Investigating the contribution of Fc function to effective antibody-based HIV prevention

Abstract

Broadly neutralizing antibodies (bNAbs) show significant potential for HIV prevention stemming from their capacity to neutralize many of the genetically diverse HIV strains currently circulating worldwide. While these antibodies are capable of blocking viral attachment and membrane fusion, previous work suggests that the fragment crystallizable (Fc) region of these antibodies may also contribute to their efficacy against HIV by mediating interactions with innate immunity to elicit effector functions. When point mutations abolishing effector function activity were introduced into the Fc region of b12, a bNAb targeting the CD4 binding site of the HIV envelope glycoprotein (Env), the antibody conferred significantly reduced protection against mucosal SHIV transmission1. Conversely, the same point mutations did not alter the protective efficacy of a more potent V3 glycan-directed bNAb, PGT121, against cell-associated SHIV transmission2. Therefore, questions still remain regarding the contribution of Fc function to bNAb-mediated prevention and whether factors such as antibody potency, epitope specificity, or the route of HIV transmission impact this contribution. Herein, we describe a model system for quantitating the minimum protective dose of bNAbs against vaginal HIV transmission, and utilize this model to determine the contribution of effector mechanisms to the protective efficacy of VRC07, a potent CD4 binding site-directed bNAb. Briefly, the Fc region of VRC07 was modified through Fc class-switching and site-directed mutagenesis in order to alter the strength and type of effector function elicited. These VRC07 Fc variants were then directly compared in humanized mouse models to define their dose-dependent efficacy against HIV challenge. Our results suggest that despite comparable in vitro neutralization activity, VRC07 Fc variants with reduced capacity to mediate effector function activity, namely antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC), fail to protect as well as more functional VRC07 variants, particularly at lower circulating antibody concentrations. Overall, this work helps to elucidate the mechanisms that govern effective antibody-mediated HIV inhibition, thus identifying optimal immune functions and antibody isotypes to target with a vaccine.