Impact of Fc N-glycan structure on HIV-specific antibody functions

 描述（由申请人提供）：艾滋病毒感染对人类健康具有重大的全球影响。尽管到目前为止，我们还不能开发出一种高效的疫苗，但人们仍然广泛认为，接种疫苗可以控制艾滋病毒的流行。一种高效的疫苗可能会诱导广泛中和抗体（bNAb），可以中和不同的HIV分离株，类似于一些长期控制HIV感染的患者产生的抗体1，2。该疫苗可能还诱导具有强效效应子功能的非中和抗体（nNAb），可降低HIV感染风险，类似于RV 144疫苗试验中某些受试者产生的抗体3 -5。在疫苗开发的同时，人们认为， 可以制备和被动施用bNAb和/或nNAb用于暴露后预防或作为抗逆转录病毒疗法的辅助，特别是针对抗性病毒。广泛中和不同HIV变体和诱导有效效应子功能的能力是HIV特异性抗体（HIV-Ab）控制感染能力的两个至关重要的因素6。反过来，已知Fc受体（FcR）介导的效应子功能的效力取决于IgG N-聚糖结构7。不幸的是，我们没有全面的信息Fc糖基化对相关的HIV抗体功能的影响，在整体免疫应答艾滋病毒感染。显然，最近的一些研究已经破土动工，提供了重要的见解，并激发了人们对这一领域的极大兴趣8 -12。但是，他们也证明了需要进一步分析糖型的更广泛选择、N-聚糖结构对HIV-Ab阻断粘膜传播能力的影响以及不同糖型在允许HIV感染的临床前动物模型中的总体保护功效。我们建议实现这些目标，在一个更全面的分析N-聚糖结构的影响，在体外和体内功能的HIV抗体在整体免疫反应的HIV感染。我们将使用VRC 01和A32作为功能性糖组学研究的模型，旨在检查迄今为止报告的任何研究中使用的最广泛的试验组中最广泛的糖型选择。我们将评估八种不同的N-糖基化谱对VRC 01和A32功能的影响，包括病毒中和（VRC 01）和效应子功能（均为HIV抗体）。我们还将评估不同VRC-01和/或A32糖型的选定子集在hu-BLT小鼠（一种临床前动物模型系统）中保护免受HIV粘膜传播的总体能力。结果将揭示基于N-聚糖的机制，调节由两种功能不同的HIV-Ab驱动的免疫应答，并确定一种或多种特定的糖型作为HIV疫苗诱导和/或在人类治疗应用之前重组制造的最佳靶标。

 DESCRIPTION (provided by applicant): 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.