PhD Thesis Proposal: Benjamin S. Goldberg

For info on how to attend this videoconference, please email benjamin.s.goldberg.TH@dartmouth.edu

"Should you throw away a good complement?: Revisiting the role of an extra-neutralizing function in antibody-mediated prevention of HIV-1 infection"

Abstract

Increasingly, antibodies are being developed to treat viral infections. In the context of HIV, efficacy is primarily attributed to antibody-specific dose-dependent neutralization potency and to a lesser extent antibody-mediated effector functions. It remains unclear whether augmenting effector functions on broadly neutralizing antibodies (bNAbs) may improve their clinical potential. The complement system is an innate arm of the immune system consisting of more than 30 serum proteins that amplify (or complement) the ability of antibodies and immune cells to clear molecular and cellular targets. The role of the complement system in HIV-1 immunity and pathogenesis is multifaceted, and improved understanding of complement activities mediated by HIV-1-specific bNAbs has the potential to inform and advance clinical development efforts. A seminal non-human primate challenge experiment suggested that complement was dispensable to the protective effect of the early bNAb b12, but recent experiments have raised questions about the breadth of circumstances under which this conclusion may hold.

To reassess the original observation, antibody variants containing synthetically-derived mutations in the Fc domain of IgG1 b12 that enhance complement activity were produced for in vitro assessments of complement function. These studies showed that activity varies among bNAbs, and specifically that b12 does not meaningfully activate the 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. To that end, bNAb 10E8v4, targeting a different part of the HIV-1 spike protein, was used to examine the role of effector-mediated activity when administered prophylactically against SHIV challenge in rhesus macaques. With sub-protective dosing, a 78-88% reduction in post-acute viremia was observed and shown to be attributable to phagocytic but not complement effector functions acting at the time of challenge. While the conclusive role of complement in antibody-mediated protection from HIV-1 infection remains elusive, this work will focus on reconciling the complement system of non-human primates so as to determine its appropriateness as a model reflective of human outcomes.

Thesis Committee

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

Contact

For more information, contact Daryl Laware at daryl.a.laware@dartmouth.edu.