Abstract
Latency-reversing agents (LRAs) are considered a potential strategy for curing cells of HIV-1 infection. Certain protein kinase C (PKC) activators have been previously reported to be LRAs because they can reverse HIV latency. In the present study, we examined the activities of a panel of benzolactam derivatives against cells latently infected with HIV. Using determination of p24 antigen in cell supernatants or altered intracellular GFP expression to measure HIV reactivation from latently infected cells along with a cytotoxicity assay, we found that some of the compounds exhibited latency-reversing activity, which was followed by enhanced release of HIV particles from the cells. One derivative, BL-V8-310, displayed activity in ACH-2 and J-Lat cells latently infected with HIV at a concentration of 10 nm or higher, which was superior to the activity of another highly active PKC activator, prostratin. These results were confirmed with peripheral blood cells from HIV-infected patients. We also found that these drugs up-regulate the expression of caspase 3 and enhance apoptosis specifically in latently HIV-infected cells. Moreover, combining BL-V8-310 with a bromodomain-containing 4 (BRD4) inhibitor, JQ1, not only enhanced HIV latency-reversing activity, but also reduced the effect on cytotoxic cytokine secretion from CD4+ T-cells induced by BL-V8-310 alone. Our results suggest that BL-V8-310 and its related benzolactam derivatives are potential LRA lead compounds that are effective in reversing HIV latency and reducing viral reservoirs in HIV-positive individuals with few adverse effects.
Highlights
Latency-reversing agents (LRAs) are considered a potential strategy for curing cells of human immunodeficiency virus (HIV)-1 infection
Our results suggest that BL-V8-310 and its related benzolactam derivatives are potential LRA lead compounds that are effective in reversing HIV latency and reducing viral reservoirs in HIV-positive individuals with few adverse effects
Recent studies have reported the development of a number of small molecule compounds that can reverse latent HIV infection [5, 14, 17, 21, 38], and protein kinase C (PKC) activators are potential candidate LRAs
Summary
We examined a panel of benzolactam derivatives (Fig. 1). Some of them reportedly have activity as PKC activators as candidates for novel LRAs. Five benzolactam compounds (Indolactam-V, BL-V8310, epi-BL-V8-310, BL-V8 –23TM, and epi-BL-V9 –310) induced virus production in ACH-2 cells and U1 cells (Fig. 2A), whereas epi-BL-V8 –23TM and BL-V9 –310, optical isomers to BL-V8 –23TM and epi-BL-V9 –310, respectively (Fig. 1), failed to show activity. Reversal of latency in J-Lat 10.6 and J-Lat 6.3 cells was examined by the increase of GFP-positive cells (Fig. 2B). Among these derivatives, BL-V8-310 (Fig. 1) was the most potent. Prostratin [16] and indolactam-V are PKC activators, which induced the HIV-latency reversal, and BL-V8-310 was found to be or more potent than these LRAs when examined with J-Lat (10.6 and 6.3), ACH-2, and U1 cells (Fig. 2). Recent studies have shown that it is important to combine LRAs to obtain higher levels of HIV–RNA transcription
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