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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：具有有效 Fc 受体介导 (FcR) 效应功能的非中和抗体 (nnAb) 是否可以阻止 HIV/SHIV 获得，目前仍存在重大争议。因此，我们的长期目标是。计划的目的是测试以下假设：疫苗引发具有有效 FcR 效应子功能的 nnAb，并针对 C1/C2 和 V2 区域的表位gp120 可以防止 SHIV 感染。首先，我们将通过此应用程序提出的目标来测试这一假设。其次，通过小型“概念验证”研究，我们将评估免疫原/佐剂制剂在重复、低剂量 SHIV162P3 攻击模型中的主要意义。该项目将支持或反驳上述假设，提供对 HIV-1 疫苗开发至关重要的新信息，表明 Abs 的 FcR 效应器功能的作用，包括抗体依赖性细胞毒性。 (ADCC) 针对 gp120 C1 区域的非中和表位（A32 样表位）预防或调节 HIV-1 感染以及疫苗诱导的人类保护作用，后者在很大程度上得到了 RV144 疫苗试验结果的支持。对 A32 亚区的抗体反应可降低一部分疫苗的感染风险。此外，针对 C1 区和线性 V2 表位的抗体可协同捕获和感染感染性病毒。 ADCC 表明，由于 FcR 效应器功能，这些特异性之间的相互作用有助于疫苗功效，通过此应用，我们的目标是开发能够仅诱导针对被确定为 FcR 靶标的表位的 nnAb 的免疫原 (ID)。 - RV144 试验中的效应器反应，我们提出了这些新的 ID 构建体，进一步优化 ADCC 表位的选择性呈现和/或多聚化以开发成有效选择性诱导的新免疫原。针对与人类保护性 ADCC 反应相关的一个（A32 亚区）和两个（A32 亚区和 V2 环）Env 靶标的 FcR 效应器 Ab 反应，由稳定在中的 gp120 核心的内部结构域组成。 CD4 结合构象在最小稳定结构单元内稳定地呈现 A32 样表位，并且是进一步基于结构优化和修饰的平台。 ID 和 ID-V1V2 均表达 ADCC 表位，Aim 2 将评估 ID 和 ID-V1V2 的单体和多聚变体的抗原性，Aim 3 将评估 BALB/c 中 ID 和 ID-V1V2 的单体和多聚变体的免疫原性。这些研究将完成检验疫苗引发的 nnAb 防止 SHIV 感染的假设的第一步；修订后的工作范围未提供。有足够的时间进行 SHIV162P3 攻击研究；但是，一旦获得合适的免疫原制剂，将为初步研究提供研究所资金，同时为项目继续寻求资金。