Eliciting B cells to produce anti-HIV gp41 MPER-specific neutralizing antibodies

诱导 B 细胞产生抗 HIV gp41 MPER 特异性中和抗体

• 批准号: 8043239
• 负责人: GARNETT H KELSOE
• 金额: $ 36.25万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043239
• 关键词: Accounting; Adoptive Transfer; Affinity; Antibodies; Antibody Formation; Antibody Repertoire; Antigens; Apoptosis; Area; B-Lymphocytes; Biological Assay; Bone Marrow; CD4 Positive T Lymphocytes; Cells; Characteristics; Development; Enzyme-Linked Immunosorbent Assay; Epitopes; Flow Cytometry; Gene Rearrangement; Genetic; Guanine Nucleotide Dissociation Inhibitors; HIV; HIV Envelope Protein gp41; HIV Infections; HIV-1; HIV-1 vaccine; Helper-Inducer T-Lymphocyte; Histologic; Humoral Immunities; Hybridomas; Immune; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; In Situ; In Vitro; Individual; Infection; Kinetics; Life; Measures; Memory; Molecular Genetics; Mus; Output; Patients; Pattern; Plasma Cells; Plasmablast; Population; Production; Serum; Site; Sorting - Cell Movement; Staging; Structure of germinal center of lymph node; Surface Antigens; Surface Plasmon Resonance; T cell response; T-Lymphocyte; Uncertainty; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Virus; cell motility; glycosylation; immunogenic; migration; nanoparticle; neutralizing antibody; prevent; response; vaccine candidate

Identifying Critical Stages in Vaccine Induced IHIV-I Immunity The emergence of neutralizing serum antibody responses only after cellular immune responses have suppressed HIV replication has led to doubts regarding the importance of humoral immunity in controlling HIV infections. Nonetheless, rare, broadly cross-reactive antibodies are capable of neutralizing multiple isolates of HIV-1 in vitro, and when passively administered can prevent experimental infections. Thus, efficacious humoral immune responses remain crucial to the development of protective HIV-1 vaccines. Why are such antibodies rarely produced by HIV-infected patients? Why are the neutralizing epitopes present on the HIV-1 envelope so poorly immunogenic? Several explanations for the remarkable scarcity of HIV-1 broadly reactive, neutralizing antibody have been offered including the complexity and genetic plasticity of the HIV envelope antigens, the shielding of crucial antigen sites by glycosylation, competitive suppression by non-neutralizing surface antigens, immunological tolerance, and insufficient diversity in the primary antibody repertoire. All of these hypotheses are plausible, but remarkably detailed in situ studies of primary immune responses to HIV-1 antigens have not been performed. We know that HIV-1 neutralizing epitopes are poorly immunogenic but we do not know why. We shall, therefore, carry out studies to identify any deficits in the humoral responses of mice immunized with HIV-1 vaccines by focusing on the characteristic patterns of cellular migration, interaction, proliferation, and differentiation necessary for robust and efficacious antibody production. Our studies will use histologic, flow cytometric and molecular genetic comparisons of responses to HIV-1 and control vaccines and will identify those differences that may account for the rarity of protective HIV-1 antibody.

确定疫苗诱导的 IHIV-I 免疫的关键阶段 仅在细胞免疫反应抑制 HIV 复制后才会出现中和血清抗体反应，这导致人们对体液免疫在控制 HIV 感染中的重要性产生怀疑。尽管如此，罕见的、广泛交叉反应的抗体能够在体外中和多种 HIV-1 分离株，并且被动施用时可以预防实验性感染。因此，有效的体液免疫反应对于保护性 HIV-1 疫苗的开发仍然至关重要。 为什么艾滋病毒感染者很少产生这种抗体？为什么 HIV-1 包膜上的中和表位免疫原性如此差？对于 HIV-1 广泛反应性中和抗体的显着稀缺，人们提出了几种解释，包括 HIV 包膜抗原的复杂性和遗传可塑性、糖基化对关键抗原位点的屏蔽、非中和性表面抗原的竞争性抑制、免疫耐受，以及一抗库多样性不足。所有这些假设都是合理的，但尚未对 HIV-1 抗原的初级免疫反应进行非常详细的原位研究。我们知道 HIV-1 中和 表位的免疫原性很差，但我们不知道为什么。因此，我们应开展研究，重点关注细胞迁移、相互作用、增殖和分化的特征模式，这些模式是稳健和有效的抗体产生所必需的，以确定用 HIV-1 疫苗免疫的小鼠体液反应中的任何缺陷。我们的研究将使用组织学、流式细胞术和分子遗传学对 HIV-1 疫苗和对照疫苗的反应进行比较，并将确定那些可能导致保护性 HIV-1 抗体稀有的差异。