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

Fc N-聚糖结构对 HIV 特异性抗体功能的影响

• 批准号: 9322012
• 负责人: Donald L. Jarvis
• 金额: $ 74.83万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322012
• 关键词: Acute; Affinity; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antiviral Agents; Baculoviridae; Baculoviruses; Biological Assay; Biological Models; Bone Marrow; Cells; Cellular Immunity; Chemicals; Chronic; Complement-Dependent Cytotoxicity; Coupled; Dendritic Cells; Effector Cell; Fc Receptor; Fc domain; Galactose; Glycobiology; Glycoproteins; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Health; Human; Immune; Immune response; Immunoglobulin G; Immunology; In Vitro; Infection; Inflammatory; Inflammatory Response; Insecta; Liver; Mannose; Measures; Mediating; Modeling; Modification; Mucous Membrane; Mus; N Domain; Natural Killer Cells; Patients; Pattern; Phagocytosis; Phagocytosis Induction; Polysaccharides; Preparation; Production; Prophylactic treatment; Recombinants; Reporting; Research Design; Research Personnel; Resistance; Risk; Sialic Acids; Signal Transduction; Site; Structure; System; Therapeutic; Thymus Gland; Training; Vaccination; Vaccines; Vagina; Variant; Viral; Virus; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; experience; glycosylation; humanized mouse; in vitro Assay; in vivo; in vivo Model; insight; interest; macrophage; mouse model; neutralizing antibody; neutrophil; pandemic disease; permissiveness; pre-clinical; protective efficacy; public health relevance; receptor binding; sialylation; transmission process; vaccine development; viral transmission; virology

 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.

 描述（由适用提供）：艾滋病毒感染对人类健康有重大影响。尽管我们迄今无法开发高效的疫苗，但仍然认为疫苗可以控制艾滋病毒大流行。高效的疫苗可能会诱导广泛中和抗体（BNAB），该抗体可以中和可能中和潜水的HIV分离株，类似于某些对HIV感染的长期控制患者产生的患者类似于HIV感染1,2。该疫苗可能还会诱导具有潜在效应子功能的非中和抗体（NNABS），可以降低HIV感染的风险，类似于RV144疫苗试验3-5中某些受试者产生的抗体感染的风险。与疫苗开发并行，我们认为我们 可以制造和被动地施用BNAB和/或NNABS，以进行预防后预防或作为抗逆转录病毒疗法的辅助手段，尤其是抗抗性病毒。在HIV特异性抗体（HIV-ABS）控制感染的能力中，广泛中和不同的HIV变体和诱导潜在效应子功能的能力都是至关重要的因素。在TUR中，已知FC受体（FCR）介导的效应函数的效力取决于IgG N-聚糖结构7。不幸的是，我们没有有关FC糖基化对HIV-AB功能对HIV感染的总体免疫响应的影响的全面信息。显然，最近的一些研究破裂了，提供了重要的见解，并激发了对该地区8-12的极大兴趣。但是，他们还表明了需要进一步分析更广泛的糖型，N-聚糖结构对HIV-ABS阻断粘膜传播的能力的影响以及临床前动物模型中不同糖型在HIV感染中不同糖型的总体保护效率的影响。我们将使用VRC01和A32作为功能性糖型的模型，旨在检查迄今为止任何报告的研究中使用的最广泛的评估集中最广泛的糖型选择。我们将评估八个不同的N-糖基化谱对VRC01和A32功能的影响，包括病毒中和（VRC01）和效应子功能（均为HIV-ABS）。我们还将评估不同VRC-01和/或A32糖型的选定子集的总体能力，以防止临床前动物模型系统HU-BLT小鼠中HIV的粘膜传播。结果将揭示基于N-聚糖的机制调节由两个功能上不同的HIV-ABS驱动的免疫调查器，并识别一种或多种特异性糖型作为HIV疫苗和/或重组制造的最佳诱导靶标。