Targeted transcriptional activation of HIV

项目摘要 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 导致免疫调节细胞死亡。免疫系统清除HIV-1感染 系统是低效的，并且将前病毒DNA整合到宿主细胞的基因组中提供了有效的免疫调节。 逃避和长期坚持的手段。这种前病毒的组成部分可能受到 调节控制，最终导致转录关闭和潜在的 在静息CD 4+细胞中的状态（在（1）中综述）。病毒潜伏期被认为是病毒 在静止的CD 4 + T细胞中保持静止和未检测到（2）。一种重新激活潜在的 病毒对于开发功能性治疗和清除病毒感染的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或携带HIV的T细胞。 潜伏前病毒我们在这里提出了三个目标，以开发一种HIV特异性和通用的T细胞 转录激活剂用于清除潜伏病毒的储库，前提是它是 可能在体内激活并清除感染ART诱导的潜伏感染T细胞中的HIV。在Aim中 1，我们将开发和对比重组蛋白，外泌体，或脂质纳米粒交付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 用于ART中HIV靶向活化的重组CD 18和截短的CD 11b I-结构域A蛋白 诱导潜伏感染的CD 4 + T细胞。AIM 3将对比ZFP-362-VPR、重组CD 18和 截短的CD 11b I-结构域A在体内用于潜伏HIV的靶向活化。这些目标旨在 相互结合使用以稳定地激活和潜在地清除HIV-1， 1个来自潜伏感染细胞的前病毒。

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.