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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| Format: | Article |
| Language: | English |
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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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| _version_ | 1823863281210621952 |
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| author | Zamaneh Hajikhezri Ioannis Zygouras Anders Sönnerborg Robert van Domselaar |
| author_facet | Zamaneh Hajikhezri Ioannis Zygouras Anders Sönnerborg Robert van Domselaar |
| author_sort | Zamaneh Hajikhezri |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7f3f8db30cf1493e8164f5b6695268d1 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-7f3f8db30cf1493e8164f5b6695268d12025-02-09T12:12:26ZengNature Publishing GroupCell Death Discovery2058-77162025-02-011111910.1038/s41420-025-02330-1Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cellsZamaneh Hajikhezri0Ioannis Zygouras1Anders Sönnerborg2Robert van Domselaar3Division of Infectious Diseases, ANA Futura Laboratory, Department of Medicine Huddinge, Karolinska InstitutetDivision of Infectious Diseases, ANA Futura Laboratory, Department of Medicine Huddinge, Karolinska InstitutetDivision of Infectious Diseases, ANA Futura Laboratory, Department of Medicine Huddinge, Karolinska InstitutetDivision of Infectious Diseases, ANA Futura Laboratory, Department of Medicine Huddinge, Karolinska InstitutetAbstract 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.https://doi.org/10.1038/s41420-025-02330-1 |
| spellingShingle | Zamaneh Hajikhezri Ioannis Zygouras Anders Sönnerborg Robert van Domselaar Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cells Cell Death Discovery |
| title | Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cells |
| title_full | Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cells |
| title_fullStr | Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cells |
| title_full_unstemmed | Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cells |
| title_short | Pan-caspase inhibitors induce secretion of HIV-1 latency reversal agent lymphotoxin-alpha from cytokine-primed NK cells |
| title_sort | pan caspase inhibitors induce secretion of hiv 1 latency reversal agent lymphotoxin alpha from cytokine primed nk cells |
| url | https://doi.org/10.1038/s41420-025-02330-1 |
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