Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cells
Abstract The persistence of HIV-1 latency reservoirs in CD4+ T cells is a significant obstacle for curing HIV-1. Shock-and-kill strategies, which aim to reactivate latent HIV-1 followed by cytotoxic clearance, have shown limited success in vivo due to insufficient efficacy of latency reversal agents...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02330-1 |
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| Summary: | Abstract The persistence of HIV-1 latency reservoirs in CD4+ T cells is a significant obstacle for curing HIV-1. Shock-and-kill strategies, which aim to reactivate latent HIV-1 followed by cytotoxic clearance, have shown limited success in vivo due to insufficient efficacy of latency reversal agents (LRAs) and off-target effects. Natural killer (NK) cells, with their ability to mediate cytotoxicity independent of antigen specificity, offer a promising avenue for enhancing the shock-and-kill approach. Previously, we observed that pan-caspase inhibitors induce NK cells to secrete an LRA in vitro. Here, we aimed to identify this LRA using a targeted proteomic approach. We identified lymphotoxin-α (LTα) as the key LRA secreted by NK cells following pan-caspase inhibitor treatment. LTα was shown to significantly induce HIV-1 LTR promoter activity, a hallmark of viral reactivation. Neutralization of LTα effectively abolished the observed LRA activity, confirming its central role. Moreover, cytokine-primed but not resting human primary NK cells exhibited LRA activity that could be neutralized with LTα neutralizing antibodies. Finally, pan-caspase inhibitor treatment did not decrease the ability of the cytokine-primed NK cells to kill target cells. These findings demonstrate that cytokine-primed NK cells, through LTα secretion, can effectively reactivate latent HIV-1 following pan-caspase inhibitor treatment, without compromising NK cell cytotoxicity. This highlights a potential enhancement strategy utilizing NK cells for shock-and-kill approaches in HIV-1 cure research. |
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| ISSN: | 2058-7716 |