Defining the role of FC effector function in natural HIV-1 infection

Abstract

Human immunodeficiency virus type 1 (HIV-1) infects 2 million individuals annually, highlighting the need for an effective vaccine. While broadly neutralizing antibodies (bNAbs), naturally elicited in some HIV-infected individuals, can prevent infection in animal models these have not yet been stimulated by vaccination. RV144, the only HIV vaccine to show any efficacy, implicated the antibody Fc region in protection through functions such as antibody dependent cellular cytotoxicity (ADCC), cellular phagocytosis (ADCP) and complement deposition (ADCD). Consequently, we aimed to characterize Fc effector functions in the context of a bNAb response to inform vaccine design and improve antibodies for passive immunization.

This thesis describes the development of a novel assay to measure antibody dependent cellular trogocytosis (ADCT) in HIV infection for the first time. ADCT results in rapid cell death of target cells through the removal of membrane fragments, which is distinct from ADCP. Individuals that developed bNAbs showed higher levels of ADCT and further investigation using assays measuring ADCP, ADCC and ADCD revealed they developed a diversified and potent Fc response early in infection that clearly separated them from other HIV-infected individuals. This profile correlated with good germinal center activity and increased subclass diversity, demonstrating a common mechanistic link between the regulation of the Fc and Fab mediated activities. An individual with bNAbs, CAP256, who also developed potent Fc effector function was found to have persistently high levels of IgG3 which is the most polyfunctional IgG subclass. Monoclonal antibodies isolated from this donor revealed natural usage of a novel IgG3 allele that showed both improved Fc effector function and neutralization compared to IgG1 versions. Hinge switch variants revealed that the increased IgG3 hinge length was responsible for improved neutralization.

Our data describe common immune determinants associated with both Fab and Fc function as well as a new Fc effector function, ADCT. This highlights how cooperation between the variable and constant regions, facilitated by the hinge region, could be exploited to enhance the functionality of antiviral antibodies for passive immunity. Overall, these studies provide further clarity on the role of Fc effector functions in HIV infection.