The Effect of Latency Reversal Agents on Primary CD8+ T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication

EBioMedicine

Victoria E. Walker-Sperling¹  Joel N. Blankson¹  Christopher W. Pohlmeyer¹  Patrick M. Tarwater² 

[1] Center for AIDS Research, Department of Medicine, Johns Hopkins University School of Medicine, USA;Division of Biostatistics and Epidemiology, Paul L. Foster School of Medicine, El Paso, TX, USA;

关键词: HIV-1;    Eradication;    Latency reversal agents;    Elite suppressors;    Elite controllers;    CD8+ T cells;   

DOI  :  10.1016/j.ebiom.2016.04.019

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown