Structural Targeting of Potentially Protective gp120 Epitopes in the C1/C2 Region

C1/C2 区域潜在保护性 gp120 表位的结构靶向

• 批准号: 9188798
• 负责人: Marzena Elzbieta Pazgier
• 金额: $ 38.55万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-04 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188798
• 关键词: AIDS prevention; Address; Adjuvant; Animals; Antibody Formation; Antibody Response; Antigens; Binding; Clinical Trials; Complication; Crystallography; Dose; Electron Microscopy; Engineering; Epitopes; Fc Receptor; Formulation; Funding; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; HIV-1 vaccine; Hand; Human; Immune; Immune response; Immunize; Immunoglobulin A; Inbred BALB C Mice; Infant; Infection; Infection Control; Institutes; Letters; Light; Link; Macaca; Mediating; Modeling; Modification; Molecular; Molecular Conformation; Mothers; Mus; Negative Staining; Neutralization Tests; Play; Process; Risk; Role; SIV; Site; Specificity; Structure; Testing; Time; Vaccines; Variant; Viral Antibodies; Viremia; Virus; Virus Diseases; Work; antibody-dependent cell cytotoxicity; atomic state; base; design; glycosylation; helix-loop-helix protein differentiation inhibitor; humanized mouse; immunogenicity; in vivo; nanoparticle; neutralizing antibody; nonhuman primate; novel; prevent; programs; protein profiling; public health relevance; response; simian human immunodeficiency virus; vaccine candidate; vaccine development; vaccine efficacy; vaccine trial; vaccine-induced immunity

 DESCRIPTION (provided by applicant): There is a major unresolved controversy of whether non-neutralizing antibodies (nnAbs) with potent Fc-receptor mediated (FcR)-effector functions can block HIV/SHIV acquisition. Accordingly, the long-term goal of our program is to test the hypothesis that vaccine-elicited nnAbs with potent FcR-effector functions and directed at epitopes in the C1/C2- and V2- regions of gp120 protect against SHIV acquisition. This hypothesis will be tested in two steps. First, through aims proposed with this application, we will identify an optimal immunogen/adjuvant formulation to elicit these responses in small animals. Second, through a small "proof of concept" study, we will evaluate the immunogen/adjuvant formulation in a repeat, low-dose SHIV162P3 challenge model. The principal significance of this project is that it will either support or refute the above hypothesis, providing new information critical to HIV-1 vaccine development. Considerable evidence points toward a role of FcR-effector functions of Abs including antibody-dependent cellular cytotoxicity (ADCC) toward non-neutralizing epitopes in the C1 region of gp120 (A32-like epitopes) in preventing or modulating HIV-1 infection and in vaccine induced protection in humans. The latter is largely supported by results of the RV144 vaccine trial that implicated Ab responses to A32 sub-region with reduced infection risk in a subset of vaccines. Furthermore, Abs specific for C1 region and linear V2-epitopes synergized for infectious virus capture and ADCC, suggesting the cross-talk between these specificities contributing to vaccine efficacy due to FcR-effector functions. With this application we aim to develop inner domain-based immunogens (ID) capable of inducing solely the nnAbs directed at epitopes identified as targets of FcR- effector response in the RV144 trial. We propose these novel ID constructs, further optimized for selective presentation of ADCC epitopes and/or multimerized to develop into new immunogens effective in selective inducing FcR-effector Ab responses directed at one (A32 sub-region) and both (A32 sub-region and V2 loop) Env targets associated with protective ADCC responses in human. Our ID immunogen candidate consists of the inner domain of the gp120 core stabilized in CD4-bound conformation. ID stably presents A32-like epitopes within a minimal stable structural unit and is a platform for further structure based optimization and modification. Aim 1 develop monomeric and multimerized variants of ID and ID-V1V2, both expressing the ADCC epitopes. Aim 2 will evaluate antigenicity of monomeric and multimeric variants of ID and ID-V1V2 and Aim 3 will evaluate the immunogenicity of monomeric and multimerized variants of ID and ID-V1V2 in BALB/c mice. These studies will complete the first step in testing the hypothesis that vaccine-elicited nnAbs protect against SHIV acquisition; identification of an immunogen. The revised work scope does not provide sufficient time to carry out a SHIV162P3 challenge study; however, once a suitable immunogen formulation is in hand, institute funds will be provided for a preliminary study while funding is sought for project continuation.

 描述（由适用提供）：关于具有潜在的FC受体介导的（FCR）效果功能的非中和抗体（NNABS）是否可以阻止HIV/SHIV的获取，存在一个主要的未解决的争议。根据我们计划的长期目标，是测试以下假设：疫苗吸收的NNAB具有潜在的FCR效应功能，并针对GP120的C1/C2-和V2-区域的表位，可预防避免SHIV习惯。该假设将通过两个步骤进行检验。首先，通过此应用程序提出的目标，我们将 确定最佳免疫原/辅助公式，以在小动物中引起这些反应。其次，通过一项小的“概念证明”研究，我们将在重复的低剂量SHIV162P3挑战模型中评估免疫原/辅助公式。该项目的主要意义是它将支持或反驳上述假设，从而为HIV-1疫苗开发至关重要。大量证据表明，在GP120的C1区域（A32样的表位）在预防或调节HIV-1感染和疫苗诱导的人类诱导的保护中的GP120（A32样表位）中，包括抗体依赖性细胞细胞毒性（ADCC）对非中和表位的作用。 RV144疫苗试验的结果在很大程度上支持了后者，该试验暗示了AB对A32子区域的反应，而在一部分疫苗中，感染风险降低。此外，针对C1区域的ABS和线性V2 ePitopes协同捕获感染性病毒和ADCC，这表明这些规格之间的串扰是由于FCR效应功能而导致疫苗效率的。通过此应用，我们旨在开发基于内部域的免疫原子（ID），能够仅诱导针对EpiTOPES的NNAB在RV144试验中被鉴定为FCR-效应响应靶标的NNAB。我们提出了这些新颖的ID构建体，进一步优化了用于选择性呈现ADCC表位和/或多层次，以发展为有效的选择性诱导的FCR-ESFERTER AB反应，该免疫原为一个针对一个（A32次区域）和（A32 sub-rgion和V2 LOOP）的AB响应，与人类受保护的ADCC响应相关。我们的ID免疫原候选者由CD4结合构象稳定的GP120核心的内部结构域组成。 ID稳定地呈现在最小稳定的结构单元中的类似A32的表位，并且是一个基于结构的优化和修改的平台。 AIM 1开发ID和ID-V1V2的单体和多介导的变体，均表达ADCC表位。 AIM 2将评估ID和ID-V1V2的单体和多介导的变体的抗原性以及AIM 3将评估BALB/C/C小鼠中ID和ID-V1V2的单体和多介导变体的免疫原性。这些研究将完成测试疫苗吸收的NNABS防止湿夫的假设的第一步。鉴定免疫原。修订后的工作范围没有足够的时间进行SHIV1623挑战研究；但是，一旦手头有合适的免疫原配方奶粉，将为初步研究提供研究所资金，同时为项目延续提供了资金。