Overcoming HIV-1 transcriptional latency in unresponsive CD4 T cells

克服无反应 CD4 T 细胞中的 HIV-1 转录潜伏期

• 批准号: 9980780
• 负责人: OLAF KUTSCH
• 金额: $ 64.79万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980780
• 关键词: AIDS therapy; ATAC-seq; Address; Affect; BACH2 gene; Binding; Biological Markers; CD28 gene; CD4 Positive T Lymphocytes; CRISPR/Cas technology; Cell Line; Cell physiology; Cell surface; Cells; Characteristics; Complex; Data; Development; Devices; Drug Combinations; Drug Compounding; Drug Targeting; Event; Exhibits; Frequencies; Future; Gene Expression; Genetic Transcription; Goals; HIV; HIV Infections; HIV-1; Infection; Intervention; Investigation; Link; Mature T-Lymphocyte; Memory; Molecular; Molecular Biology; Molecular Target; PPM1D gene; Patients; Pattern; Peroxisome Proliferator-Activated Receptors; Pharmacology; Phenotype; Phosphotransferases; Population; Proliferating; Reporting; Research; Resistance; Signal Transduction Pathway; System; Systems Biology; T cell differentiation; T memory cell; T-Lymphocyte; TCR Activation; Testing; Therapeutic; Viral reservoir; Virus; Virus-Cell Membrane Interaction; base; design; genetic manipulation; in vitro Model; in vivo; innovation; latent HIV reservoir; latent infection; molecular phenotype; multicatalytic endopeptidase complex; new therapeutic target; novel; prevent; reconstitution; restoration; small hairpin RNA; specific biomarkers; transcription factor

ABSTRACT Latent HIV-1 infection has been recognized as a major obstacle to the development of a curative HIV-1 therapy, but host cell-virus interactions that control latent infection are still ill defined. Key to this application is the realization that the host cells of latent HIV-1 infection events are actually phenotypically altered in a manner that (i) forces the virus into a latent state and that (ii) renders the host cells unresponsive to stimulation, thereby preventing efficient therapeutic induction of HIV-1 reactivation. These changes go beyond a simple quiescent state that is characteristic for functional memory T cells. This proposal will extend on these findings and seek to address three major roadblocks in the field of HIV latency research. Roadblock #1 (Aim 1) concerns our inability to identify biomarkers that specifically define T cell sub-populations in which latently infected T cells are highly enriched. Such biomarkers would allow us to detail the molecular biology of the host cell state that enables and maintains latent HIV-1 infection. Leading to this application, we found that the intracellular changes allowing latent HIV-1 infected to persist are associated with a unique CD4+CD28– CD9+CD151+ phenotype, a T cell phenotype that also demarcates a small CD4 T cell sub-population that is increased in HIV patients on ART. We already demonstrate that CD151 expression by itself is associated with reservoir capacity. We will now detail the viral reservoir capacity of T cell sub-populations described by CD28, CD151 and CD9 expression. Roadblock #2 (Aim 2) addressed in this application is the question how the intracellular changes observed in host cells of latent HIV infection events act (i) to control HIV transcription and and (ii) to suppress T cell responsiveness. In addition to the proposed research on host-cell factors/networks controlling latent HIV infection, we already have identified several targets/interaction networks that control latent infection and that will be immediately probed. We will further address roadblock #3 (Aim 3), the question why stimulation of ex vivo T cell material from HIV patients seems to only trigger HIV-1 reactivation in a small fraction of the latently HIV-infected cells. Based on our results, we predict that T cell subpopulations described by differential CD28, CD9 and CD151 expression patterns, will exhibit varying levels of unresponsiveness to stimulation, allowing latent HIV infection to persist with different efficacies. Based on the results we have obtained leading to this application and the additional results we will generate, we will immediately begin to rationally design compound-based intervention strategies that would (i) first reconstitute T cell responsiveness in reservoir populations and then (ii) trigger efficient HIV reactivation, a prerequisite for any HIV-1 eradication strategy and the ultimate goal of this application.

摘要