generation bnAbs in new translational studies in animal models. IMPORTANCE Given the suboptimal outcome of VRC01 antibody-mediated prevention of HIV-1 infection in its first field trial, means to improve diverse antiviral activities in vivo have renewed importance. This work revisits a loss-of-function experiment that investigated the mechanism of action of b12, a similar antibody, and finds that the reason why complement-mediated antiviral activities were not observed to contribute to protection may be the inherent lack of activity of wild-type b12, raising the prospect that this mechanism may contribute in the context of other HIV-specific antibodies.
KW - Antibody
KW - Antibody-mediated prevention
KW - C1q
KW - CDC
KW - Complement
KW - Fc
KW - HIV
KW - Human immunodeficiency virus
KW - Mechanism of action
KW - Viral lysis
UR - http://www.scopus.com/inward/record.url?scp=85121014836&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85121014836&partnerID=8YFLogxK
U2 - 10.1128/mBio.01743-21
DO - 10.1128/mBio.01743-21
M3 - Article
C2 - 34634936
AN - SCOPUS:85121014836
SN - 2161-2129
VL - 12
JO - mBio
JF - mBio
IS - 5
M1 - e01743-21
ER -