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We evaluated the effects of the caspase-1 inhibitor VX-765 on HIV-1 infection in humanized NSG mice engrafted with human CD34\n                    <jats:sup>+<\/jats:sup>\n                    hematopoietic stem cells. Expression of caspase-1, NLRP3, and IL-1\u03b2 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&lt;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\n                    <jats:sup>+<\/jats:sup>\n                    T cells loss in blood (p&lt;0.005 and p&lt;0.0001, for the spleen respectively). Treatment with VX-765 significantly reduced TNF-\u03b1 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\n                    <jats:sup>+<\/jats:sup>\n                    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 \/10\n                    <jats:sup>6<\/jats:sup>\n                    cells, p=0.029). We demonstrated that targeting inflammasome activation early after infection may represent a therapeutic strategy towards HIV cure to prevent CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell depletion and reduce immune activation, viral load, and the HIV-1 reservoir formation.\n                  <\/jats:p>","DOI":"10.7554\/elife.83207","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T07:15:33Z","timestamp":1675062933000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.83207","source":"Crossref","is-referenced-by-count":32,"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"],"prefix":"10.7554","volume":"12","author":[{"given":"Mathieu","family":"Amand","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012m8gv78","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infection and 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