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Strategies aimed at HIV-1 latency reversal and subsequent elimination of infected cells are being explored. Targeting the inhibitor of apoptosis proteins (IAP) and DEAD-box polypeptide 3 (DDX3) RNA helicase reduces the HIV-1 reservoir ex vivo. However, the mechanisms driving apoptosis of HIV-1 infected cells remain unclear. Here, we uncovered the mechanism regarding HIV-1 transcriptional activation and induction of apoptosis specific for HIV-1 infected cells using an acute in vitro infection model. Inhibition of IAP by second mitochondrial-derived activator of caspases mimetic (SMACm; AZD5582) resulted in activation of non-canonical NF-\u03baB pathway (RelB\/p52) that induced HIV-1 transcription, confirming previous reports, whereas inhibition of DDX3 sensitized HIV-1 infected cells for apoptosis (DDX3i; FH1321). Transcriptome analysis revealed that HIV-1 actively suppressed apoptosis-related genes in HIV-1 infected cells. SMACm treatment resulted in a broad induction of these genes irrespective of infection. Notably, DDX3 inhibition specifically restored the expression of the majority of HIV-1 suppressed genes, and when combined with SMACm, restored almost all HIV-1 downregulated genes, thereby rendering HIV-1 infected cells sensitive to apoptosis. Thus, our data strongly suggest that inhibition of host factors IAP and DDX3 not only induces activation of HIV-1 transcription but also restores HIV-1 suppressed apoptotic processes in infected cells.<\/jats:p>","DOI":"10.3390\/pathogens15060575","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:31:56Z","timestamp":1779885116000},"page":"575","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Blocking Host Factors IAP and DDX3 Activates HIV-1 Transcription and Increases Apoptosis Sensitivity of HIV-1 Infected Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4143-732X","authenticated-orcid":false,"given":"Jade","family":"Jansen","sequence":"first","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Man","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenna","family":"Kootstra","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ad C.","family":"van Nuenen","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karel A.","family":"van Dort","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Zamperini","sequence":"additional","affiliation":[{"name":"First Health Pharmaceuticals B.V., 1098 XH Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conraed Willem","family":"Houck","sequence":"additional","affiliation":[{"name":"First Health Pharmaceuticals B.V., 1098 XH Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9429-7754","authenticated-orcid":false,"given":"Neeltje A.","family":"Kootstra","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5710-2839","authenticated-orcid":false,"given":"Teunis B. H.","family":"Geijtenbeek","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15109","DOI":"10.1073\/pnas.96.26.15109","article-title":"HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression","volume":"96","author":"Davey","year":"1999","journal-title":"Proc. Natl. Acad. Sci. 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