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: 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
• 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

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， 让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CD 8 T细胞清除。 除了MHC-I下调外，在开发有效的CD 8细胞毒性T细胞（CTL）方面也存在挑战。 针对复制能力前病毒的应答。细胞内的HIV储库被病毒控制 含有对免疫应答有抗性的CTL逃逸突变和缺陷型HIV前病毒的变体 可以产生作为CTL应答诱饵的病毒蛋白。然而，最近的研究表明， CD 8 T细胞的应答和/或靶向来自结构上重要的T细胞表位（即，高度网络化） 病毒蛋白的遗传保守区域对于HIV控制是必需的。此外，携带T细胞的细胞 细胞表位逃逸突变可以通过将CD 8 T细胞应答重定向至未突变的病毒表位来消除 通过采用一种创新的技术--体外艾滋病毒根除试验--使用来自参与者的细胞 在有效治疗的基础上，我们期望这项探索性研究将揭示Nef阻断能显著增强CD 8 T细胞介导的含有诱导型前病毒的HIV感染细胞的消除。与Nef联合使用 阻断后，我们将通过扩增HIV特异性CD 8 T细胞来增加这些HIV储库细胞的清除， 诱导多功能/效应CD 8 T细胞应答的免疫原性肽库。这些肽是 从六种HIV蛋白的拓扑学重要和遗传保守区域中选择， 免疫信息学分析管道。由于这些肽在其蛋白质内高度联网， 由于T细胞表位的起源，预期它们代表缺乏逃逸突变的T细胞表位。因此，在进行这项工作时， 本研究将确定Nef阻断剂和免疫原性肽库的最佳组合，以诱导CD 8 T细胞介导的HIV感染细胞的清除。这项研究将加速开发一种新的艾滋病毒 治疗策略，结合Nef阻断MHC-I恢复和免疫治疗， CTL应答，并为在该方法可用于治疗之前进展到体内模型提供证据基础。 应用于临床环境。