Targeted transcriptional activation of HIV

项目概要 HIV 的靶向转录激活 人类免疫缺陷病毒 1 型 (HIV-1) 是一种慢病毒，可引起持续性病毒感染 从而导致免疫调节细胞的死亡。免疫系统清除 HIV-1 感染 系统效率低下，将原病毒 DNA 整合到宿主细胞基因组中提供了有效的方法 逃避和长期坚持的手段。该前病毒整合体可能会受到 监管控制最终导致转录关闭和潜在的转录的协调 静息 CD4 细胞的状态（在 (1) 中进行了回顾）。病毒潜伏期被认为是病毒的结果 在静息 CD4 T 细胞中保持静止且未被检测到 (2)。重新激活潜伏的方法 病毒对于开发功能性治疗方法和清除病毒感染 T 细胞库至关重要。我们 最近开发了三种重组蛋白，可以直接激活 HIV 或 T 细胞 潜伏原病毒。我们在此建议制定三个目标来开发 HIV 特异性和通用 T 细胞 转录激活剂用于清除潜伏病毒的储存库，前提是它是 可以激活并清除体内受感染的 ART 诱导的潜伏感染 T 细胞中的 HIV。瞄准 1，我们将开发并对比重组蛋白、外泌体或脂质纳米颗粒递送的 ZFP- 362-VPR 用于潜伏 HIV 的转录激活，而在目标 2 中，我们将开发和测试 重组 CD18 和截短的 CD11b I 结构域 A 蛋白用于 ART 中 HIV 的靶向激活 诱导潜伏感染的CD4 T细胞。 AIM 3 将对比 ZFP-362-VPR、重组 CD18 和 体内截短的 CD11b I-结构域 A 用于靶向激活潜在的 HIV。这些目标旨在 相互配合使用可稳定激活并可能清除 HIV- 1 来自潜伏感染细胞的原病毒。

Project Summary Targeted transcriptional activation of HIV Human Immunodeficiency Virus type 1 (HIV-1) is a lentivirus that causes a persistent viral infection that results in the demise of immune regulatory cells. Clearance of HIV-1 infection by the immune system is inefficient, and integration of proviral DNA into the genome of host cells provides an efficient means for evasion and long-term persistence. This proviral integrant is potentially subjected to the regulatory control which ultimately leads to the orchestration of transcriptional shutdown and a latent state in resting CD4+ cells (reviewed in (1)). Viral latency is thought to be the result of the virus remaining quiescent and undetected in resting CD4+ T-cells (2). A methodology to reactivate latent virus is paramount to developing afunctional cure and purging reservoirs of viral infected T-cells. We have recently developed three recombinant proteins that can activate HIV directly or T-cells harboring latent provirus. We propose here to develop three aims to develop an HIV specific and general T-cell transcriptional activator to be used to purge reservoirs of latent virus, with the premise that it is possible to activate, and purge HIV from infected ART induced latent infected T-cells in vivo. In Aim 1, we will develop and contrast recombinant protein, exosome, or lipid nanoparticle delivered ZFP- 362-VPR for transcriptional activation of latent HIV while in Aim 2 we will we will Develop and test recombinant CD18 and truncated CD11b I-domain A proteins for targeted activation of HIV in ART induced latently infected CD4+ T-cells. AIM 3 will contrast ZFP-362-VPR, recombinant CD18, and truncated CD11b I-domain A in vivo for targeted activation of latent HIV. These Aims are designed to be complimentary used in conjunction with one another to stably activate and potentially purge HIV- 1 provirus from latently infected cells.