HIV infections have a significant impact on worldwide human health. Despite our inability to develop a highly effective vaccine to date, it is still widey believed that vaccination will be the best way to control the HIV pandemic. A highly effective vaccine might induce broadly neutralizing antibodies (bNAbs) that can neutralize diverse HIV isolates, analogous to those produced by some patients exhibiting long-term control over HIV infection. In addition to their ability to bind and/or neutralize different HIV variants, the Fc receptor (FcR)-mediated effector functions of these and other HIV-specific antibodies are essential for HIV control. Importantly, these effector functions can be influenced by the structures of the N-glycans found on all IgG Fc domains1. However, we need more comprehensive information on the impact of glycosylation profiles on bNAb functions in the overall immune response to HIV infection. Recent functional glycomic studies have generated interesting results, which not only support the idea that this research is necessary and important, but also demonstrate the need for further studies in this area. To date, functional glycomic studies have focused on a limited selection of bNAbs and bNAb glycoforms. Only one has involved in vivo analysis of different glycoforms15, none has assessed the impact of N-glycan structure on the ability of bNAbs to block mucosal transmission, and none has exploited a preclinical animal model permissive for HIV infection. Thus, we propose a comprehensive analysis of the impact of N-glycan structure on the in vitro and in vivo functions of representativ bNAbs in context of the overall immune response to HIV infection. Our functional glycomic approach will examine the broadest selection of bNAb glycoforms in the broadest set of assays used in any study reported to date. We will assess the impact of eight distinct N-glycosylation profiles on various antibody functions, including a wide variety of in vitro effector functions. We also will assess their overall abilities to protect against mucosal transmission of HIV in the hu-BLT mouse model. The results will reveal N-glycan-based mechanisms modulating the immune responses driven by two distinct HIV-specific bNAbs and identify one or more specific glycoforms as optimal targets for induction by an HIV vaccine and/or production for human therapeutic applications.
HIV infections are a major source of human disease, suffering, and death. However, some patients produce broadly neutralizing antibodies (bNAbs) associated with a higher level of control over HIV infection. The proposed project focuses on the impact of IgG Fc glycosylation patterns on the Fc receptor (FcR)-dependent and independent functions of HIV-specific bNAbs. We expect to determine mechanistic relationships between Fc glycan structure and bNAb function in the overall immune response to HIV infection, which will inform efforts to develop vaccines and reveal how bNAbs could be optimized for therapeutic applications.
