A Phase II/II Investigation of the Effect of Vorinostat (VOR) in HIV Infection

描述(由申请人提供)：终生抗逆转录病毒疗法(ART)带来了巨大的问题。因此，未来艾滋病毒研究的许多重要目标之一是开发能够根除艾滋病毒感染的临时控制疗法。艾滋病毒在一小部分长期存活的CD4+T细胞中的持续感染是目前根除艾滋病毒感染的主要障碍。人类转录因子将组蛋白脱乙酰酶(HDACs)招募到HIV长末端重复序列启动子上，介导浓缩的异染色质的形成，从而抑制LTR的表达和病毒的产生。对弱HDAC抑制剂丙戊酸的研究未能测量到ART患者静息细胞感染的持续耗竭，但这种效应远远低于HDAC抑制剂的主要分子机制。我们已经证明了被许可用于肿瘤学的有效抑制剂Suberoylanilide羟肟酸(Vorinostat，VOR)的能力，它对I类HDAC具有选择性，能够诱导细胞系中HIV启动子的表达，并从抗逆转录病毒治疗的无菌HIV感染患者的静止CD4+T细胞中产生病毒。我们提出了一项主要证据研究，以衡量有效的HDAC抑制剂在体内诱导持久性前病毒HIV表达的潜力。具体目的1：体内暴露VOR后，静息的CD4--T细胞中可检测到的HIV RNA表达的频率将增加：我们将比较稳定服用VOR前后HIV感染患者静息CD4+细胞中HIV RNA的表达。具体目标2：对HIV-1感染的患者，有限剂量的VOR联合ART将是安全和耐受的：我们将描述接受联合抗逆转录病毒治疗的成年HIV-1感染患者VOR的安全性、耐受性和副作用谱。虽然根除艾滋病毒感染的目标还很遥远，但该项目可能会验证HDAC抑制剂对清除持续感染的贡献能力，并为这种方法的早期人类测试建立一个新的范例。 相关性(见说明)：如果要从HIV感染者身上根除病毒，就必须开发干扰静止的CD4+T淋巴细胞潜伏感染的疗法。组蛋白脱乙酰酶(HDAC)抑制剂可阻断体外潜伏的前病毒感染。我们将直接评估HDAC抑制剂在体内对HIV潜伏期的影响。

DESCRIPTION (provided by applicant): Lifelong antiretroviral therapy (ART) presents formidable problems. Therefore, among the many important goals for future HIV research is the development of temporally contained therapies capable of eradicating HIV infection. The persistence of quiescent HIV infection within a small population of long-lived CD4+ T cells is currently a major obstacle to the eradication of HIV infection. Human transcription factors recruit histone deacetylases (HDACs) to the HIV long terminal repeat promoter, mediating the formation of condensed heterochromatin, resulting in repression of LTR expression and viral production. Studies of the weak HDAC inhibitor valproic acid failed to measure a consistent depletion of resting cell infection in patients on ART, but this effect is far downstream of the primary molecular mechanism of HDAC inhibitors. We have demonstrated the ability of the potent inhibitor licensed for use in oncology, suberoylanilide hydroxamic acid (Vorinostat, VOR), selective for Class I HDACs, to induce HIV promoter expression in cell lines and virus production from the resting CD4+ T cells of antiretroviral-treated, aviremic HIV-infected patients. We propose a proof-of-principal study to measure the potential of potent HDAC inhibitors to induce the expression of persistent proviral HIV in vivo. Specific Aim 1: The frequency of detectable HIV RNA expression within resting CD4-- T cells will increase after VOR exposure in vivo: We will compare HIV RNA expression within resting CD4+ cells in HIV-infected patients on stable ART before and after VOR dosing. Specific Aim 2: Limited dosing of VOR in combination with ART to patients with HIV-1 infection will be safe and tolerable: We will characterize the safety, tolerability and spectrum of side effects of VOR in adult patients with HIV-1 infection receiving combination antiretroviral therapy. Although the goal of eradication of HIV infection is a distant one, this project may validate the ability of HDAC inhibitors to contribute to the purging of persistent infection and establish a new paradigm for early phase human testing of such approaches. RELEVANCE (See instructions): If eradication of virus from HIV-infected individuals is ever to be achieved, therapies that disrupt latent infection of resting CD4+ T-lymphocytes must be developed. Histone deacetylase (HDAC) inhibitors disrupt latent proviral infection ex vivo. We will directly assess the effect of HDAC inhibitors on HIV latency in vivo.