Project 1

项目1

• 批准号: 10731713
• 负责人: DENNIS J. HARTIGAN-O'CONNOR
• 金额: $ 55.12万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-22 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731713
• 关键词: Activities of Daily Living; Adenoviruses; Aftercare; Alleles; Antigens; Antiviral Response; Binding; Blinded; Blood; Blood specimen; CD8-Positive T-Lymphocytes; Cells; Cellular Assay; Chad; Clinical Data; Clinical Trials; Clone Cells; DNA; Data; Elements; Enrollment; Epitopes; Exhibits; Flow Cytometry; Genetic Transcription; HIV; Home; Human; Immunity; Immunology; Individual; Interferon Type II; Interruption; Kinetics; Macaca; Measurable; Measurement; Memory; Modality; Participant; Persons; Phenotype; Placebos; Proliferating; Property; Randomized; Receptor Signaling; Regimen; Reporting; Residual state; Route; SIV; Sampling; Site; Specificity; Structure; System; T cell receptor repertoire sequencing; T cell response; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Vaccination; Vaccine Therapy; Vaccinee; Vaccines; Viral; Viral Load result; Virus; antiretroviral therapy; clinically relevant; cohort; efficacy evaluation; exhaustion; experience; high dimensionality; improved; lymph nodes; multimodality; multiple omics; peripheral blood; recruit; response; therapeutic candidate; therapeutic vaccine; transcriptome; vaccine candidate; vaccine delivery

ABSTRACT In order to effectively control HIV after ART is stopped, HIV-specific T cell responses to therapeutic vaccination must not only be increased in magnitude, but they also must be long- lived, have the capacity to home to sites of reservoir persistence, have the T cell memory-like capacity to robustly proliferate and execute effector functions in response to antigen (i.e., they need to overcome the residual T cell exhaustion that persists in pre-existing HIV-specific T cells despite viral load suppression with ART), and be refocused to have dominant responses that target vulnerable epitopes. Due to the limitations of standard T cell assays, and despite emerging data from clinical trials showing at least partial control of HIV post-vaccination, little is known about the mechanisms by which HIV therapeutic vaccine regimens transform ineffective pre-existing HIV-specific T cell immunity into an effective antiviral response. In this Project, we will leverage our experience performing integrated multi-modal systems immunology analysis with paired single cell transcriptome and TCR sequencing (scRNA/TCRseq) data and high- dimensional flow cytometry data. We will perform clonal-level analysis on HIV/SIV therapeutic vaccine-elicited CD8+ T cells from highly unique and clinically relevant human and macaque HIV/SIV cohorts in which therapeutic vaccines have exerted a measurable effect on altering viral load kinetics after treatment interruption to ask: to what extent are current top-candidate therapeutic vaccine regimens capable of recruiting new and/or pre-existing T cell clones with optimal memory-like properties (function and differentiation state; Aims 1 and 2), and to what extent do memory-like features (or other features) of the vaccine-elicited T cell response correlate with post-treatment control of HIV (Aim 3)? These studies will allow us to characterize in unprecedented depth the impact of different therapeutic vaccine regimens on critical – and previously unmeasurable – facets of the quality of the virus-specific T cell response. Our results will lay the groundwork for us to develop reliable measurements of virus-specific T cell clonal structure and differentiation state that will inform iterative studies in humans and macaques.

摘要