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

HIV 特异性体外扩增 T 细胞疗法 (HXTC) 可消除持续性 HIV 感染的潜在储库

• 批准号: 9889986
• 负责人: Catherine M. Bollard
• 金额: $ 73.53万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889986
• 关键词: Address; Adenoviruses; Allogenic; Antigens; Antiviral Agents; Archives; Autologous; Bypass; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Therapy; Cells; Combined Modality Therapy; Cytomegalovirus; Cytotoxic T-Lymphocytes; Data; Dose; Epitopes; Frequencies; Future; Goals; HIV; HIV Antigens; HIV Infections; HIV-1; Half-Life; Histone Deacetylase; Histone Deacetylase Inhibitor; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunologics; Immunotherapy; In Vitro; Individual; Infection; Infusion procedures; Innovative Therapy; Interphase Cell; Interruption; Malignant Neoplasms; Mutation; Participant; Patients; Pharmaceutical Preparations; Population; Residual state; Rest; Risk; Safety; T cell response; T cell therapy; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Transplantation; Vaccines; Variant; Viral; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Latency; Vorinostat; Work; antigen-specific T cells; antiretroviral therapy; appropriate dose; chronic infection; clinically relevant; cytotoxic; experience; immune function; in vivo; latent infection; novel; post-transplant; public health relevance; response; therapeutic vaccine; tool; virology

 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.

 描述（由适用提供）：无法从潜在感染的储量中消除HIV-1仍然是HIV辐射的关键限制。放射性艾滋病毒感染的一种方法是1）通过干扰维持潜伏期的机制来暴露潜在的，持续的艾滋病毒，2）通过增强T细胞免疫反应而无需中断ART，消除了暴露的潜在受感染的细胞。研究表明，组蛋白脱乙酰基酶（HDAC）是HIV潜伏期的关键调节剂，我们自己的工作表明HDAC抑制剂Vorinostat（VOR）可以诱导潜在的HIV-1表达。正如承诺在使用诸如VOR这样的代理商中逆转体内潜伏的有效剂量策略的有效剂量策略上所承诺的工作，越来越重要的是解决如何有效利用免疫响应抵抗潜在的HIV感染。增强现有的HIV免疫增强剂的一种策略是使用自体内的，体内扩展的细胞毒性T淋巴细胞（CTLS）的产物T细胞疗法。这种方法成功治疗了与病毒相关的癌症和移植后病毒重生。尽管事实证明，T细胞疗法在HIV患者中是安全的，但过去效率受到限制。在这里，我们提出，HLA类型不受限制的具有更广泛识别的HIV特异性T细胞产物将提高T细胞靶向潜在感染细胞的能力。 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与延迟反向剂结合使用时，感染。我们将研究CD8 T细胞表位靶向，免疫降低层次结构和病毒逃生突变是否会改变体外病毒抑制和HXTC输注之前和之后静止的CD4细胞感染的体内水平。该提案建立在U01 AI095052产生的数据上，该数据探讨了VOR和定义最佳剂量策略的抗延迟活动，其最终目标是将VOR与自适应T细胞疗法相结合，以诱导静止CD4+ T细胞的持续感染频率的显着降低。