Clearing Persistently HIV-Infected CD4+ T Lymphocytes

清除持续感染 HIV 的 CD4 T 淋巴细胞

• 批准号: 6948093
• 负责人: DAVID M. MARGOLIS
• 金额: $ 4.57万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6948093
• 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）：无论有效的抗逆转录病毒疗法的发展如何，都没有治愈HIV感染的人。然而，稳定的缓解或治愈感染是艾滋病毒治疗的最终目标。终身治疗的困难使得必须了解根除HIV感染的障碍。 尽管高度活跃的抗逆转录病毒疗法（HAART），静息CD4细胞的持续感染和残留的病毒复制都可以防止感染。除了新型的抗病毒药物外，还需要诱导潜在艾滋病毒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全局T细胞激活。 我们已经表明，染色质重塑酶组蛋白脱乙酰基酶1（HDAC1）在HIV潜伏期中起关键作用。一种临床上可用的HDAC抑制剂丙戊酸（VPA）诱导潜在的HIV离体生长，而无需T细胞激活或从头hiv感染增加。应用独特而既定的基础架构，并通过专家合作者，我们的工作将重点放在一个特定的目标上。 具体目的：在抑制性HAART治疗中，静止的CD4+ T细胞静止的CD4+ T细胞将下降，而抑制HAART治疗将下降 IA：从静止的CD4+ T细胞中恢复的量化复制能力的HIV：Haart Plus VPA在静止的CD4细胞中会耗尽复制能力的HIV。 IB：通过超敏化测定法测量血浆HIV RNA，并在CDS缺失的PBMC中定量复制能力的HIV：HAART将防止VPA后防止病毒感染传播 1C：测量HAART基线和HAART PLUS VPA时的HIV特异性免疫力：更大的HIV特异性免疫反应将与VPA治疗期间IUPM下降的陡峭斜率相关。 概念概念表明，可以实现的HIV感染静止CD4+ T细胞的储存库可以显着改变当前的HIV感染治疗方法。