[HTML][HTML] The effect of latency reversal agents on primary CD8+ T cells: implications for shock and kill strategies for human immunodeficiency virus eradication

VE Walker-Sperling, CW Pohlmeyer, PM Tarwater… - …, 2016 - thelancet.com
VE Walker-Sperling, CW Pohlmeyer, PM Tarwater, JN Blankson
EBioMedicine, 2016thelancet.com
Shock and kill strategies involving the use of small molecules to induce viral transcription in
resting CD4+ T cells (shock) followed by immune mediated clearance of the reactivated cells
(kill), have been proposed as a method of eliminating latently infected CD4+ T cells. The
combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C
(PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found
that primary HIV-1 specific CD8+ T cells were not able to eliminate autologous resting CD4+ …
Abstract
Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4+ T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4+ T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8+ T cells were not able to eliminate autologous resting CD4+ T cells that had been reactivated with these drugs. We tested the hypothesis that the drugs affected primary CD8+ T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8+ T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8+ T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies.
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