Combining immunogenic peptides and Nef blockade to enhance CD8 T-cell-mediated clearance of HIV-infected cells

结合免疫原性肽和 Nef 阻断来增强 CD8 T 细胞介导的 HIV 感染细胞清除

基本信息

批准号：
10482443
负责人：
Sarah Elizabeth Palmer
金额：
$ 13.61万
依托单位：
UNIVERSITY OF SYDNEY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-17 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482443
关键词：
Address Affinity Agreement Alleles Amino Acids Antigen Presentation Antigens Binding Biological Assay Biological Markers CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Count Cell surface Cells Clinical Cytotoxic T-Lymphocytes DNA Development Down-Regulation Epitopes HIV HIV Antigens HIV Genome HIV Infections HLA Antigens Histocompatibility Antigens Class I I-antigen Immune Immune response Immune system Immunologic Surveillance Immunotherapeutic agent Immunotherapy Individual Length Maintenance Major Histocompatibility Complex Mediating Modeling Mutate Mutation Participant Patients Peptides Protein Fragment Protein Region Proteins Proviruses Sequence Analysis Surface T cell response T memory cell T-Lymphocyte T-Lymphocyte Epitopes Techniques Variant Viral Viral Load result Viral Proteins Virus acute infection analysis pipeline antiretroviral therapy cytokine cytotoxic CD8 T cells effective therapy effectiveness evaluation experimental study immunogenic in vivo Model inhibitor innovation memory CD4 T lymphocyte nef Protein prevent protein structure resistance mutation response restoration small molecule small molecule inhibitor treatment strategy viral rebound

项目摘要

Project Summary The expression of the HIV protein Nef during therapy contributes to the persistence of HIV in cells by downregulating cell-surface major histocompatibility complex type I (MHC-I) and antigen presentation which allows the virus to evade immune response. Therefore, inhibiting the expression of Nef would allow for MHC-I expression of HIV antigens on the surface of HIV-infected cells and their clearance by HIV-specific CD8 T cells. In addition to MHC-I downregulation, there are challenges in developing an effective CD8 cytotoxic T cell (CTL) response against replication-competent proviruses. The intracellular HIV reservoir becomes dominated by viral variants containing CTL escape mutations that are resistant to immune response and defective HIV proviruses can produce viral proteins that act as decoys for CTL response. However, recent studies show polyfunctional response of CD8 T cells and/or the targeting of T cell epitopes from structurally important (i.e., highly networked) and genetically-conserved regions of viral proteins are essential for HIV control. In addition, cells harboring T cell epitope escape mutations can be eliminated by redirecting CD8 T cell response to unmutated viral epitopes By employing an innovative technique-- an ex vivo HIV eradication assay --using cells from participants on effective therapy, we expect this exploratory study will reveal that Nef blockade significantly enhances CD8 T cell–mediated elimination of HIV-infected cells containing inducible proviruses. In combination with Nef blockade, we will augment the clearance of these HIV reservoir cells by expanding HIV-specific CD8 T cells with a pool of immunogenic peptides that induce polyfunctional/effector CD8 T cell response. These peptides are selected from topologically important and genetically-conserved regions of six HIV proteins by applying an immunoinformatics analysis pipeline. Due to the fact these peptides are highly networked within their protein of origin, they are expected to represent T cell epitopes which lack escape mutations. Therefore, in conducting this study we will determine the best combination of Nef blockers and immunogenic peptide pools for eliciting CD8 T cell-mediated clearance of HIV-infected cells. This study will accelerate the development of a new HIV treatment strategy that combines Nef blockade for MHC-I restoration and immunotherapies that elicit effective CTL response and provide the evidentiary basis for progressing to an in vivo model before this approach can be applied in a clinical setting.

项目概要治疗期间 HIV 蛋白 Nef 的表达通过以下方式促进 HIV 在细胞中的持续存在：下调细胞表面主要组织相容性复合体 I 型 (MHC-I) 和抗原呈递，允许病毒逃避免疫反应，因此，抑制 Nef 的表达将允许 MHC-I。 HIV 抗原在 HIV 感染细胞表面的表达及其被 HIV 特异性 CD8 T 细胞的清除。除了 MHC-I 下调之外，开发有效的 CD8 细胞毒性 T 细胞 (CTL) 还面临挑战针对具有复制能力的原病毒的反应。细胞内的HIV病毒库变得以病毒为主。含有 CTL 逃逸突变的变体，可抵抗免疫反应和有缺陷的 HIV 原病毒可以产生作为 CTL 反应诱饵的病毒蛋白，但最近的研究表明具有多功能性。 CD8 T 细胞的反应和/或结构上重要的 T 细胞表位的靶向（即高度网络化）病毒蛋白的遗传保守区域对于 HIV 控制至关重要。此外，细胞还含有 T。通过将 CD8 T 细胞反应重定向至未突变的病毒表位，可以消除细胞表位逃逸突变通过采用创新技术——离体 HIV 根除——使用来自关于有效的治疗，我们预计这项探索性研究将揭示 Nef 阻断显着增强 CD8 与 Nef 联合使用 T 细胞介导消除含有诱导型原病毒的 HIV 感染细胞。封锁后，我们将通过扩大 HIV 特异性 CD8 T 细胞来增强这些 HIV 储存细胞的清除诱导多功能/效应 CD8 T 细胞反应的免疫原性肽库。通过应用一种方法从六种 HIV 蛋白的拓扑重要且遗传保守的区域中选择由于这些肽在其蛋白质内高度网络化。起源，他们预计代表缺乏逃逸突变的T细胞表位，因此，在进行这一过程中。研究中，我们将确定 Nef 阻滞剂和免疫原性肽库的最佳组合，以引发 CD8 T 细胞介导的 HIV 感染细胞清除这项研究将加速新的 HIV 的开发。治疗策略结合了用于 MHC-I 恢复的 Nef 阻断和引发有效的免疫疗法 CTL 反应并为在该方法得以应用之前进展到体内模型提供证据基础应用于临床环境。