Clearing Persistently HIV-Infected CD4+ T Lymphocytes

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，没有一名艾滋病毒感染者被治愈。然而，感染的稳定缓解或治愈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艾滋病毒感染的障碍。 尽管进行了高效的抗逆转录病毒治疗(HAART)，但静止的CD4细胞的持续感染和残留的病毒复制都可能阻止感染的清除。除了新的抗病毒药物外，还需要诱导潜伏的艾滋病毒表达但不会增强新发感染的药物。我们的研究提出了一种方法，可以在不激活全球T细胞的情况下增强HIV启动子和病毒的表达。 我们已经证明染色质重塑酶组蛋白脱乙酰酶1(HDAC1)在HIV潜伏期中起着关键作用。临床上可用的HDAC抑制剂丙戊酸(VPA)可以在不激活T细胞或增加新发HIV感染的情况下，在体外诱导潜伏的HIV生长。应用独特和成熟的基础设施，并与专家合作，我们的工作将集中于单一的特定目标。 具体目的：在抑制性HAART治疗中加入VPA后，静息CD4+T细胞感染单位(IUPM)将下降 IA：定量从静止的CD4+T细胞中回收具有复制能力的HIV：HAART加VPA将耗尽静止的CD4细胞中具有复制能力的HIV。 IB：用超敏方法检测血浆HIV RNA并定量检测CDS缺失的PBMC中复制能力的HIV：HAART将防止VPA后病毒感染的传播 1C：在HAART和HAART加VPA治疗后，在基线时测量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下降的斜率更大相关。 概念验证表明，可以耗尽艾滋病毒感染的静止CD4+T细胞的储存库，这可能会显著改变目前治疗艾滋病毒感染的方法。

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.