Harnessing CD4+ T cell responses for long-term protective immunity against HIV

利用 CD4 T 细胞反应实现针对 HIV 的长期保护性免疫

• 批准号: 9089827
• 负责人: Rafi Ahmed
• 金额: $ 361万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089827
• 关键词: AIDS Vaccines; AIDS/HIV problem; Address; Adjuvant; Affinity; Antibodies; Antibody Formation; Antibody Response; Antigens; Antiviral Agents; B Cell Proliferation; B cell repertoire; B-Lymphocytes; Biological Markers; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell physiology; Cells; Characteristics; Complex; Containment; Development; Dose; Evaluation; Figs - dietary; Generations; Goals; HIV; HIV Antibodies; HIV Infections; HIV vaccine; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immunity; Immunization; Immunology; Individual; Infection; Knock-in Mouse; Knowledge; Lead; Learning; Licensing; Life; Maintenance; Memory B-Lymphocyte; Mission; Molecular; Mus; Nature; Outcome; Pathway interactions; Patients; Phenotype; Plasma Cells; Pre-Clinical Model; Preventive; Process; Regimen; Regulation; Research Support; Role; Serum; Signal Transduction; Specificity; Staging; Structure of germinal center of lymph node; Surface; System; T cell response; T-Lymphocyte; Translating; Vaccination; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral Vaccines; base; cohort; cytotoxicity; design; improved; in vivo; nanoparticle; neutralizing antibody; novel; plasma cell differentiation; product development; response; standard measure; success; transcription factor; vaccine development; vaccine efficacy; vaccine evaluation; vaccine trial

The overall mission of this CHAVI-ID application is to define immunogens and immunization regimens that induce sustained HIV cross-protective B cell and CD4+ T cell responses in preclinical models and, thereby, guide product development strategies for a preventive human AIDS vaccine. For Focus #2, our hypothesis is that long-term humoral immunity is critically dependent on CD4+ T cells, and particularly T follicular helper (Tfh) cells, and that the efficient generation of these cells is an essential and obligatory component of an effective HIV vaccine. Nearly all licensed anti-viral vaccines induce neutralizing antibodies and the development of such antibodies is typically CD4+ T cell dependent. Therefore understanding and controlling CD4+ T cells, and Tfh cells in particular, is important for rational vaccine strategies. Focus #2 is designed to improve our knowledge of: 1) the specificity, phenotype and function of Tfh cells in HIV infection and in humans who have received licensed successful vaccines; 2) the pathways involved that lead to the induction of Tfh cells; 3) the precise Tfh signals that lead to the induction of affinity maturation and broadly neutralizing HIV antibodies; and 4) the role of HIV-specific effector CD4+ T cells in the early focal control of mucosal HIV infection. Tfh cells are also potentially extremely useful biomarkers in human vaccine clinical trials as predictors of long-term humoral immunity and antibody quality. The information gained in Focus #2 will be translated into the design of immunogens and immunization strategies in Focus #1 for evaluation in knock-in mice and NHPs. As we gather together information on optimal immunogens and immunization strategies, we will move forward with small-scale human trials with the advice and close involvement of our Vaccine Discovery Scientific Research Support Component.

CHAVI-ID应用程序的总体任务是定义免疫原和免疫方案，在临床前模型中诱导持续的HIV交叉保护B细胞和CD4+T细胞反应，从而指导预防性人类艾滋病疫苗的产品开发战略。对于Focus#2，我们的假设是，长期体液免疫严重依赖于CD4+T细胞，特别是T滤泡辅助细胞(TFH)，这些细胞的有效生成是有效的HIV疫苗必不可少的组成部分。 几乎所有获得许可的抗病毒疫苗都会诱导中和抗体，而这种抗体的产生通常依赖于CD4+T细胞。因此，了解和控制CD4+T细胞，特别是Tfh细胞，对于合理的疫苗策略是重要的。Focus#2旨在提高我们对以下方面的了解：1)在HIV感染和已获得许可的成功疫苗的人类中，TFH细胞的特异性、表型和功能；2)导致TFH细胞诱导的途径；3)导致亲和力成熟和广泛中和HIV抗体的精确TFH信号；以及4)HIV特异性效应者CD4+T细胞在粘膜HIV感染的早期局部控制中的作用。在人类疫苗临床试验中，TFH细胞也可能是非常有用的生物标记物，作为长期体液免疫和抗体质量的预测因子。在焦点#2中获得的信息将被转化为焦点#1中的免疫原和免疫策略的设计，用于在转基因小鼠和NHP中进行评估。随着我们收集关于最佳免疫原和免疫策略的信息，我们将在我们的疫苗发现科学研究支持部门的建议和密切参与下，推进小规模人体试验。