{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:09:33Z","timestamp":1790806173890,"version":"4.1.0"},"reference-count":48,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HealthHolland\/Aidsfonds","award":["LSHM19101"],"award-info":[{"award-number":["LSHM19101"]}]},{"name":"HealthHolland\/AMC","award":["2019-1167"],"award-info":[{"award-number":["2019-1167"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2024,1,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Latency reversal and subsequent elimination of the human immunodeficiency virus-1 (HIV-1) reservoir using a combination of compounds with different mechanisms of action are considered a promising tool for HIV-1 cure. Here, we analyzed HIV-1 reservoir reduction by targeting the two host factors; inhibitor of apoptosis proteins (IAPs) and DEAD-box polypeptide 3 (DDX3) using a SMAC mimetic (SMACm) and DDX3 inhibitor (DDX3i), respectively. We observed that SMACm efficiently reactivated HIV-1 in a latency Jurkat model, which was further enhanced by DDX3 inhibition. Strikingly, this compound combination strongly decreased the proportion of latently as well as transcriptionally active infected cells in a T cell line model with a dual-reporter virus. To determine the efficacy of compounds to eradicate the HIV-1 reservoir in people living with HIV (PWH), a novel\n            <jats:italic>ex vivo<\/jats:italic>\n            HIV-1 reservoir reduction assay (HIVRRA) was developed. DDX3i and SMACm alone reduced the HIV-1 reservoir in peripheral blood mononuclear cells (PBMCs) from the majority of PWH, whereas notably, the SMACm\/DDX3i combination reduced the HIV-1 reservoir even further with 53%\u201390% in all PWH analyzed, while uninfected bystander cells were not affected. Our data highlight that IAPs as well as factors involved in HIV-1 replication like DDX3 are excellent targets for HIV-1 cure strategies. We show for the first time that the combination of SMACm and DDX3i reverses viral latency and specifically eliminates the HIV-1-infected cells\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>ex vivo<\/jats:italic>\n            .\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              HIV-1 continues to be a major global health challenge. Current HIV-1 treatments are effective but need lifelong adherence. An HIV-1 cure should eliminate the latent viral reservoir that persists in people living with HIV-1. Different methods have been investigated that focus on reactivation and subsequent elimination of the HIV-1 reservoir, and it is becoming clear that a combination of compounds with different mechanisms of actions might be more effective. Here, we target two host factors, inhibitor of apoptosis proteins that control apoptosis and the DEAD-box helicase DDX3, facilitating HIV mRNA transport\/translation. We show that targeting of these host factors with SMAC mimetics and DDX3 inhibitors induce reversal of viral latency and eliminate HIV-1-infected cells\n              <jats:italic>in vitro<\/jats:italic>\n              and\n              <jats:italic>ex vivo<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.03180-23","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T14:00:21Z","timestamp":1701784821000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Noncanonical-NF-\u03baB activation and DDX3 inhibition reduces the HIV-1 reservoir by elimination of latently infected cells\n            <i>ex-vivo<\/i>"],"prefix":"10.1128","volume":"12","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 , Amsterdam, the Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity , Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Kroeze","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam , Amsterdam, the Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity , 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 , Amsterdam, the Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity , Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Andreini","sequence":"additional","affiliation":[{"name":"First Health Pharmaceuticals B.V , Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-Willem","family":"Bakker","sequence":"additional","affiliation":[{"name":"First Health Pharmaceuticals B.V , Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Zamperini","sequence":"additional","affiliation":[{"name":"First Health Pharmaceuticals B.V , Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Tarditi","sequence":"additional","affiliation":[{"name":"First Health Pharmaceuticals B.V , Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9429-7754","authenticated-orcid":true,"given":"Neeltje A.","family":"Kootstra","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam , Amsterdam, the Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity , Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5710-2839","authenticated-orcid":true,"given":"Teunis B. 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