TY - JOUR
T1 - The effect of Ingenol-B on the suppressive capacity of elite suppressor HIV-specific CD8+ T cells
AU - Kwaa, Abena K.
AU - Goldsborough, Kennedy
AU - Walker-Sperling, Victoria E.
AU - Pianowski, Luiz F.
AU - Gama, Lucio
AU - Blankson, Joel N.
N1 - Publisher Copyright:
© 2017 Kwaa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/5
Y1 - 2017/5
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85018725997&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018725997&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0174516
DO - 10.1371/journal.pone.0174516
M3 - Article
C2 - 28467486
AN - SCOPUS:85018725997
SN - 1932-6203
VL - 12
JO - PLoS One
JF - PLoS One
IS - 5
M1 - 0174516
ER -