HIV infections have a significant worldwide impact on human health. Despite our inability to develop a highly effective vaccine to date, it is still widey believed that vaccination could 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 with long-term control over HIV infection1,2. This vaccine would probably also induce non-neutralizing antibodies (nNAbs) with potent effector functions that can reduce the risk of HIV infection, analogous to those produced by some subjects in the RV144 vaccine trial3-5. In parallel with vaccine development, it is thought that we can manufacture and passively administer bNAbs and/or nNAbs for post-exposure prophylaxis or as an adjunct to antiretroviral therapy, particularly against resistant viruses. The ability to broadly neutralize different HIV variants and induce potent effector functions are both critically important factors in the ability of HIV-specific antibodies (HIV-Abs) to control infection6. In tur, the potency of Fc receptor (FcR)-mediated effector functions is known to depend upon IgG N-glycan structure7. Unfortunately, we do not have comprehensive information on the impact of Fc glycosylation on relevant HIV-Ab functions in the overall immune response to HIV infection. Clearly, some recent studies have broken ground, provided important insights, and stimulated great interest in this area8-12. But, they also demonstrated the need for further analysis of a broader selection of glycoforms, of the impact of N-glycan structure on the ability of HIV- Abs to block mucosal transmission, and of the overall protective efficacy of different glycoforms in preclinical animal models permissive for HIV infection. We propose to achieve these goals in a more comprehensive analysis of the impact of N-glycan structure on the in vitro and in vivo functions of HIV-Abs in the overall immune response to HIV infection. We will use a VRC01 and A32 as models for functional glycomic studies designed to examine the broadest selection of 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 VRC01 and A32 functions, including viral neutralization (VRC01) and effector functions (both HIV-Abs). We also will assess the overall abilities of a selected subset of different VRC-01 and/or A32 glycoforms to protect against mucosal transmission of HIV in the hu-BLT mouse, a preclinical animal model system. The results will reveal N-glycan- based mechanisms modulating the immune responses driven by two functionally distinct HIV-Abs and identify one or more specific glycoforms as optimal targets for induction by an HIV vaccine and/or for recombinant manufacturing in advance of human therapeutic applications.
The proposed project focuses on the impact of IgG Fc glycosylation patterns on the Fc receptor (FcR)- dependent and independent functions of broadly cross-neutralizing and non-neutralizing, HIV-specific antibodies. We expect to elucidate the mechanistic relationships between Fc glycan structure and antibody functions and their impact on the overall immune response to HIV infection. The results could inform efforts to develop vaccines and will likely reveal how HIV-specific antibody preparations can be optimized for therapeutic applications.
