{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T20:08:57Z","timestamp":1771618137787,"version":"3.50.1"},"reference-count":60,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:00:00Z","timestamp":1741824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health~Holland","award":["LSHM19101\/P-44802"],"award-info":[{"award-number":["LSHM19101\/P-44802"]}]},{"name":"Health~Holland","award":["2019-1167"],"award-info":[{"award-number":["2019-1167"]}]},{"name":"Health~Holland","award":["446002508"],"award-info":[{"award-number":["446002508"]}]},{"DOI":"10.13039\/100016036","name":"Top Sector Life Sciences and Health","doi-asserted-by":"publisher","award":["LSHM19101\/P-44802"],"award-info":[{"award-number":["LSHM19101\/P-44802"]}],"id":[{"id":"10.13039\/100016036","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016036","name":"Top Sector Life Sciences and Health","doi-asserted-by":"publisher","award":["2019-1167"],"award-info":[{"award-number":["2019-1167"]}],"id":[{"id":"10.13039\/100016036","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016036","name":"Top Sector Life Sciences and Health","doi-asserted-by":"publisher","award":["446002508"],"award-info":[{"award-number":["446002508"]}],"id":[{"id":"10.13039\/100016036","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Amsterdam UMC","award":["LSHM19101\/P-44802"],"award-info":[{"award-number":["LSHM19101\/P-44802"]}]},{"name":"Amsterdam UMC","award":["2019-1167"],"award-info":[{"award-number":["2019-1167"]}]},{"name":"Amsterdam UMC","award":["446002508"],"award-info":[{"award-number":["446002508"]}]},{"name":"ZonMW\/Aidsfonds","award":["LSHM19101\/P-44802"],"award-info":[{"award-number":["LSHM19101\/P-44802"]}]},{"name":"ZonMW\/Aidsfonds","award":["2019-1167"],"award-info":[{"award-number":["2019-1167"]}]},{"name":"ZonMW\/Aidsfonds","award":["446002508"],"award-info":[{"award-number":["446002508"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>HIV-1 infection is successfully treated by antiretroviral therapy; however, it is not curative as HIV-1 remains present in the viral reservoir. A strategy to eliminate the viral reservoir relies on the reactivation of the latent provirus to subsequently trigger immune-mediated clearance. Here, we investigated whether the activation of Toll-like receptor 8 (TLR8) or RIG-I-like receptor (RLR) together with the latency reversal agent (LRA) second mitochondrial-derived activator of caspases mimetics (SMACm) leads to HIV-1 reservoir reduction and antiviral immune activation. The TLR8 and RLR agonist elicited a robust pro-inflammatory cytokine response in PBMCs from both PWH and uninfected people. Notably, co-stimulation with SMACm specifically enhanced TLR8 induced pro-inflammatory cytokine as well as CD8 T cell responses. Ex vivo treatment of PBMCs from PWH with SMACm significantly decreased the size of the inducible HIV-1 reservoir, whereas targeting TLR8 or RLR reduced the HIV-1 reservoir in 50% of PWH ex vivo. Although co-stimulation with TLR8\/RLR agonists further reduced the HIV-1 reservoir in 25% of PWH ex vivo, effectively inducing antiviral immunity may help eliminate reactivated HIV-1 cells in vivo. Our findings strongly suggest that LRAs can be used in combination with agonists for pattern recognition receptors to reactivate HIV-1 and induce antiviral immunity.<\/jats:p>","DOI":"10.3390\/ijms26062575","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T06:53:00Z","timestamp":1741848780000},"page":"2575","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Synergistic Activity of Second Mitochondrial-Derived Activator of Caspases Mimetic with Toll-like Receptor 8 Agonist Reverses HIV-1-Latency and Enhances Antiviral Immunity"],"prefix":"10.3390","volume":"26","author":[{"given":"Killian E.","family":"Vlaming","sequence":"first","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4143-732X","authenticated-orcid":false,"given":"Jade","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Godelieve J.","family":"de Bree","sequence":"additional","affiliation":[{"name":"Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Internal Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teunis B. H.","family":"Geijtenbeek","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13193","DOI":"10.1073\/pnas.94.24.13193","article-title":"Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy","volume":"94","author":"Chun","year":"1997","journal-title":"Proc. Natl. Acad. Sci. 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