PhD Thesis Defense: Benjamin Goldberg

To attend via videoconference, please email benjamin.s.goldberg.th@dartmouth.edu

"Fishing for complements: towards effective antibody-mediated prevention of HIV-1"

Abstract

Antibodies have proven effective prophylactic agents for intractable and emergent viruses. In the context of HIV, protective efficacy is primarily attributed to virus neutralization and to a lesser extent antibody-mediated effector function. Unfortunately, the first clinical efficacy trial of a broadly neutralizing antibody (bnAb) resulted in less benefit than expected. However, with caveats, it provided proof that this approach can prevent the acquisition of HIV in humans, and suggested that improvements in these activities are needed in order to prevent HIV infection.

To date, efforts to augment protection through targeted modification to the host-interfacing Fc portion of the antibody have been confined to modest success in mouse models and improvements in half-life in humans. Among Fc-mediated effector functions, activation of the innate complement system has been under studied due to an early experiment suggesting its dispensability. However, robust complement activation shows a high degree of context dependence and was observed to correlate with reduced risk of infection in the only effective HIV-1 vaccine trial to date, motivating revisiting this mechanism of action.

To that end, functionally modified variants of the clinical bnAb 10-1074 were used to examine the role of effector-mediated activity when administered prophylactically against viral challenge in rhesus macaques. In contrast to studies involving early generation bnAbs, the results of the 10-1074 study indicate that complement can indeed contribute to protection. Collectively, these studies suggest that enhancement of antibody-mediated activation of complement may contribute to the further development of antibody-mediated prevention strategies. Furthermore, these studies highlight the structural and spatial aspects of antibody function, adding to the reports from other viral and cancer immunotherapy contexts.

Thesis Committee

• Margaret Ackerman, PhD (Chair)
• Karl Griswold, PhD
• Jiwon Lee, PhD
• Ronald Taylor, PhD

Contact

For more information, contact Theresa Fuller at theresa.d.fuller@dartmouth.edu.