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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.

项目总结