The effect of Ingenol-B on the suppressive capacity of elite suppressor HIV-specific CD8+ T cells

Abena K. Kwaa, Kennedy Goldsborough, Victoria E. Walker-Sperling, Luiz F. Pianowski, Lucio Gama, Joel N. Blankson

Research output: Research - peer-reviewArticle

Abstract

Some latency-reversing agents (LRAs) inhibit HIV-specific CD8+ T cell responses. In a prior study of protein kinase C (PKC) agonists, we found that bryostatin-1 inhibited elite controller/suppressor (ES) CD8+ T cell suppressive activity whereas prostratin had no effect. Ingenol-B is another PKC agonist with potent LRA activity both by itself and in combination with the bromodomain inhibitor JQ1; however its effect on CD8+ T cell mediated control of HIV-1 replication is unknown. Methods CD8+ T cells were isolated from ES and treated with bryostatin-1, prostratin, ingenol-B, and JQ1 as well as a combination of each PKC-agonist with JQ1. The cells were then tested in the viral suppression assay. To assess possible mechanisms of inhibition, CD8+ T cells were treated with the LRAs and analyzed for the expression of various immune cell markers. Results Ingenol-B had no effect on the ability of ES CD8+ T cells to suppress viral replication, however, the combination of ingenol-B and JQ1 caused a modest, but significant decrease in this suppressive capacity. The mechanism of the inhibitory effect of the JQ1 and ingenol-B combination relative to ingenol-B alone was unclear but the effect appeared to be dose dependent. Conclusions Ingenol-B does not inhibit HIV-specific CD8+ T cell responses in vitro. These responses are however modestly inhibited when 100 nMingenol-B is combined with JQ1. Since HIV- specific CD8+ T cell activity may be essential for the eradication of reactivated latently infected cells, the potency of latency-reversal activity of drug combinations must be balanced against the effects of the combinations on HIV-specific CD8+ T cell responses.

LanguageEnglish (US)
Article number0174516
JournalPLoS ONE
Volume12
Issue number5
DOIs
StatePublished - May 1 2017

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HIV
T-Lymphocytes
ingenol
T-lymphocytes
HIV long-term survivors
T-cells
Protein Kinase C
protein kinase C
agonists
cells
Controllers
prostratin
bryostatin 1
bryostatins
Drug Combinations
HIV-1
Biomarkers
In Vitro Techniques
combination drug therapy
virus replication

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

The effect of Ingenol-B on the suppressive capacity of elite suppressor HIV-specific CD8+ T cells. / Kwaa, Abena K.; Goldsborough, Kennedy; Walker-Sperling, Victoria E.; Pianowski, Luiz F.; Gama, Lucio; Blankson, Joel N.

In: PLoS ONE, Vol. 12, No. 5, 0174516, 01.05.2017.

Research output: Research - peer-reviewArticle

Kwaa AK, Goldsborough K, Walker-Sperling VE, Pianowski LF, Gama L, Blankson JN. The effect of Ingenol-B on the suppressive capacity of elite suppressor HIV-specific CD8+ T cells. PLoS ONE. 2017 May 1;12(5). 0174516. Available from, DOI: 10.1371/journal.pone.0174516
Kwaa, Abena K. ; Goldsborough, Kennedy ; Walker-Sperling, Victoria E. ; Pianowski, Luiz F. ; Gama, Lucio ; Blankson, Joel N./ The effect of Ingenol-B on the suppressive capacity of elite suppressor HIV-specific CD8+ T cells. In: PLoS ONE. 2017 ; Vol. 12, No. 5.
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abstract = "Some latency-reversing agents (LRAs) inhibit HIV-specific CD8+ T cell responses. In a prior study of protein kinase C (PKC) agonists, we found that bryostatin-1 inhibited elite controller/suppressor (ES) CD8+ T cell suppressive activity whereas prostratin had no effect. Ingenol-B is another PKC agonist with potent LRA activity both by itself and in combination with the bromodomain inhibitor JQ1; however its effect on CD8+ T cell mediated control of HIV-1 replication is unknown. Methods CD8+ T cells were isolated from ES and treated with bryostatin-1, prostratin, ingenol-B, and JQ1 as well as a combination of each PKC-agonist with JQ1. The cells were then tested in the viral suppression assay. To assess possible mechanisms of inhibition, CD8+ T cells were treated with the LRAs and analyzed for the expression of various immune cell markers. Results Ingenol-B had no effect on the ability of ES CD8+ T cells to suppress viral replication, however, the combination of ingenol-B and JQ1 caused a modest, but significant decrease in this suppressive capacity. The mechanism of the inhibitory effect of the JQ1 and ingenol-B combination relative to ingenol-B alone was unclear but the effect appeared to be dose dependent. Conclusions Ingenol-B does not inhibit HIV-specific CD8+ T cell responses in vitro. These responses are however modestly inhibited when 100 nMingenol-B is combined with JQ1. Since HIV- specific CD8+ T cell activity may be essential for the eradication of reactivated latently infected cells, the potency of latency-reversal activity of drug combinations must be balanced against the effects of the combinations on HIV-specific CD8+ T cell responses.",
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AB - Some latency-reversing agents (LRAs) inhibit HIV-specific CD8+ T cell responses. In a prior study of protein kinase C (PKC) agonists, we found that bryostatin-1 inhibited elite controller/suppressor (ES) CD8+ T cell suppressive activity whereas prostratin had no effect. Ingenol-B is another PKC agonist with potent LRA activity both by itself and in combination with the bromodomain inhibitor JQ1; however its effect on CD8+ T cell mediated control of HIV-1 replication is unknown. Methods CD8+ T cells were isolated from ES and treated with bryostatin-1, prostratin, ingenol-B, and JQ1 as well as a combination of each PKC-agonist with JQ1. The cells were then tested in the viral suppression assay. To assess possible mechanisms of inhibition, CD8+ T cells were treated with the LRAs and analyzed for the expression of various immune cell markers. Results Ingenol-B had no effect on the ability of ES CD8+ T cells to suppress viral replication, however, the combination of ingenol-B and JQ1 caused a modest, but significant decrease in this suppressive capacity. The mechanism of the inhibitory effect of the JQ1 and ingenol-B combination relative to ingenol-B alone was unclear but the effect appeared to be dose dependent. Conclusions Ingenol-B does not inhibit HIV-specific CD8+ T cell responses in vitro. These responses are however modestly inhibited when 100 nMingenol-B is combined with JQ1. Since HIV- specific CD8+ T cell activity may be essential for the eradication of reactivated latently infected cells, the potency of latency-reversal activity of drug combinations must be balanced against the effects of the combinations on HIV-specific CD8+ T cell responses.

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