Controlling HIV latency by manipulating CycT1 turnover

通过操纵 CycT1 更新来控制 HIV 潜伏期

• 批准号: 10680481
• 负责人: Koh Fujinaga
• 金额: $ 39.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-09 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680481
• 关键词: AIDS related cancer; Biological Assay; CAR T cell therapy; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Complement Factor B; Complex; Cyclins; Down-Regulation; Equilibrium; Gene Expression; Genes; Genetic Transcription; HIV; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immune response; Immune system; Individual; Interphase Cell; Kinetics; Maintenance; Mediating; Memory; Methods; Monitor; NF-kappa B; Pathway interactions; Persons; Phosphorylation; Phosphotransferases; Physiological; Play; Positive Transcriptional Elongation Factor B; Process; Productivity; Protein Dephosphorylation; Proteins; Receptor Signaling; Regulation; Rest; Role; Small Nuclear Ribonucleoproteins; Stimulation of Cell Proliferation; System; T cell regulation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; TCF Transcription Factor; Transactivation; Transcription Elongation; Viral; Virus; Virus Diseases; antiretroviral therapy; co-infection; cyclin T1; effector T cell; exhaust; immune function; improved; latent HIV reservoir; mimetics; mutant; neoplastic cell; new therapeutic target; nuclear factors of activated T-cells; pathogen; pharmacologic; posttranscriptional; prevent; programs; reactivation from latency; response; tat Protein; transcription factor; tumor; ubiquitin-protein ligase

Abstract Immune dysfunction associated with co-infection and AIDS-related cancers is commonly observed in HIV-infected individuals. In particular, gene expression programs in the immune system are often abnormally regulated in these individuals. We and other groups have recently discovered that the positive transcription factor b (P-TEFb), a critical cellular factor required for productive elongation of transcription, is severely down-regulated in quiescent and aberrant T cells. In resting CD4+ T cells, representing major latent HIV reservoirs, the expression of the cyclin T1 (CycT1) subunit of P-TEFb is diminished post-transcriptionally via currently unknown mechanisms, this being a main cause of HIV latency and tumor-specific T cells' defective response to check-point inhibitors and/or CAR-T cell therapies. Since increasing CycT1 is a prerequisite and mandatory step for optimal HIV reactivation and proper immune response against other pathogens and tumor cells, understanding the mechanism of CycT1 down-regulation is crucial. We have recently demonstrated that P-TEFb assembly regulated by phosphorylation determines the stability of CycT1. Also, we have identified all key players, including E3 ligases, involved in CycT1-degradation. Therefore, we hypothesize that increasing CycT1 proteins in resting and aberrant CD4+ T cells by manipulating cellular pathways to regulate P-TEFb assembly will reverse HIV latency and improve immune functions in HIV-infected individuals. In the proposed study, we will manipulate the cellular pathways regulating P-TEFb assembly and CycT1 stability to control HIV latency and improve immune functions. We will also identify previously uncharacterized "CycT1-degradation complexes", which will serve as new therapeutic targets. Successful completion of the proposed study will result in a new concept of T cell regulation modulated by the protein level of a master transcriptional regulator.

摘要