TY - JOUR
T1 - Complement contributes to antibody-mediated protection against repeated SHIV challenge
AU - Goldberg, Benjamin S.
AU - Spencer, David A.
AU - Pandey, Shilpi
AU - Ordonez, Tracy
AU - Barnette, Philip
AU - Yu, Yun
AU - Gao, Lina
AU - Dufloo, Jérémy
AU - Bruel, Timothée
AU - Schwartz, Olivier
AU - Ackerman, Margaret E.
AU - Hessell, Ann J.
N1 - Publisher Copyright:
Copyright © 2023 the Author(s).
PY - 2023
Y1 - 2023
N2 - The first clinical efficacy trials of a broadly neutralizing antibody (bNAb) resulted in less benefit than expected and suggested that improvements are needed to prevent HIV infection. While considerable effort has focused on optimizing neutralization breadth and potency, it remains unclear whether augmenting the effector functions elicited by broadly neutralizing antibodies (bNAbs) may also improve their clinical potential. Among these effector functions, complement-mediated activities, which can culminate in the lysis of virions or infected cells, have been the least well studied. Here, functionally modified variants of the second-generation bNAb 10-1074 with ablated and enhanced complement activation profiles were used to examine the role of complement-associated effector functions. When administered prophylactically against simian-HIV challenge in rhesus macaques, more bNAb was required to prevent plasma viremia when complement activity was eliminated. Conversely, less bNAb was required to protect animals from plasma viremia when complement activity was enhanced. These results suggest that complement-mediated effector functions contribute to in vivo antiviral activity, and that their engineering may contribute to the further improvements in the efficacy of antibody-mediated prevention strategies.
AB - The first clinical efficacy trials of a broadly neutralizing antibody (bNAb) resulted in less benefit than expected and suggested that improvements are needed to prevent HIV infection. While considerable effort has focused on optimizing neutralization breadth and potency, it remains unclear whether augmenting the effector functions elicited by broadly neutralizing antibodies (bNAbs) may also improve their clinical potential. Among these effector functions, complement-mediated activities, which can culminate in the lysis of virions or infected cells, have been the least well studied. Here, functionally modified variants of the second-generation bNAb 10-1074 with ablated and enhanced complement activation profiles were used to examine the role of complement-associated effector functions. When administered prophylactically against simian-HIV challenge in rhesus macaques, more bNAb was required to prevent plasma viremia when complement activity was eliminated. Conversely, less bNAb was required to protect animals from plasma viremia when complement activity was enhanced. These results suggest that complement-mediated effector functions contribute to in vivo antiviral activity, and that their engineering may contribute to the further improvements in the efficacy of antibody-mediated prevention strategies.
KW - HIV
KW - antibody engineering
KW - complement-dependent cytotoxicity
KW - effector function
KW - neutralizing antibody
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U2 - 10.1073/pnas.2221247120
DO - 10.1073/pnas.2221247120
M3 - Article
C2 - 37155897
AN - SCOPUS:85158078777
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
M1 - e2221247120
ER -