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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,7,16]]},"abstract":"<jats:p>\n                    Intron-containing RNA expressed from the HIV-1 provirus activates type 1 interferon in primary human blood cells, including CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, macrophages, and dendritic cells. To identify the innate immune receptor required for detection of intron-containing RNA expressed from the HIV-1 provirus, a loss-of-function screen was performed with short hairpin RNA-expressing lentivectors targeting twenty-one candidate genes in human monocyte-derived dendritic cells. Among the candidate genes tested, only knockdown of XPO1 (CRM1), IFIH1 (MDA5), or MAVS prevented activation of the interferon-stimulated gene ISG15. The importance of IFIH1 protein was demonstrated by rescue of the knockdown with nontargetable IFIH1 coding sequence. Inhibition of HIV-1-induced ISG15 by the IFIH1-specific Nipah virus V protein, and by IFIH1-transdominant 2-CARD domain-deletion or phosphomimetic point mutations, indicates that IFIH1 (MDA5) filament formation, dephosphorylation, and association with MAVS are all required for innate immune activation in response to HIV-1 transduction. Since both IFIH1 (MDA5) and DDX58 (RIG-I) signal via MAVS, the specificity of HIV-1 RNA detection by IFIH1 was demonstrated by the fact that DDX58 knockdown had no effect on activation. RNA-Seq showed that IFIH1 knockdown in dendritic cells globally disrupted the induction of IFN-stimulated genes by HIV-1. Finally, specific enrichment of unspliced HIV-1 RNA by IFIH1 (MDA5), over two orders of magnitude, was revealed by formaldehyde cross-linking immunoprecipitation (f-CLIP). These results demonstrate that IFIH1 is the innate immune receptor for intron-containing RNA from the HIV-1 provirus and that IFIH1 potentially contributes to chronic inflammation in people living with HIV-1, even in the presence of effective antiretroviral therapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2404349121","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T13:34:02Z","timestamp":1720618442000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":31,"title":["IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9080-7128","authenticated-orcid":false,"given":"Mehmet Hakan","family":"Guney","sequence":"first","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthika","family":"Nagalekshmi","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7616-7902","authenticated-orcid":false,"given":"Sean Matthew","family":"McCauley","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Carbone","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3458-6527","authenticated-orcid":false,"given":"Ozkan","family":"Aydemir","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5650-4054","authenticated-orcid":false,"given":"Jeremy","family":"Luban","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605"},{"name":"Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605"},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142"},{"name":"Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA 02139"},{"name":"Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,7,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5341.1291"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI171554"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/374786"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz442"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.60.041807.123549"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.10.001"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000545"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","unstructured":"E. 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