Mentored Scientist Award

Modulating Interleukin-2-Inducible T-cell Kinase (ITK) to Target HIV Persistence

Headshot of Prerna Dabral, PhD
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Inducible T-cell kinase (ITK) belongs to the Tec family of tyrosine kinases, and is expressed in mast cells and T lymphocytes. ITK functions downstream of the T-cell receptor (TCR) and regulates T-cell development, activation and differentiation. The role of ITK signaling in HIV persistence is yet unknown. In this proposal we aim to determine the impact of ITK on?HIV latency reversal and infected cell proliferation in primary CD4+?T cells and cell lines. In addition, we propose to investigate mechanisms regulating establishment of latency by regulating activation status of CD4+T cells. Our preliminary data shows robust effect of the drug CPI-818, a small molecular ITK inhibitor, on T-cell signaling in Jurkat, J-Lat 5A8 (HIV infected Jurkat) and primary CD4+?T cells where a dose dependent decrease was observed when assaying for phosphorylated ERK expression after CD3/CD28 stimulation. We also observed a similar decrease in T-cell activation markers, CD25 and CD69 with increasing concentrations of the drug. In addition, we also observed an effect on T-cell proliferation when cell were treated with high doses of CPI-818, which was assayed by labelling cells with a cell-tracker dye. Hence in this RAP proposal, we will measure the effect of ITK inhibition on latency reversal, infected cell proliferation and reservoir side (Aim 1). Also, we will use ITK inhibitor to modulate activation status of the cells and evaluate the effect on establishment of latency and determine pathways regulating latency. Aim 1 will be completed in 2 months and aim 2 will be concluded in 4 months. We will be performing appropriate statistical test based on the sample type and size, one-way ANOVA for comparison across treatments, non-parametric paired Wilcoxon tests for experiments with donor cells and Mann-Whitney tests for cell-line based data.