Defining the Effects of PKC Modulator HIV Latency-Reversing Agents on Natural Killer Cells

Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way. Here, we compare the transcriptional profiles of PKC-treated NK and CD4+ T cells to assess their generalized cellular effects. Transcriptomic profiles from both cell types displayed signatures of cellular activation and enrichment of genes associated with the NF?B pathway. However, the transcriptomic effects of PKC stimulation on NK cells are much milder than that in CD4+ T cells. This finding, combined with our experimental data testing killing capacity of PKC-stimulated NK cells against K562 cells and infected CD4+ T cells suggests that their contribution in “kick and kill” strategies is primarily due to upregulating HIV expression in CD4+ T cells, rather than directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the “kick” rather than the “kill” arm of this HIV cure approach. Overall design: Gene expression profiling analyis of RNA-seq data from primary human NK and resting CD4+ T cells treated with PKC modulators (10nM bryostatin-1, 1µM prostratin, or 10nM of the designed, synthetic bryostatin-1 analog SUW133). Samples were collected after 24 hours of stimulation (n=4-5 donors for each cell type in singlicate).