The persistent, latent viral reservoir remains a significant barrier to the eradication of HIV-1. Recently, there have been a number of breakthroughs that now give a roadmap on how to severely reduce or eliminate this HIV-1 reservoir. Of most relevance to this application, the Siliciano Lab recently reported that CTL activity is required to reduce the latent reservoir once HIV-1 gene expression induced by HDAC inhibition. In the R21 portion of this grant, we will evaluate the ability of several agents to induce HIV-1 gene expression in the absence of toxicity or T cell activation. We hypothesize that HDAC6 inhibitors will be especially potent as HDAC potently opposes HIVTAT activity. Next, as a high risk, high reward series of experiments we will engineer T cells to recognize HIV-1ENV or HIV-1GAG with high affinity and specificity and ask if either of these engineered T cells can reduce the latent reservoir using several validated in vitro latency assays. If our results from the R21 portion of the grant are successful, we will then move into the R33 phase in which we test the ability of engineered T cells to reduce the HIV-1 reservoir in well controlle HAART patients~ test the ability of enhanced affinity TCRs to control the HIV-1 reservoir in patients as a standalone treatment and evaluate the ability of engineered T cells to target the latent reservoir in vivo using a recently described humanized mouse model of latency.
An especially promising area of immunotherapy is adoptive T cell transfer, where T cells are removed from HIV-1 infected patients, genetically altered o better recognize and kill HIV-1 infected T cells and reinfused back into the patient. We hypothesize that engineered T cells that recognized HIV-1 antigens with high sensitivity and specificity will be ideal agents to reduce the persistent viral reservoir which serves as a significant barrier to cure HIV-1 infection. Completion of these aims will advance the entir field of studying HIV-1 persistence and latency by understanding how to best induce HIV-1 gene expression and then to how best target latently infected T cells with engineered T cells. These data will also provide key preclinical data so we can rapidly move these approaches into clinical trials at Penn and at other places.
|Richardson, Max W; Guo, Lili; Xin, Frances et al. (2014) Stabilized human TRIM5? protects human T cells from HIV-1 infection. Mol Ther 22:1084-95|