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

描述（由申请人提供）：终身抗逆转录病毒治疗（ART）提出了令人生畏的问题。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暂时遏制疗法。在一小群长寿命的CD4+ T细胞中，静止HIV感染的持续存在是目前根除HIV感染的主要障碍。人类转录因子将组蛋白去乙酰化酶（hdac）募集到HIV长末端重复启动子上，介导凝聚异染色质的形成，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抗逆转录病毒治疗患者静息细胞感染的持续减少，但这种影响远低于HDAC抑制剂的主要分子机制。我们已经证明了一种被许可用于肿瘤学的强效抑制剂——亚eroylanilide羟肟酸（Vorinostat， VOR），选择性用于I类hdac，能够诱导细胞系中的HIV启动子表达，并从抗逆转录病毒治疗的病毒血症HIV感染患者的静息CD4+ T细胞中产生病毒。我们提出了一项验证性研究，以测量强效HDAC抑制剂在体内诱导持久性前HIV表达的潜力。特异性目的1：在体内暴露于VOR后，静息CD4- T细胞内可检测到的HIV RNA表达频率将增加：我们将比较接受稳定抗逆转录病毒治疗的HIV感染患者在VOR剂量前后静息CD4+细胞内的HIV RNA表达。特定目标2：有限剂量的VOR联合ART治疗HIV-1感染患者将是安全且可耐受的：我们将描述VOR在接受联合抗逆转录病毒治疗的成年HIV-1感染患者中的安全性、耐受性和副作用范围。尽管根除HIV感染的目标还很遥远，但该项目可能会验证HDAC抑制剂有助于清除持续性感染的能力，并为此类方法的早期人体测试建立新的范例。

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.