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)是一种导致持续性病毒感染的慢病毒 这会导致免疫调节细胞的死亡。免疫清除HIV-1感染 系统效率低下，而将前病毒DNA整合到宿主细胞的基因组中提供了一种有效的 逃避和长期坚持的手段。这一前病毒整合因子可能受到 监管控制，最终导致转录关闭和潜在的 静息状态下的CD4细胞(在(1)中回顾)。病毒潜伏时间被认为是病毒的结果 静息的CD4T细胞保持静止，未被检测到(2)。重新激活潜伏期的方法论 病毒对于开发功能性治疗和清除受病毒感染的T细胞至关重要。我们 我最近开发了三种重组蛋白，可以直接激活艾滋病毒或窝藏T细胞 潜伏的前病毒。我们在这里建议开发三个目标来开发HIV特异性和一般性的T细胞 转录激活剂用于清除水库中的潜伏病毒，前提是它是 有可能激活和清除体内感染的ART诱导的潜伏感染的T细胞中的HIV。在AIM 1，我们将开发和对比重组蛋白、外切体或脂纳米颗粒传递的ZFP- 362-vpr用于潜伏的HIV的转录激活，而在目标2中，我们将开发和测试 重组CD18和截短型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CD4T细胞。AIM 3将与ZFP-362-VPR、重组CD18和 体内截短CD11b I结构域A用于靶向激活潜伏的HIV。这些目标旨在 相互补充使用，以稳定地激活和潜在地清除艾滋病毒- 1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.