{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:54:46Z","timestamp":1790762086219,"version":"4.1.0"},"posted":{"date-parts":[[2023,11,18]]},"group-title":"Microbiology","reference-count":119,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,12,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Antiretroviral therapy (ART) suppresses HIV-1 viremia and prevents progression to AIDS. Nonetheless, chronic inflammation is a common problem for people living with HIV-1 on ART. One possible cause of inflammation is ongoing transcription from HIV-1 proviruses, whether or not the sequences are competent for replication. Previous work has shown that intron-containing RNA expressed from the HIV-1 provirus in primary human blood cells, including CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells, macrophages, and dendritic cells, activates type 1 interferon. This activation required HIV-1\n                  <jats:italic>rev<\/jats:italic>\n                  and was blocked by the XPO1 (CRM1)-inhibitor leptomycin. 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 shRNA-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 IFN-stimulated gene ISG15. The importance of IFIH1 protein was demonstrated by rescue of the knockdown with non-targetable IFIH1 coding sequence. Inhibition of HIV-1-induced ISG15 by the IFIH1-specific Nipah virus V protein, and by IFIH1-transdominant inhibitory CARD-deletion or phosphomimetic point mutations, indicates that IFIH1 filament formation, dephosphorylation, and association with MAVS, are all required for innate immune activation in response to HIV-1 transduction. Since both IFIH1 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. Finally, specific enrichment of unspliced HIV-1 RNA by IFIH1 was revealed by formaldehyde crosslinking immunoprecipitation (f-CLIP). These results demonstrate that IFIH1 is required for innate immune activation by intron-containing RNA from the HIV-1 provirus, and potentially contributes to chronic inflammation in people living with HIV-1.\n                <\/jats:p>","DOI":"10.1101\/2023.11.17.567619","type":"posted-content","created":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T18:40:11Z","timestamp":1700332811000},"source":"Crossref","is-referenced-by-count":2,"title":["IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus"],"prefix":"10.64898","author":[{"given":"Mehmet Hakan","family":"Guney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-3631","authenticated-orcid":false,"given":"Karthika","family":"Nagalekshmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean Matthew","family":"McCauley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2420-8629","authenticated-orcid":false,"given":"Claudia","family":"Carbone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozkan","family":"Aydemir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5650-4054","authenticated-orcid":false,"given":"Jeremy","family":"Luban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023121511101582000_2023.11.17.567619v2.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5341.1291"},{"key":"2023121511101582000_2023.11.17.567619v2.2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI171554"},{"key":"2023121511101582000_2023.11.17.567619v2.3","doi-asserted-by":"publisher","DOI":"10.1086\/374786"},{"key":"2023121511101582000_2023.11.17.567619v2.4","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1093\/cid\/ciz442","article-title":"Antiretroviral 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