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CARD8 harbors a motif in its N-terminus that functions as a HIV protease substrate mimic, permitting innate immune recognition of HIV-1 protease activity, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses in the context of HIV-1 cell-to-cell transmission via a viral synapse. We observed that cell-to-cell transmission of HIV-1 between infected T cells and primary human monocyte-derived macrophages induces CARD8 inflammasome activation in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor-resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.<\/jats:p>","DOI":"10.7554\/elife.102676","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T06:25:17Z","timestamp":1730960717000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.102676","source":"Crossref","is-referenced-by-count":0,"title":["CARD8 inflammasome activation during HIV-1 cell-to-cell transmission"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3881-4686","authenticated-orcid":true,"given":"Jessie","family":"Kulsuptrakul","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00cvxb145","id-type":"ROR","asserted-by":"publisher"}],"name":"Molecular and Cellular Biology Graduate Program, University of 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