title: Determinants of the Antibody Response against HIV Env induced by Nanoparticle Vaccination and Intrastructural Help
Creators: name: Di Vincenzo, Riccardo
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 2024

description: A robust and durable antibody response with broad neutralization capabilities is imperative for the development of an effective HIV vaccine. However, in murine models, existing vaccine candidates primarily induce an antibody response characterized by a Th2-associated cytokine milieu and IgG1 dominance, correlated with limited functionality of Fc receptors. Recent evidence indicates a potential association between the protective capacity of antibodies and their IgG Fc effector functions. Notably, our previous work demonstrated that Gag-specific T helper cells induced by DNA priming can positively modulate the HIV Env-specific B cell response upon HIV virus-like particle (VLP) boost through a mechanism known as intrastructural help (ISH), resulting in a more desirable TH1-associated IgG2a response. This phenomenon is postulated to involve T follicular helper cells, which imprint the persistence of the antibody response onto Env-specific B-cells by driving their differentiation into long-lived plasma cells. In the current study, we investigated in mice the impact of a heterologous priming immunization with GagPol-DNA on Fc-effector functions. The results demonstrate that Gag-specific T helper cells induced by DNA priming enhance and modulate the HIV Env-specific B cell response upon HIV VLP boost by intrastructural help, resulting in a more desirable Th1-associated IgG2c response. Importantly, this shift towards an IgG2c-dominated response corresponded with enhanced Fc effector functions, namely antibody-dependent phagocytosis (ADCP), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular cytotoxicity (ADCC). Additionally, the study made a secondary observation that, despite variations in priming strategies designed to induce ISH, alterations in IgG glycosylation within individual IgG subclasses were minor and heterogeneous. However, more pronounced differences in IgG glycosylation became evident when examining differences across the various IgG subclasses. Consequently, it appears that CD4+ T cell help initiated by GagPol priming has a limited influence on the glycosylation patterns of subtype-specific antibodies produced by Env-specific B cells. This implies that the observed differences in glycosylation of total Env-specific IgGs of Gag-primed mice in prior studies are primarily influenced by the inherent distribution of individual IgG subclasses triggered by GagPol priming. Consequently, our results suggest that enhancements in antibody functionality shown in our study stem from the IgG subclass distribution rather than modifications in their glycan profiles. These findings underscore the significance of comprehending the impact of T helper cells on the quality of the antibody response and offer insights that can contribute to the development of more effective HIV vaccines capable of eliciting a robust and protective antibody response, particularly at the site of infection.