HIV-specific ex-vivo expanded T cell therapy (HXTC) to Deplete the Latent Reservoir of Persistent HIV Infection

 描述（由申请人提供）：无法从潜伏感染的宿主中消除HIV-1仍然是HIV根除的关键限制。根除HIV感染的一种方法是1）通过干扰维持潜伏期的机制来暴露潜伏的、持续的HIV，以及2）通过增强T细胞免疫应答而不中断ART来消除暴露的潜伏感染细胞。研究已经证明组蛋白脱乙酰酶（HDAC）是HIV潜伏期的关键调节剂，并且我们自己的工作已经表明HDAC抑制剂伏立诺他（VOR），可以诱导潜伏HIV-1的表达。随着使用诸如VOR的药剂描绘用于体内潜伏期逆转的有效给药策略的有希望的工作正在推进，解决如何有效地利用针对潜伏性HIV感染的免疫应答变得越来越重要。增强现有HIV免疫应答的一种策略是使用自体的、离体扩增的细胞毒性T淋巴细胞（CTL）的过继性T细胞疗法。这种方法成功地治疗了病毒相关的癌症和移植后的病毒再激活。虽然T细胞疗法已被证明在HIV患者中是安全的，但过去的疗效有限。在这里，我们提出，具有更广泛识别的HIV特异性T细胞产物，不受HLA类型的限制，将增加T细胞靶向潜伏感染细胞的能力。我们已经开发了一种新的符合GMP的策略，以扩增来自接受ART的患者的功能性、广泛特异性T细胞（HXTC），并假设在接受抑制性ART的HIV感染参与者中体内施用识别多种HIV-1抗原的自体离体扩增的HXTC将a）安全，B）体内增加，HIV-1抗原特异性T细胞免疫应答和c）当与潜伏逆转剂VOR组合时减少静息细胞感染。我们将研究是否CD 8 T细胞表位靶向，免疫优势层次，和病毒逃逸突变改变体外病毒抑制和体内水平的静息CD 4细胞感染之前和之后HXTC输注。该提案建立在U 01 AI 095052生成的数据基础上，U 01 AI 095052已经探索了VOR的抗潜伏活性并定义了最佳给药策略，最终目标是将VOR与过继性T细胞治疗相结合，以诱导静息CD 4 + T细胞持续感染频率的显著降低。

 DESCRIPTION (provided by applicant): The inability to eliminate HIV-1 from latently infected reservoirs remains the critical limitation to HIV eradication. One approach to eradicate HIV infection is to 1) expose latent, persistent HIV by interfering with mechanisms that maintain latency, and 2) eliminate exposed latently infected cells by enhanced T- cell immune response without interrupting ART. Studies have demonstrated that Histone Deacetylase (HDAC) is a critical regulator of HIV latency, and our own work has shown that the HDAC inhibitor, vorinostat (VOR), can induce the expression of latent HIV-1. As promising work on delineating effective dosing strategies for latency reversal in vivo using agents such as VOR is advancing, it is increasingly important to address how to effectively harness the immune response against latent HIV infection. One strategy to enhance the existing HIV immune response is adoptive T cell therapy using autologous, ex vivo expanded cytotoxic T lymphocytes (CTLs). This approach successfully treats virus-associated cancers and viral reactivation after transplant. While T cell therapy has proven to be safe in HIV patients, efficacy has been limited in the past. Here, we propose that an HIV-specific T cell product with broader recognition, unrestricted by HLA type, would increase the ability of the T-cells to target latently infected cells. We have developed a novel GMP compliant strategy to expand functional, broadly-specific T-cells (HXTCs) from patients on ART and hypothesize that in vivo administration of autologous ex vivo expanded HXTCs that recognize multiple HIV-1 antigens in HIV-infected participants on suppressive ART will a) be safe, b) increase in vivo, HIV-1 antigen specific T-cell immune responses and c) decrease resting cell infection when combined with the latency reversing agent, VOR. We will investigate whether CD8 T cell epitope targeting, immunodominance hierarchies, and viral escape mutations alter in vitro virus inhibition and in vivo levels of resting CD4 cell infection before and after HXTC infusion. This proposal builds upon the data generated by U01 AI095052, which has explored the anti-latency activity of VOR and defined optimal dosing strategies, with an ultimate goal to combine VOR with adoptive T cell therapy to induce a significant decrease in the frequency of persistent infection of resting CD4+ T cells.