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.