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

Victoria E. Walker-Sperling, Christopher W. Pohlmeyer, Patrick M. Tarwater, Joel N. Blankson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)217-229
Number of pages13
JournalEBioMedicine
Volume8
DOIs
StatePublished - Jun 1 2016

Keywords

  • CD8+ T cells
  • Elite controllers
  • Elite suppressors
  • Eradication
  • HIV-1
  • Latency reversal agents

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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