Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery

描述（由申请人提供）：本CHAVI-ID申请的中心假设是，成功的HIV疫苗应引起保护性抗体（Abs），并且B细胞和CD4+ T细胞反应的结合对于诱导和长期维持疫苗保护至关重要。该申请的总体任务是确定免疫原和免疫方案，在临床前模型中诱导持续的HIV交叉保护性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策略。我们建议在深入了解免疫反应的关键属性的基础上，通过两项重点突出和高度综合的努力，开发一种艾滋病毒疫苗，以提供对艾滋病病毒的保护。焦点#1将集中于B细胞和抗体研究，以指导免疫原的开发，在适当的动物模型中引发保护性HIV抗体反应。焦点#2将集中于CD4+ T细胞的研究，利用关键的初步数据，通过免疫最大化T细胞对B细胞反应的帮助，并利用CD4+ T细胞的直接抗病毒活性。我们认为，这种结合的方法将导致新的免疫原和免疫策略的发现，将产生可测量的交叉保护抗体反应。然后，我们将在这些进展的基础上不断改进最有希望的结构和方案，直到实现疫苗保护。我们建议的一个关键组成部分是我们在免疫学，病毒学和结构生物学方面的研究团队的实力。主任Dennis Burton在了解艾滋病毒的广泛抗体中和和艾滋病毒感染动物模型中的抗体保护方面作出了重大贡献。科学领导小组（SLG）成员是Rati Ahmed、Michel Nussenzweig、Bruce Walker和Ian Wilson，他们在描述抗艾滋病毒抗体的结构和功能以及诱导和维持对该病毒的B细胞和T细胞免疫方面取得了重要进展。该团队将由五个科学研究支持组件（SRSCs）维持，包括强大的运营和管理，这些组件已经组装起来，以最大限度地加速实现指定目标的进展。

DESCRIPTION (provided by applicant): The central hypotheses of this CHAVI-ID application are that a successful HIV vaccine should elicit protective antibodies (Abs), and that the combination of B cell and CD4+ T ceil responses is critical for the induction and long-term maintenance of vaccine protection. The overall mission of the 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. We propose to develop an HIV vaccine based on a deep understanding of the critical attributes of immune responses that provide protection against AIDS viruses, through two focused and highly integrated efforts. Focus #1 will concentrate on B cell and antibody research to guide the development of immunogens that elicit protective HIV antibody responses in appropriate animal models. Focus #2 will concentrate on CD4+ T cell research, taking advantage of key preliminary data to maximize the T cell help offered to B cell responses through immunization, and to harness the direct antiviral activity of CD4+ T cells. We argue that this combined approach will lead to the discovery of novel immunogens and immunization strategies that will generate measurable cross-protective antibody responses. We will then build on such advances iteratively, by improving the most promising constructs and protocols until vaccine protection is achieved. A critical component of our proposal is the strength of our research team in immunology, virology and structural biology. The Director, Dennis Burton, has made major contributions to understanding broad antibody neutralization of HIV and antibody protection in animal models of HIV infection. The Scientific Leadership Group (SLG) members are Rati Ahmed, Michel Nussenzweig, Bruce Walker and Ian Wilson, who have made crucial advances in describing the structure and function of antibodies against HIV and the induction and maintenance of B and T cell immunity to the virus. The team will be sustained by five Scientific Research Support Components (SRSCs), including strong Operations and Management, that have been assembled to maximally accelerate progress toward the designated goals. PUBLIC HEALTH RELEVANCE: With 33 million infected individuals worldwide, an HIV vaccine is urgently needed to slow and eventually eliminate new infections. This proposal seeks to discover immunogens and immunization strategies that induce antibody and cellular immune responses that, in concert, are able to protect against exposure to the enormous diversity of global HIV isolates.