Clearing Persistently HIV-Infected CD4+ T Lymphocytes

清除持续感染 HIV 的 CD4 T 淋巴细胞

• 批准号: 7130391
• 负责人: DAVID M. MARGOLIS
• 金额: $ 68.52万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7130391
• 关键词: AIDS therapy; HIV infections; amidohydrolases; antiAIDS agent; clinical research; combination chemotherapy; gene expression; helper T lymphocyte; human immunodeficiency virus; human subject; human therapy evaluation; immune response; latent virus infection; leukocyte activation /transformation; leukocyte count; therapy design /development; valproate; virus RNA; virus load

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）：没有一个艾滋病毒感染者被治愈，无论有效的抗逆转录病毒疗法的发展。然而，稳定缓解或治愈感染是HIV治疗的最终目标。终身治疗的困难使得必须了解消除艾滋病毒感染的障碍。 尽管进行了高效抗逆转录病毒治疗（HAART），但静息CD 4细胞的持续感染和残余病毒复制都可能阻止感染的清除。除了新型抗病毒药物外，还需要诱导潜伏HIV表达但不增强从头感染的药物。我们的研究提出了一种方法，可以增强HIV启动子和病毒表达，而无需整体T细胞活化。 我们已经表明，染色质重塑酶组蛋白脱乙酰酶1（HDAC 1）在HIV潜伏期中起着关键作用。临床上可用的HDAC抑制剂丙戊酸（VPA）诱导潜伏的HIV离体生长，而没有T细胞活化或增加从头HIV感染。应用独特和成熟的基础设施，并与专家合作，我们的工作将集中在一个特定的目标。 具体目的：在抑制性HAART治疗中加入VPA后，每百万感染单位（IUPM）静息CD 4 + T细胞将下降 IA：在生长试验中定量从静息CD 4 + T细胞中回收的可复制HIV：HAART + VPA将耗尽静息CD 4细胞中的可复制HIV。 研究者手册：通过超灵敏测定法测量血浆HIV RNA，并定量CDS-depleted PBMC中有复制能力的HIV：HAART将预防VPA后病毒感染的传播 1C：在HAART治疗的基线和HAART加VPA治疗后测量HIV特异性免疫：在VPA治疗期间，更大的HIV特异性免疫应答将与IUPM下降的更陡斜率相关。 耗尽HIV感染的静息CD 4 + T细胞的储存库是可以实现的概念验证可以显著改变目前治疗HIV感染的方法。