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

基本信息

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
项目类别：
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

项目摘要

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.

这种CHAVI-ID应用的总体任务是定义免疫原和免疫方案，这些免疫原则和免疫方案在临床前模型中诱导HIV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AIDS疫苗的产品开发策略。对于焦点＃2，我们的假设是长期的体液免疫与CD4+ T细胞，尤其是T卵泡辅助器（TFH）细胞有关，并且这些细胞的有效产生是有效HIV疫苗的必不可少的组成部分。几乎所有许可的抗病毒疫苗都会诱导中和抗体，并且此类抗体的发展通常依赖于CD4+ T细胞。因此，了解和控制CD4+ T细胞，尤其是TFH细胞，对于理性疫苗策略很重要。焦点＃2旨在提高我们对以下方面的了解：1）TFH细胞在HIV感染中的特异性，表型和功能以及已获得许可成功疫苗的人类的特异性，表型和功能； 2）导致TFH细胞诱导的途径； 3）导致亲和力成熟并广泛中和HIV抗体的确切TFH信号； 4）HIV特异性效应子CD4+ T细胞在粘膜HIV感染的早期局灶性控制中的作用。 TFH细胞在人类疫苗临床试验中也可能是极其有用的生物标志物，作为长期体液免疫和抗体质量的预测指标。焦点2中获得的信息将转化为焦点1中免疫原和免疫策略的设计，以评估敲入小鼠和NHP。当我们聚集有关最佳免疫原子和免疫策略的信息时，我们将进行小规模的人类试验，并与我们的疫苗发现科学研究支持部分的建议和密切参与。