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

• 批准号: 10685405
• 负责人: Sarah Elizabeth Palmer
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF SYDNEY
• 依托单位国家: 美国
• 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/10685405
• 关键词: Acceleration; 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; Immune; Immune Evasion; 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; immune clearance; 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

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.

项目摘要 治疗过程中HIV蛋白NEF的表达有助于通过 下调细胞表面的主要组织相容性I型I型（MHC-I）和抗原表现 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通过HIV特异性CD8 T细胞清除。 除了MHC-I下调外，开发有效的CD8细胞毒性T细胞（CTL）还有挑战 反对复制能力病毒的反应。细胞内HIV储藏室由病毒占主导 含有抗免疫响应和HIV病毒缺陷的CTL逃生突变的变体 可以产生作为CTL反应的诱饵的病毒蛋白。但是，最近的研究表明多功能 CD8 T细胞和/或T细胞表位的响应在结构上很重要（即高度网络） 病毒蛋白的遗传保存区域对于HIV控制至关重要。另外，具有T的细胞 可以通过重定向CD8 T细胞反应对未物质病毒表位的反应来消除细胞表位逃生突变 通过采用创新技术 - 通过参与者的细胞进行了体内艾滋病毒的消除测定法 关于有效的治疗，我们预计这项探索性研究将表明，NEF封锁会显着增强CD8 T细胞介导的消除了含有诱导病毒的HIV感染细胞。结合NEF 封锁，我们将通过扩展使用HIV特异性CD8 T细胞来增加这些HIV储层细胞的清除 影响多功能/效应子CD8 T细胞反应的一系列免疫原性宠物。这些宠物是 通过应用一个 免疫信息分析管道。由于这些宠物在其蛋白质中高度联网的事实 来源，预计它们将代表缺乏逃脱突变的T细胞表位。因此，进行此操作 研究我们将确定NEF阻滞剂和免疫原性胡椒池的最佳组合，以吸引CD8 T细胞介导的HIV感染细胞清除。这项研究将加速新的艾滋病毒 将NEF封锁结合了MHC-I修复和免疫疗法的治疗策略，这些策略有效 CTL响应并提供了在这种方法之前先进行体内模型的证据基础 应用于临床环境。