Induced and Infected: The Characterization of HIV-1 Neutralizing Antibodies Isolated from Vaccinated and Infected Humans

Abstract

Human Immunodeficiency Virus type 1 (HIV-1) continues to pose a major global health challenge, with nearly one million new infections annually and no licensed vaccine capable of eliciting broad protection. Antibodies remain central to vaccine- and therapy-based interventions, yet eliciting or identifying those with sufficient breadth and potency has proven difficult due to the extensive sequence diversity and glycan shield of the viral envelope (Env). This dissertation contains my research efforts to characterize HIV-1-reactive antibodies isolated from both vaccinated and infected individuals to better understand how humoral immunity can be harnessed to counteract this persistent virus. In Chapter 2, I describe the isolation and functional characterization of glycan-reactive monoclonal antibodies from human participants in the HVTN124 multivalent DNA-protein HIV-1 vaccine trial. These antibodies display broad pathogen cross-reactivity, Fab-dimerization, and neutralizing activity, revealing that antibodies can target the HIV-1 Env glycan shield, a traditional mechanism of immune evasion, as an antigenic vulnerability. In Chapter 3, I describe antibodies isolated from HIV-1-infected participants in the ACTG A5340 passive-immunization clinical trial, which evaluated the broadly neutralizing antibody VRC01. Examining the autologous responses provides new perspectives of how therapeutic infusions interact with a person’s own immune repertoire and suggests that strategic combinations of antibodies may better suppress viral rebound. Overall, these studies improve our understanding of antibody responses during HIV-1 immunity to and point toward new strategies for designing vaccines and antibody-based therapies to effectively combat HIV-1.