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.
The inability to eliminate HIV-1 from latently infected reservoirs remains the critical limitation to HIV eradication. This proposal will generate critical data that will inform future cellular and immune therapies to effect eradication of the latent reservoir.
|Turner, Anne-Marie W; Margolis, David M (2017) Chromatin Regulation and the Histone Code in HIV Latency?. Yale J Biol Med 90:229-243|
|Sung, Julia A; Sholtis, Katherine; Kirchherr, Jennifer et al. (2017) Vorinostat Renders the Replication-Competent Latent Reservoir of Human Immunodeficiency Virus (HIV) Vulnerable to Clearance by CD8 T Cells. EBioMedicine 23:52-58|