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

Date Published: May 3, 2017

Publisher: Public Library of Science

Author(s): Abena K. Kwaa, Kennedy Goldsborough, Victoria E. Walker-Sperling, Luiz F. Pianowski, Lucio Gama, Joel N. Blankson, Mathias Lichterfeld.


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.

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.

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.

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.

Partial Text

Shock and kill strategies have been proposed as a possible mechanism for HIV-1 eradication [1, 2]. The strategies involve the use of latency-reversing agents (LRAs) such as Histone Deacetylase (HDAC) inhibitors and PKC-agonists to “shock” latently infected CD4+ T cells and myeloid cells into producing viral proteins that could then be recognized by effector cells leading to the “kill” component of the strategy. Several studies have shown that LRAs do in fact lead to an increase in HIV transcription and/or blips of viremia in clinical trials; however this has not been accompanied by a decrease in the size of the latent reservoir [3, 4, 5, 6]. One possible reason for this disconnect is that the number of latently infected cells that were eradicated in these studies represent a very small proportion of the total latent reservoir. Another potential explanation is that the LRAs inhibit the responses of HIV-specific effector cells thereby leading to ‘shocking’ without ‘killing’.

Ingenol derivatives have been shown to function efficiently both as monotherapy and in combination with other drugs such as JQ1 and vorinostatin vitro [15, 19, 20, 21] and in vivo [22].




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