Complement contributes to antibody-mediated protection against repeated SHIV challenge.

Area of Science:

• Immunology
• Virology
• Antibody Engineering

Background:

• Clinical trials of broadly neutralizing antibodies (bNAbs) for HIV prevention showed limited efficacy, necessitating further improvements.
• Focus has been on antibody neutralization potency and breadth, with less attention to effector functions like complement activation.
• Complement-mediated activities, crucial for clearing pathogens, are understudied in the context of bNAb efficacy.

Purpose of the Study:

• To investigate the role of complement-mediated effector functions in the in vivo efficacy of broadly neutralizing antibodies (bNAbs).
• To determine if enhancing complement activation can improve the protective potential of bNAbs against HIV infection.

Main Methods:

• Functionally modified variants of the bNAb 10-1074 with ablated and enhanced complement activation profiles were engineered.
• These variants were tested for prophylactic efficacy against simian-HIV challenge in a rhesus macaque model.

Main Results:

• Higher doses of bNAb were needed to prevent plasma viremia when complement activity was eliminated.
• Lower doses of bNAb were sufficient for protection when complement activity was enhanced.
• These findings demonstrate a significant contribution of complement-mediated functions to antiviral activity.

Conclusions:

• Complement-mediated effector functions play a critical role in the in vivo antiviral activity of broadly neutralizing antibodies.
• Engineering enhanced complement activation profiles in bNAbs holds promise for improving antibody-mediated HIV prevention strategies.