The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice
HIV-1 infection results in the activation of inflammasome that may facilitate viral spread and establishment of viral reservoirs. We evaluated the effects of the caspase-1 inhibitor VX-765 on HIV-1 infection in humanized NSG mice engrafted with human CD34+ hematopoietic stem cells. Expression of cas...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/83207 |
| _version_ | 1828012793204310016 |
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| author | Mathieu Amand Philipp Adams Rafaela Schober Gilles Iserentant Jean-Yves Servais Michel Moutschen Carole Seguin-Devaux |
| author_facet | Mathieu Amand Philipp Adams Rafaela Schober Gilles Iserentant Jean-Yves Servais Michel Moutschen Carole Seguin-Devaux |
| author_sort | Mathieu Amand |
| collection | DOAJ |
| description | HIV-1 infection results in the activation of inflammasome that may facilitate viral spread and establishment of viral reservoirs. We evaluated the effects of the caspase-1 inhibitor VX-765 on HIV-1 infection in humanized NSG mice engrafted with human CD34+ hematopoietic stem cells. Expression of caspase-1, NLRP3, and IL-1β was increased in lymph nodes and bone marrow between day 1 and 3 after HIV-1 infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p<0.001, respectively). IFI16 and AIM2 expression peaked at day 24 and coincides with increased IL-18 levels (6.89 vs 83.19 pg/ml, p=0.004), increased viral load and CD4+ T cells loss in blood (p<0.005 and p<0.0001, for the spleen respectively). Treatment with VX-765 significantly reduced TNF-α at day 11 (0.47 vs 2.2 pg/ml, p=0.045), IL-18 at day 22 (7.8 vs 23.2 pg/ml, p=0.04), CD4+ T cells (44.3% vs 36,7%, p=0.01), viral load (4.26 vs 4.89 log 10 copies/ml, p=0.027), and total HIV-1 DNA in the spleen (1 054 vs 2 889 copies /106 cells, p=0.029). We demonstrated that targeting inflammasome activation early after infection may represent a therapeutic strategy towards HIV cure to prevent CD4+ T cell depletion and reduce immune activation, viral load, and the HIV-1 reservoir formation. |
| first_indexed | 2024-04-10T09:38:14Z |
| format | Article |
| id | doaj.art-0b59b14420b948f0b3af8786ec5169fc |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-10T09:38:14Z |
| publishDate | 2023-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0b59b14420b948f0b3af8786ec5169fc2023-02-17T16:18:55ZengeLife Sciences Publications LtdeLife2050-084X2023-02-011210.7554/eLife.83207The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized miceMathieu Amand0Philipp Adams1Rafaela Schober2Gilles Iserentant3Jean-Yves Servais4Michel Moutschen5Carole Seguin-Devaux6https://orcid.org/0000-0003-0636-5222Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, LuxembourgDepartment of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, LuxembourgDepartment of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, LuxembourgDepartment of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, LuxembourgDepartment of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, LuxembourgDepartment of Infectious Diseases, University of Liège, CHU de Liège, Liège, BelgiumDepartment of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, LuxembourgHIV-1 infection results in the activation of inflammasome that may facilitate viral spread and establishment of viral reservoirs. We evaluated the effects of the caspase-1 inhibitor VX-765 on HIV-1 infection in humanized NSG mice engrafted with human CD34+ hematopoietic stem cells. Expression of caspase-1, NLRP3, and IL-1β was increased in lymph nodes and bone marrow between day 1 and 3 after HIV-1 infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p<0.001, respectively). IFI16 and AIM2 expression peaked at day 24 and coincides with increased IL-18 levels (6.89 vs 83.19 pg/ml, p=0.004), increased viral load and CD4+ T cells loss in blood (p<0.005 and p<0.0001, for the spleen respectively). Treatment with VX-765 significantly reduced TNF-α at day 11 (0.47 vs 2.2 pg/ml, p=0.045), IL-18 at day 22 (7.8 vs 23.2 pg/ml, p=0.04), CD4+ T cells (44.3% vs 36,7%, p=0.01), viral load (4.26 vs 4.89 log 10 copies/ml, p=0.027), and total HIV-1 DNA in the spleen (1 054 vs 2 889 copies /106 cells, p=0.029). We demonstrated that targeting inflammasome activation early after infection may represent a therapeutic strategy towards HIV cure to prevent CD4+ T cell depletion and reduce immune activation, viral load, and the HIV-1 reservoir formation.https://elifesciences.org/articles/83207anti-inflammatory agentsHIVhiv reservoirspyroptosiscytokineinflammasome inhibitors |
| spellingShingle | Mathieu Amand Philipp Adams Rafaela Schober Gilles Iserentant Jean-Yves Servais Michel Moutschen Carole Seguin-Devaux The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice eLife anti-inflammatory agents HIV hiv reservoirs pyroptosis cytokine inflammasome inhibitors |
| title | The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice |
| title_full | The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice |
| title_fullStr | The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice |
| title_full_unstemmed | The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice |
| title_short | The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice |
| title_sort | anti caspase 1 inhibitor vx 765 reduces immune activation cd4 t cell depletion viral load and total hiv 1 dna in hiv 1 infected humanized mice |
| topic | anti-inflammatory agents HIV hiv reservoirs pyroptosis cytokine inflammasome inhibitors |
| url | https://elifesciences.org/articles/83207 |
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