Programming Dendritic Cells to Expose the Persistent HIV-1 Latent Reservoir for Immune Targeting

项目总结/文摘

PROJECT SUMMARY/ABSTRACT While current therapies to treat chronic HIV infection are effective at controlling the virus, the disease is still not curable, and there is a life-long Despite the success of highly active anti-retroviral therapy (HAART), over 36 million people currently live with HIV infection, which is now managed as a chronic rather than acute disease, but requires a lifelong commitment to HAART. The latent reservoir of replication-competent HIV in HAART- suppressed individuals is considered a critical barrier to a cure, due to the long half-life and persistence of the infected CD4+ T cell reservoir. Moreover, in its latent state, the lack of viral transcription and protein expression in the infected targets allows the reservoir to escape immune surveillance. The ‘kick and kill’ approach to curing or controlling HIV involves inducing HIV latency reversal during HAART to expose the infected cells, while creating an arsenal of immune effector cells, such as cytotoxic T cell lymphocytes (CTL), capable of eliminating these targets. Finding an effective pharmacologic means to expose and purge the viral reservoir in a non-toxic manner has been elusive and remains major barrier to this cure approach. While dendritic cells (DC) have been used safely in clinical trials to drive CTL responses in the settings of cancer and HIV, a recent report by our group linked the administration of a DC-based HIV vaccine with increased residual viremia in HAART- suppressed individuals following analytic treatment interruption, suggesting that the DC-based therapeutic acted as an LRA. However, that clinical study was not designed to specifically address the use of the DC therapeutic as an LRA, and a number of important questions remain including the roles that DC polarization and antigen presentation played in this effect, the particular CD4 T cell reservoir that was affected, and the underlying mechanisms involved. In this proposal, we will investigate the use of two clinically applicable differentially polarized DC types as an in vitro approach to induce HIV re-activation in latently infected CD4+ T cells utilizing cells obtained from virally suppressed HIV-1 positive MACS participants. We will determine the optimal DC activation strategy to promote their LR function, assess CD4+ T cell subsets affected by the DC-based LRA approach, explore the role of antigen presentation the system, and perform novel assays to qualitatively assess DC exposure of the HIV-1 reservoir for CTL targeting. Information from these studies will ultimately be used in development of a personalized DC-based cellular therapy designed to facilitate both the ‘kick’ and ‘kill’ of the HIV- 1 reservoir as a strategy towards curing or controlling chronic HIV-1 infection.