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.

该CHAVI-ID申请的总体使命是确定在临床前模型中诱导持续的HIV交叉保护性B细胞和CD 4 + T细胞应答的免疫原和免疫方案，从而指导预防性人类艾滋病疫苗的产品开发策略。对于焦点#2，我们的假设是长期体液免疫严重依赖于CD 4 + T细胞，特别是T滤泡辅助细胞（Tfh），并且这些细胞的有效产生是有效HIV疫苗的必要和强制性组成部分。 几乎所有许可的抗病毒疫苗都诱导中和抗体，并且这种抗体的产生通常依赖于CD 4 + T细胞。因此，理解和控制CD 4 + T细胞，特别是Tfh细胞，对于合理的疫苗策略是重要的。焦点#2旨在提高我们对以下方面的认识：1）Tfh细胞在HIV感染和接受许可的成功疫苗的人中的特异性、表型和功能; 2）导致Tfh细胞诱导的相关途径; 3）导致亲和力成熟和广泛中和HIV抗体诱导的精确Tfh信号;和4）HIV特异性效应CD 4 + T细胞在粘膜HIV感染的早期病灶控制中的作用。Tfh细胞在人类疫苗临床试验中也是潜在的非常有用的生物标志物，作为长期体液免疫和抗体质量的预测因子。将焦点#2中获得的信息转化为焦点#1中的免疫原和免疫策略的设计，以在敲入小鼠和NHP中进行评价。当我们收集关于最佳免疫原和免疫策略的信息时，我们将在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。