Clearing Persistently HIV-Infected CD4+ T Lymphocytes

清除持续感染 HIV 的 CD4 T 淋巴细胞

基本信息

批准号：
7685980
负责人：
DAVID M. MARGOLIS
金额：
$ 3.72万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-15 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7685980
关键词：
AIDS clinical trial group Adult Affinity Amprenavir Anemia Anti-Retroviral Agents Antibodies Antiviral Agents Antiviral Therapy Arts Back Binding Biohazardous Substance Biological Assay Blood Blood Component Removal Budgets CD4 Positive T Lymphocytes CYP2C9 gene Case Study Cell surface Cells Chronic Clinical Clinical Trials Clinical Trials Design Colloids Complex Confidence Intervals Count Data Data Analyses Detection Development Disease remission Distant Dose Drug Interactions Drug usage Enrollment Enzyme-Linked Immunosorbent Assay Enzymes Excision Exclusion Criteria Exposure to Frequencies Funding Future Gene Expression Generations Generic Drugs Goals Gray unit of radiation dose HIV HIV Antigens HIV Core Protein p24 HIV Infections HIV Long Terminal Repeat HIV therapy HIV-1 Hematopoietic Stem Cell Mobilization Heterochromatin Highly Active Antiretroviral Therapy Histone Deacetylase Hour Human IL2 gene Imidazole Immune response Immunity Immunotherapy Individual Infection Interleukin-2 Interruption Isoenzymes Leukocytes Licensing Liver Failure Liver diseases Long Terminal Repeats Measurable Measurement Measures Mediating Memory Metabolism Minor Mitogens Molecular Monitor Nature Numbers Nylons Patients Peripheral Personal Communication Pharmaceutical Preparations Pharmacologic Substance Physicians Phytohemagglutinins Plasma Plastics Play Population Principal Investigator Procedures Production Protease Inhibitor Proteins Published Comment Pyrroles RNA Reagent Recovery Recruitment Activity Reporting Repression Research Research Design Research Infrastructure Residual state Rest Riots Risk Ritonavir Role Safety Sample Size Sampling Schools Seizures Series Serum Site Statistical Data Interpretation Sterility Sting Injury Study Section System T-20 T-Cell Activation T-Lymphocyte Testing Therapeutic Time Tissues Toxic effect Transcription Regulatory Protein Transferase Valproic Acid Viral Viremia Virus Diseases Walkers Week Wit Work Zidovudine antiretroviral therapy chromatin remodeling cohort concept cost cytotoxic dosage efavirenz experience human HDAC1 protein improved in vivo inhibitor/antagonist latent infection magnetic beads member novel prevent programs promoter research study response small molecule transcription factor volunteer

项目摘要

DESCRIPTION (provided by applicant): No one with HIV infection has been cured, regardless of the development of effective antiretroviral therapy. Nevertheless, stable remission or cure of infection is the ultimate goal of HIV therapy. The difficulties of lifelong therapy make it imperative to understand the obstacles to eradication of HIV infection. Both persistent infection of resting CD4 cells and residual viral replication despite highly active antiretroviral therapy (HAART) may prevent clearance of infection. In addition to novel antiviral drugs, agents that induce expression of latent HIV but do not enhance de novo infection are needed. Our studies suggest an approach that may augment HIV promoter and viral expression without global T cell activation. We have shown that the chromatin remodeling enzyme histone deacetylase 1 (HDAC1) plays a critical role in HIV latency. A clinically available HDAC inhibitor, valproic acid (VPA), induces outgrowth of latent HIV ex vivo without T cell activation or increased de novo HIV infection. Applying unique and established infrastructure, and with expert collaborators, our work will focus on a single specific aim. Specific Aim: Infected units per million (IUPM) resting CD4+ T cells will decline after VPA is added to suppressive HAART therapy IA: Quantitate replication-competent HIV recovered from resting CD4+ T cells in outgrowth assays: HAART plus VPA will deplete replication-competent HIV in resting CD4 cells. IB: Measure plasma HIV RNA by a supersensitive assay and quantitate replication-competent HIV in CDS-depleted PBMCs: HAART will prevent dissemination of viral infection following VPA 1C: Measure HIV-specific immunity at baseline on HAART, and after HAART plus VPA: Greater HIV-specific immune response will correlate with a steeper slope of decline of IUPM during VPA therapy. Proof-of-concept that depletion of the reservoir of HIV-infected resting CD4+ T cells is achievable could significantly alter the current approach to therapy for HIV infection.

描述（由申请人提供）：无论有效的抗逆转录病毒疗法如何发展，尚未治愈任何艾滋病毒感染者。尽管如此，感染的稳定缓解或治愈是HIV治疗的最终目标。终身治疗的困难使得了解根除艾滋病毒感染的障碍势在必行。尽管采用高效抗逆转录病毒治疗 (HAART)，静息 CD4 细胞的持续感染和残留的病毒复制可能会阻碍感染的清除。除了新型抗病毒药物外，还需要诱导潜伏 HIV 表达但不增强新感染的药物。我们的研究提出了一种无需全局 T 细胞激活即可增强 HIV 启动子和病毒表达的方法。我们已经证明染色质重塑酶组蛋白脱乙酰酶 1 (HDAC1) 在 HIV 潜伏期中发挥着关键作用。临床上可用的 HDAC 抑制剂丙戊酸 (VPA) 可以在体外诱导潜伏 HIV 的生长，而不会激活 T 细胞或增加新的 HIV 感染。通过应用独特且成熟的基础设施，并与专家合作者，我们的工作将专注于一个特定的目标。具体目标：在抑制性 HAART 治疗中添加 VPA 后，每百万感染单位 (IUPM) 静息 CD4+ T 细胞将下降 IA：在生长检测中定量从静息 CD4+ T 细胞中回收的具有复制能力的 HIV：HAART 加 VPA 将消除静息 CD4 细胞中具有复制能力的 HIV。 IB：通过超灵敏测定法测量血浆 HIV RNA，并定量 CDS 耗尽的 PBMC 中具有复制能力的 HIV：HAART 将防止 VPA 后病毒感染的传播 1C：在 HAART 基线和 HAART 加 VPA 后测量 HIV 特异性免疫：在 VPA 治疗期间，更强的 HIV 特异性免疫反应将与 IUPM 下降的更陡斜率相关。概念验证表明，消除 HIV 感染的静息 CD4+ T 细胞库是可以实现的，这可能会显着改变当前治疗 HIV 感染的方法。